AU2004210578A1 - Method of using a cyclooxygenase-2 inhibitor and a matrix metalloproteinase inhibitor as a combination therapy in the treatment of neoplasia - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: G.D. SEARLE CO.

Invention Title: METHOD OF USING A CYCLOOXYGENASE-2 INHIBITOR AND A MATRIX METALLOPROTEINASE INHIBITOR AS A COMBINATION THERAPY IN THE TREATMENT OF NEOPLASIA The following statement is a full description of this invention, including the best method of performing it known to me/us: METHOD OF USING A CYCLOOXYGENASE-2 INHIBITOR AND AN MATRIX METALLOPROTEINASE INHIBITOR AS A COMBINATION THERAPY IN THE TREATMENT OF NEOPLASIA Field of the Invention The present invention relates to combinations and methods for treatment or prevention of neoplasia disorders in a mammal using two or more components with at least one component being an antiangiogenesis agent.

Background of the Invention A neoplasm, or tumor, is an abnormal, unregulated, and disorganized proliferation of cell growth. A neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness and metastasis. Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system. Metastasis typically refers to the dissemination of tumor cells by lymphotics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces.

Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance.

Cancer is now the second leading cause of death in the United States and over 8,000,000 persons in the United States have been diagnosed with cancer. In 1995, cancer accounted for 23.3% of all deaths in the United States.

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(See U.S. Dept. of Health and Human Services, National Center for Health Statistics, Health United States 1996- 97 and Injury Chartbook 117 (1997)).

Cancer is not fully understood on the molecular level. It is known that exposure of a cell to a carcinogen such as certain viruses, certain chemicals, or radiation, leads to DNA alteration that inactivates a "suppressive" gene or activates an "oncogene".

Suppressive genes are growth regulatory genes, which upon mutation, can no longer control cell growth.

Oncogenes are initially normal genes (called prooncogenes) that by mutation or altered context of expression become transforming genes. The products of transforming genes cause inappropriate cell growth. More than twenty different normal cellular genes can become oncogenes by genetic alteration. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and mortality (transformed cells can grow indefinitely).

Cancer is now primarily treated with one or a combination of three types of therapies: surgery, radiation, and chemotherapy. Surgery involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be'used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia.

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Chemotherapy involves the disruption of cell replication or cell metabolism. It is used most often in the treatment of breast, lung, and testicular cancer.

The adverse effects of systemic chemotherapy used in the treatment of neoplastic disease is most feared by patients undergoing treatment for cancer. Of these adverse effects nausea and vomiting are the most common and severe side effects. Other adverse side effects include cytopenia, infection, cachexia, mucositis in patients receiving high doses of chemotherapy with bone marrow rescue or radiation therapy; alopecia (hair loss cutaneous complications (see M.D. Abeloff, et al: Alopecia and Cutaneous Complications. P. 755-56.- In Abeloff, Armitage, Lichter, and Niederhuber, J.E. (eds) Clinical Oncology. Churchill Livingston, New York, 1992, for cutaneous reactions to chemotherapy agents), such as pruritis, urticaria, and angioedema; neurological complications; pulmonary and cardiac complications in patients receiving radiation or chemotherapy; and reproductive and endocrine complications.

Chemotherapy-induced side effects significantly impact the quality of life of the patient and may dramatically influence patient compliance with treatment.

Additionally, adverse side effects associated with chemotherapeutic agents are generally the major doselimiting toxicity (DLT) in the administration of these drugs. For example, mucositis, is one of the major dose limiting toxicity for several anticancer agents, including the antimetabolite cytotoxic agents methotrexate, and antitumor antibiotics, such as doxorubicin. Many of these chemotherapy-induced side effects if severe, may lead to hospitalization, or require treatment with analgesics for the treatment of pain.

The adverse side effects induced by chemotherapeutic agents and radiation therapy have become of major importance to the clinical management of cancer patients.

FR 2,771,005 describes compositions containing a cyclooxygenase- 2 inhibitor and a N-methyl-d-aspartate (NMDA) antagonist used to treat cancer and other diseases. WO 99/18,960 describes a combination comprising a cyclooxygenase-2 inhibitor and an induced nitric-oxide synthase inhibitor (iNOS) that can be used to treat colorectal and breast cancer. WO 99/13,799 describes the combination of a cyclooxygenase-2 inhibitor and an opioid analgesic. WO 98/41,511 describes 5- (4-sulphunyl-phenyl) -pyridazinone derivatives used for treating cancer. WO 98/41,516 describes derivatives that can be used in the treatment of cancer.

WO 98/16,227 describes the use of cyclooxygenase- 2 inhibitors in the treatment or prevention of neoplasia.

WO 97/36,497 describes a combination comprising a cyclooxygenase- 2 inhibitor and a inhibitor useful in treating cancer. WO 97/29,776 describes a composition comprising a cyclooxygenase-2 inhibitor in combination with a leukotriene B4 receptor antagonist and an immunosuppressive drug. WO 97/29,775 describes the use of a cyclooxygenase-2 inhibitor in combination-with a leukotriene A4 hydrolase inhibitor and an immunosuppressive drug. WO 97/29,774 describes the combination of a cyclooxygenase- 2 inhibitor and protstaglandin or antiulcer agent useful in treating cancer. WO 97/11,701 describes a combination comprising a cyclooxygenase-2 inhibitor and a leukotriene B4 receptor antagonist useful in treating colorectal cancer. WO 96/41,645 describes a'combination comprising a cyclooxygenase-2 inhibitor and a leukotriene

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hydrolase inhibitor. WO 96/03,385 describes 3,4,-Di substituted pyrazole compounds given alone or in combination with NSAIDs, steroids, 5-LO inhibitors, LTB4 antagonists, or LTA4 hydrolase inhibitors that may be useful in the treatment of cancer. WO 98/47,890 describes substituted benzopyran derivatives that may be used alone or in combination with other active principles. WO 98/16,227 describes a method of using cyclooxygenase- 2 inhibitors in the treatment and prevention of neoplasia.

U.S. Patent No. 5,854,205 describes an isolated endostatin protein that is an inhibitor of endothelial cell proliferation and angiogenesis. U.S. Patent No.

5,843,925 describes a method for inhibiting angiogenesis and endothelial cell proliferation using a 7-[substituted amino]-9-[(substituted glycyl0amido]-6demethyl-6-deoxytetracycline. U.S. Patent No. 5,863,538 describes methods and compositions for targeting tumor vasculature of solid tumors using immunological and growth factor-based reagents in combination with chemotherapy and radiation. U.S. Patent No. 5,837,682 describes the use of fragments of an endothelial cell

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-6proliferation inhibitor, angiostatin. U.S. Patent No.

5,861,372 describes the use of an aggregate endothelial inhibitor, angiostatin, and it use in inhibiting angiogenesis. U.S. Patent No. 5,885,795 describes methods and compositions for treating diseases mediated by undesired and uncontrolled angiogenesis by administering purified angiostatin or angiostatin derivatives.

PCT/GB97/00650 describes the use of cinnoline derivatives for use in the production of an antiangiogenic and/or vascular permeability reducing effect. PCT/US97/09610 describes administration of an anti-endogin monoclonal antibody, or fragments thereof, which is conjugated to at least one angiogenesis inhibitor or antitumor agent for use in treating tumor and angiogenesis-associated diseases. PCT/IL96/00012 describes a fragment of the Thrombin B-chain for the treatment of cancer. PCT/US95/16855 describes compositions and methods of killing selected tumor cells using recombinant viral vectors.

Ravaud, A. et al. describes the efficacy and tolerance of interleukin-2 interferon alpha-2a, and fluorouracil in patients with metastatic renal cell carcinoma. .J.Clin.Oncol. '16, No. 8, 2728-32, 1998.

Stadler, W.M. et al. describes the response rate and toxicity of oral 13-cis-retinoic acid added to an outpatient regimen of subcutaneous interleukin-2 and interferon alpha in patients with metastatic renal cell carcinoma. J.Clin.Oncol. 16, No. 5, 1820-25, 1998 Rosenbeg, S.A. et al. describes treatment of patients with metastatic melanoma using chemotherapy with

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-7cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alpha-2b.

J.Clin.Oncol. 17, No. 3, 968-75, 1999. Tourani, J-M.

et al describes treatment of renal cell carcinoma using interleukin-2, and interferon alpha-2a administered in combination with fluorouracil. J.Clin.Oncol. 16, No. 7, 2505-13, 1998. Majewski, S. describes the anticancer action of retinoids, vitamin D3 and cytokines (interferons and interleukin-12) as related to the antiangiogenic and antiproliferative effects.

J.Invest.Dermatol. 108, No. 4, 571, 1997. Ryan, C.W.

describes treatment of patients with metastatic renal cell cancer w*ith GM-CSF, Interleukin-2, and interferonalpha plus oral cis-retinoic acid in patients with metastatic renal cell cancer. J.Invest.Med. 46, No. 7, 274A, 1998. Tai-Ping, D. describes potential antiangiogenic therapies. Trends Pharmacol.Sci. 16, No. 2, 57-66, 1995. Brembeck, F.H. describes the use of 13cis retinoic acid and interferon alpha to treat UICC stage III/IV pancreatic cancer. Gastroenterology 114, No. 4, Pt. 2, A569, 1998. Brembeck, F.H. describes the use of 13-cis retinoic acid and interferon alpha in patients with advanced pancreatic carcinoma. Cancer 83, No. 11, 2317-23, 1998. Mackean, M.J. describes the use of roquinimex (Linomide) and alpha interferon in patients with advanced malignant melanoma or renal carcinoma. Br.J.Cancer 78, No. 12, 1620-23, 1998 Jayson, G.C. describes the use of interleukin 2 and interleukin -interferon alpha in advanced renal cancer.

Br.J.Cancer 78, No. 3, 366-69, 1998. Abraham, J.M.

describes the use of Interleukin-2, interferon alpha and in patients with metastatic renal carcinoma. Br.J.Cancer 78, Suppl. 2, 8, 1998. Soori, G.S. describes the use of chemo-biotherapy with chlorambucil and alpha interferon in patients with nonhodgkins lymphoma. Blood 92, No. 10, Pt. 2 Suppl. 1, 240b, 1998. Enschede, S.H. describes the use of interferon alpha added to an anthracycline-based regimen in treating low grade and intermediate grade nonhodgkin's lymphoma. Blood 92, No. 10, Pt. 1 Suppl. 1, 412a, 1998. Schachter, J. describes the use of a sequential multi-drug chemotherapy and biotherapy.with interferon alpha, a four drug chemotherapy regimen and GM-CSF. Cancer Biother.Radiopharm. 13, No. 3, 155-64, 1998. Mross, K. describes the use of retinoic acid, interferon alpha and tamoxifen in metastatic breast cancer patients. J.Cancer Res. Clin. Oncology. 124 Suppl. 1 R123, 1998. Muller, H. describes the use of suramin and tamoxifen in the treatment of advanced and metastatic pancreatic carcinoma. Eur.J.Cancer 33, Suppl. 8, S50, 1997. Rodriguez, M.R. describes the use of taxol and cisplatin, and taxotere and vinorelbine in the treatment of metastatic breast cancer. Eur.J.Cancer 34, Suppl. 4, S17-S18, 1998. Formenti, C. describes concurrent paclitaxel and radiation therapy in locally advanced breast cancer patients. Eur.J.Cancer 34, Suppl. 5, S39, 1998. Durando, A. describes combination chemotherapy with paclitaxel and epirubicin for metastatic breast cancer. Eur.J.Cancer 34, Suppl. S41, 1998. Osaki, A. describes the use of a combination therapy with mitomycin-C, etoposide, doxifluridine and medroxyprogesterone acetate as second-line therapy for advanced breast cancer. Eur.J.Cancer 34, Suppl. 5, S59, 1998.

The use of TNP-470 and minocycline in combination with cyclophasphamide, CDDP, or thiotepa have been observed to substantially increase the tumor growth delay in one pre-clinical solid tumor model. (Teicher, B. A. et al., Breast Cancer Research and Treatment, 36: 227-236, 1995). Additionally, improved results were observed when the antiangiogenesis agents were used in combination with cyclophosphamide and fractionated radiation therapy. (Teicher, B. A. et al., European Journal of Cancer 32A(14): 2461-2466, 1996).

Neri et al. examined the use of AG-3340 in combination with carboplatin and taxol for the treatment of cancer. (Neri et al., Proc Am Assoc Can Res, Vol 39, 89 meeting, 302 1998). U.S. Patent No. 5,837,696 describes the use of tetracycline compounds to inhibit cancer growth. WO 97/48,685 describes various substituted compounds that inhibit metalloproteases.

EP 48/9,577 describes peptidyl derivatives used to prevent tumor cell metastasis and invasion.

WO 98/25,949 describes the use of N5-substituted amino-l,3,4-thiadiazole-2-thiols to inhibit metallopreteinase enzymes. WO 99/21,583 describes a method of inhibiting metastases in patients having cancer in which wildtype p53 is predominantly expressed using a combination of radiation therapy and a selective matrix metalloproteinase- 2 inhibitor. WO 98/33,768 describes arylsulfonylamino hydroxanic acid derivatives in the treatment of cancer.

WO 98/30,566 describes cyclic sulfone derivatives useful in the treatment of cancer.

WO 98/34,981 describes arylsulfonyl hydroxamic acid derivatives useful in the treatment of cancer.

WO 98/33,788 discloses the use of carboxylic or hyroxamic acid derivatives for treatment of tumors.

WO 97/41,844 describes a method of using combinations of angiostatic compounds for the prevention and/or treatment of neovascularization in human patients.

EP 48/9,579 describes peptidyl derivatives with selective gelatinase action that may be of use in the treatment of cancer and to control tumor metastases.

WO 98/11,908 describes the use of carboxylic or hyroxamic acid derivatives and a cyclosporin in combination therapy for treating mammals suffering from arthritic disease.

WO 98/03,516 describes phasphinate based compounds useful in the treatment of cancer.

WO 95/23,811 describes novel carbocyclic compounds which inhibit platelet aggregation.

WO 93/24,475 describes sulphamide derivatives may be useful in the treatment of cancer to control the development of metastases.

WO 98/16,227 describes a method of using [Pyrozol- 1-yl]benzenesulfonamides in the treatment of and prevention of neoplasia.

WO 98/22,101 describes a method of using [Pyrozol- 1-yl]benzenesulfonamides as anti-angiogenic agents.

-*ii- Description of the Invention A method for treating or preventing a neoplasia disorder in a mammal, including a human, in need of such treatment or prevention is provided. The method comprises treating the mammal with a therapeutically effective amount of a combination comprising two or more components, the first component is a cyclooxygenase- 2 inhibitor, the second component is a MMP inhibitor, and the additional component or components is optionally selected from an antiangiogenesis agent; an antineoplastic agent; an adjunctive agent; (d) an imunotherapeutic agent; a device; a vaccine; an analgesic agent; and a radiotherapeutic agent; provided that the additional component(s) is other than the cycloxygenase- 2 inhibitor selected as the first component and the matrix metalloproteinase inhibitor selected as the second component.

In one embodiment the combination comprises a cyclooxygenase- 2 inhibitor, a matrix metalloproteinase inhibitor and an antineoplastic agent.

Besides being useful for human treatment, the present invention is also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

The methods and combinations of the present invention may be used for the treatment or prevention of -12neoplasia disorders including acral lentiginous, melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquam~ous carcinoma, astrocytic tumors, bartholin gland carcinoma, 3basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarciloma, chondosarcoma, choriod plexus papilloma/carcinoma., clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, erdometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinona, germ cell tumors, glioblastoma, glucagonoma, hemangibla stomas, heinangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neopilasia, invasive squamous cell carcinoma, large cell carcinoma, lejomyosarcoma, lentigo maligna melanomas, malignant melanoma,-malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal,*mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastona, neuroepithelial adenocarcifloma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatjn-secreting tumor, squamous carcinoma, squamous cell carcinoma,

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-13submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor.

The methods and combinations of the present invention provide one or more benefits. Combinations of COX-2 inhibitors and MMP inhibitors with the compounds, compositions, agents and therapies of the present invention are useful in treating and preventing neoplasia disorders. Preferably, the COX-2inhibitors and MMP inhibitors or agents and the compounds, compositions, agents and therapies of the present invention are administered in combination at a low dose, that is, at a dose lower than has been conventionally used in clinical situations.

A benefit of lowering the dose of the compounds, compositions, agents and therapies of the present invention administered to a mammal includes a decrease -in the incidence of adverse effects associated with higher dosages. For example, by the lowering the dosage of a chemotherapeutic agent such as methotrexate, a reduction in the frequency and the severity of nausea and vomiting will result when compared to that observed at higher dosages. Similar benefits are contemplated for the compounds, compositions, agents and therapies in combination with the COX-2inhibitors and MMP inhibitors of the present invention.

By lowering the incidence of adverse effects, an improvement in the quality of life of a patient undergoing treatment for cancer is contemplated.

Further benefits of lowering the incidence of adverse

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-14effects include an improvement in patient compliance, a reduction in the number of hospitalizations needed for the treatment of adverse effects, and a reduction in the administration of analgesic agents needed to treat pain associated with the adverse effects.

Alternatively, the methods and combination of the present invention can also maximize the therapeutic effect at higher doses.

When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

When used as a therapeutic the compounds described herein are preferably administered with a physiologically acceptable carrier. A physiologically acceptable carrier is a formulation to which the compound can be added to dissolve it or otherwise facilitate its administration. Examples of physiologically acceptable carriers include, but are not limited to, water, saline, physiologically buffered saline. Additional examples are provided below.

The term "pharmaceutically acceptable" is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product.

Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences.

Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine,

N,N'-

dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine

(N-

methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic.acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.

A compound of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975. Another example of includes Liberman, H.A. and

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-16- Lachman, Eds., Pharmaceutical Dosaqe Forms, Marcel Decker, New York, 1980.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable dilutent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules.

-17- In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.. If administered per os, a contemplated aromatic sulfone hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.

Such capsules or tablets can contain a controlledrelease formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate.

Tablets and pills can additionally be prepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in theformulations for oral administration. A contemplated aromatic sulfone hydroximate inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or -18various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.

Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.

The present invention further includes kits comprising a cyclooxygenase-2 inhibitor, a MMP inhibitor, and optionally an antineoplastic agent.

The term "treatment" refers to any process, action, application, therapy, or the like, wherein a mammal, including a human being, is subject to medical aid with the object of improving the mammal's condition, directly or indirectly.

The term "inhibition," in the context of neoplasia, tumor growth or tumor cell growth, may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention.

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-19- The term "prevention" includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of initiation for malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia.

The term "angiogenesis" refers to the process by which tumor cells trigger abnormal blood vessel growth to create their own blood supply, and is a major target of cancer research. Angiogenesis is believed to be the mechanism via which tumors get needed nutrients to grow and metastasize to other locations in the body.

Antiangiogenic agents interfere with these processes and destroy or control tumors.

Angiogenesis is an attractive therapeutic target because it is a multi-step process that occurs in a specific sequence, thus providing several possible targets for drug action. Examples of agents that interfere with several-of these steps include thrombospondin-l, angiostatin, endostatin, interferon alpha and compounds.such as matrix metalloproteinase (MMP) inhibitors that block the actions of enzymes that clear and create paths for newly forming blood vessels to follow; compounds, such as avP3 inhibitors, that interfere with molecules that blood vessel cells use to bridge between a parent blood vessel and a tumor; agents, such as specific COX-2 inhibitors, that prevent the growth of cells that form new blood vessels; and 1 protein-based compounds that simultaneously interfere with several of these targets.

Antiangiogenic therapy may offer several advantages over conventional chemotherapy for the treatment of' cancer.

Antiangiogenic agents have low toxicity in preclinical trials and development of drug resistance has not been observed (Folkman, Seminars in Medicine of the Beth Israel Hospital, Boston 333(26): 1757-1763, 1995). As angiogenesis is a complex process, made up of many steps including invasion, proliferation and migration of endothelial cells, it can be anticipated that combination therapies will be most effective. Kumar and Armstrong describe anti-angiogenesis therapy used as an adjunct to chemotherapy, radiation therapy, or surgery. (Kumar, CC, and Armstrong, Tumor-induced angiogenesis: a novel target for drug therapy?, Emerging Drugs (1997), 2, 175-190).

The phrase "therapeutically-effective" is intended to qualify the amount of each agent that will achieve the goal of improvement in neoplastic disease severity and the frequency of neoplastic disease over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

A "therapeutic effect" or therapeutic effective amount" is intended to qualify the amount of an anticancer agent required to relieve to some extent one or more of the symptoms of a neoplasia disorder, including, but is not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition slowing to some extent, preferably -21stopping) of cancer cell infiltration into peripheral organs; 3) inhibition slowing to some extent, preferably stopping) of tumor metastasis; 4) inhibition, to some extent, of tumor growth; 5) relieving or reducing to some extent one or more of the symptoms associated with the disorder; and/or 6) relieving or reducing the side effects associated with the administration of anticancer agents.

The phrase "combination therapy" (or "co-therapy") embraces the administration of a cyclooxygenase- 2 inhibitor, a metalloproteinase inhibitor, and optionally an antineoplastic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.

Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). "Combination therapy" generally is not intended to encompass the administration of two or more of these therapeutic agents as part.of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a -22substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes.

For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other two therapeutic agents of the combination may be administered orally. Alternatively, for example, all three therapeutic agents may be administered orally or all three therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and -23radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

The phrases "low dose" or "low dose amount", in characterizing a therapeutically effective amount-of the antiangiogenesis agent and the antineoplastic agent or therapy in the combination therapy, defines a quantity of such agent, or a range of quantity of such agent, that is capable of improving the neoplastic disease severity while reducing or avoiding one or more antineoplastic-agent-induced side effects, such as myelosupression, cardiac toxicity, alopecia, nausea or vomiting.

The phrase "adjunctive therapy" encompasses treatment of a subject with agents that reduce or avoid side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for example, that reduce the toxic effect of anticancer drugs, bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.

The phrase an "immunotherapeutic agent" refers to agents used to transfer the immunity of an immune donor, another person or an animal, to a host by inoculation. The term embraces the use of serum or gamma gobulin containing performed antibodies produced -24by another individual or an animal; nonspecific systemic stimulation; adjuvants; active specific immunotherapy; and adoptive immunotherapy. Adoptive immunotherapy refers to the treatment of a disease by therapy or agents that include host inoculation of sensitized lymphocytes, transfer factor, immune RNA, or antibodies in serum or gamma globulin.

The phrase a "device" refers to any appliance, usually mechanical or electrical, designed to perform a particular function.

The phrase a "vaccine" includes agents that induce the patient's immune system to mount an immune response against the tumor by attacking cells that express tumor associated antigens (TAAs).

The phrase "multi-functional proteins" encompass a variety of pro-angiogenic factors that include basic and acid fibroblast growth factors (bFGF and aFGF) and vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) Bikfalvi, A. et al., Endocrine Reviews 18: 26-45, 1997). Several endogenous antiangiogenic factors have also been characterized as multi-functional proteins and include angiostatin (O'Reilly et al., Cell (Cambridge, Mass) 79(2): 315-328, 1994), endostatin (O'Reilly et al, Cell (Cambridge, Mass) 88(2): 277-285, 1997), interferon .alpha.

(Ezekowitz et al, N. Engl. J. Med., May 28, 326(22) 1456-1463, 1992), thrombospondin (Good et al, Proc Natl Acad Sci USA 87(17): 6624-6628, 1990; Tolsma et al, J Cell Biol 122(2): 497-511, 1993), and platelet factor 4 (PF4) (Maione et al, Science 247:(4938): 77-79, 1990).

The phrase an "analgesic agent" refers to an agent that relieves pain without producing anesthesia or loss of consciousness generally by altering the perception of nociceptive stimuli.

The phrase a "radiotherapeutic agent" refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia.

The term "pBATT" embraces"or "Protein-Based Anti- Tumor Therapies," refers to protein-based therapeutics for solid tumors. The PBATTs are including proteins that have demonstrated efficacy against tumors in animal models or in humans. The protein is then modified to increase its efficacy and toxicity profile by enhancing its bioavailability and targeting.

"Angiostatin" is a 38 kD protein comprising the first three or four kringle domains of plasminogen and was first described in 1994 (O'Reilly, M. S. et al., Cell (Cambridge, Mass.) 79(2): 315-328, 1994). Mice bearing primary (Lewis lung carcinoma-low metastatic) tumors did not respond to angiogenic stimuli such as bFGF in a corneal micropocket assay and the growth of metastatic tumors in these mice was suppressed until the primary tumor was excised. The factor responsible for the inhibition of angiogenesis and tumor growth was designated mouse angiostatin. Angiostatin was also shown to inhibit the growth of endothelial cells in vitro.

Human angiostatin can be prepared by digestion of plasminogen by porcine elastase (O'Reilly, et al., Cell 79(2): 315-328, 1994) or with human metalloelastase (Dong et al., Cell 88, 801-810, 1997). The angiostatin

I

-26produced via porcine elastase digestion inhibited the growth of metastases and primary tumors in mice.

O'Reilly et al (Cell 79(2): 315-328, 1994) demonstrated that human angiostatin inhibited metastasis of Lewis lung carcinoma in SCID mice. The same group (O'Reilly, M. S. et al., Nat. Med. 689-692, 1996) subsequently showed that human angiostatin inhibited the growth of the human tumors PC3 prostate carcinoma, clone A colon carcinoma, and MDA-MB breast carcinoma in SCID mice. Human angiostatin also inhibited the growth of the mouse tumors Lewis lung carcinoma, T241 fibrosarcoma and M5076 reticulum cell carcinoma in C57B1 mice.

Because these enzymatically-prepared angiostatins are not well characterized biochemically, the precise composition of the molecules is not known.

Angiostatins of known composition can be prepared by means of recombinant DNA technology and expression in heterologous cell systems. Recombinant human angiostatin comprising Kringle domains one through four (Kl-4) has been produced in the yeast Pichia pastoris (Sim et al., Cancer Res 57: 1329-1334, 1997). The recombinant human protein inhibited growth of endothelial cells in vitro and inhibited metastasis of Lewis lung carcinoma in C57B1 mice. Recombinant murine angiostatin (Kl-4) has been produced in insect cells (Wu et al., Biochem Biophys Res Comm 236: 651-654, 1997).

The recombinant mouse protein inhibited endothelial .cell growth in vitro and growth of primary Lewis lung carcinoma in vivo. These experiments demonstrated that the first four kringle domains are sufficient for -27angiostatin activity but did not determine which kringle domains are necessary.

Cao et al. Biol. Chem. 271: 29461-29467, 1996), produced fragments of human plasminogen by proteolysis and by expression of recombinant proteins in E. coli.

These authors showed that kringle one and to a lesser extent kringle four of plasminogen were responsible for the inhibition of endothelial cell growth in vitro.

Specifically, kringles 1-4 and 1-3 inhibited at similar concentrations, while Kl alone inhibited endothelial cell growth at four-fold higher concentrations.

Kringles two and three inhibited to a lesser extent.

More recently Cao et al. (J Biol Chem 272:' 22924-22928, 1997), showed that recombinant mouse or human kringle five inhibited endothelial cell growth at lower concentrations than angiostatin These experiments demonstrated in vitro angiostatin-like activity but did not address in vivo action against tumors and their metastases.

World patent applications WO 95/29242 Al, WO 96/41194 Al, and WO 96/35774 A2 describe the expression, purification, and characterization of angiostatin.

WO

95/29242 Al 951102 discloses purification of a protein from blood and urine by HPLC that inhibits proliferation of endothelial cells. The protein has a molecular weight between 38 kilodaltons and 45 kilodaltons and an amino acid sequence substantially similar to that of a murine plasminogen fragment beginning at amino acid number 79 of a murine plasminogen molecule. WO 96/41194 Al 961219, discloses compounds and methods for the diagnosis and monitoring of angiogenesis-dependent

I

-28diseases. WO 96/35774 A2 961114 discloses the structure of protein fragments, generally corresponding to kringle structures occurring within angiostatin. It also discloses aggregate forms of angiostatin, which have endothelial cell inhibiting activity, and provides a means for inhibiting angiogenesis of tumors and for treating angiogenic-mediated diseases.

"Endostatin" is a 20-kDa (184 amino acid) carboxy fragment of collagen XVIII, is an angiogenesis inhibitor produced by a hemangioendothelioma (O'Reilly, M. S. et al., Cell (Cambridge, Mass.) 88(2): 277-285, 1997).; and WO 97/15666). Endostatin specifically inhibits endothelial proliferation and inhibits angiogenesis and tumor growth. Primary tumors treated with non-refolded suspensions of E. coli-derived endostatin regressed to dormant microscopic lesions. Toxicity was not observed and immunohistochemical studies revealed a blockage of angiogenesis accompanied by high proliferation balanced by apoptosis in tumor cells.

"Interferon .alpha." (IFN.alpha.) is a family of highly homologous, species-specific proteins that possess complex antiviral, antineoplastic and immunomodulating activities (Extensively reviewed in the monograph "Antineoplastic agents, interferon alfa", American Society of Hospital Pharmacists, Inc., 1996).

Interferon .alpha. also has anti-proliferative, and antiangiogenic properties, and has specific effects on cellular differentiation (Sreevalsan, in "Biologic Therapy of Cancer", pp. 347-364, (eds. V.T. DeVita Jr., S. Hellman, and S.A. Rosenberg}, J.B. Lippincott Co, Philadelphia, PA, 1995).

-29- Interferon .alpha. is effective against a variety of cancers including hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, and Kaposi's sarcoma. The precise mechanism by which IFN.alpha.

exerts its anti-tumor activity is not entirely clear, and may differ based on the tumor type or stage of disease. The anti-proliferative properties of IFN.alpha., which may result from the modulation of the expression of oncogenes and/or proto-oncogenes, have been demonstrated on both tumor cell lines and human tumors growing in nude mice (Gutterman, J. Proc.

Natl. Acad. Sci., USA 91: 1198-1205, 1994).

Interferon is also considered an anti-angiogenic factor, as demonstrated through the successful treatment of hemangiomas in infants (Ezekowitz et al, N. Engl. J.

Med., May 28, 326(22) 1456-1463, 1992) and the effectiveness of IFN.alpha. against Kaposi's sarcoma (Krown, Semin Oncol 14(2 Suppl 27-33, 1987). The mechanism underlying these anti-angiogenic effects is not clear, and may be the result of IFN.alpha. action on the tumor (decreasing the secretion of pro-angiogenic factors) or on the neo-vasculature. IFN receptors have been identified on a variety of cell types (Navarro et al., Modern Pathology 150-156, 1996).

United States Patent 4,530,901, by Weissmann, describes the cloning and expression of IFN-.alpha.-type molecules in transformed host strains. United States Patent 4,503,035, Pestka, describes an improved processes for purifying 10 species of human leukocyte interferon using preparative high performance liquid chromatography. United States Patent 5,231,176, Goeddel, describes the cloning of a novel distinct family of human leukocyte interferons containing in their mature form greater than 166 and no more than 172 amino acids.

United States Patent 5,541,293, by Stabinsky, describes the synthesis, cloning, and expression of consensus human interferons. These are non-naturally occurring analogues of human (leukocyte) interferon- .alpha. assembled from synthetic oligonucleotides. The sequence of the consensus interferon was determined by comparing the sequences of 13 members of the IFN-. alpha.

family of interferons and selecting the preferred amino acid at each position. These variants differ from naturally occurring forms in terms of the identity and/or location of one or more amino acids, and one or more biological and pharmacological properties antibody reactivity, potency, or duration effect) but retain other such properties.

"Thrombospondin-l" (TSP-1) is a trimer containing three copies of a 180 kDa polypeptide. TSP-1 is produced by many cell types including platelets, fibroblasts, and endothelial cells (see Frazier, Curr Opin Cell Biol 792-799, 1991) and the cDNA encoding the subunit has been cloned (Hennessy, et al., 1989, J Cell Biol 108(2): 729-736; Lawler and Hynes, J Cell Biol 103(5): 1635-1648, 1986). Native TSP-I has been shown to block endothelial cell migration in vitro and neovascularization in vivo (Good et al, Proc Natl Acad Sci USA 87(17): 6624-6628, 1990). Expression of TSP-1 in tumor cells also suppresses tumorigenesis and tumor-induced angiogenesis (Sheibani and Frazier, Proc

I

-31- Natl Acad Sci USA 92(15) 6788-6792, 1995; Weinstat- Saslow et al., Cancer Res 54(24):6504-6511, 1994). The antiangiogenic activity of TSP-1 has been shown to reside in two distinct domains of this protein (Tolsma et al, J Cell Biol 122(2): 497-511, 1993). One of these domains consists of residues 303 to 309 of native TSP-1 and the other consists of residues 481 to 499 of TSP-1.

Another important domain consists of the sequence CSVTCG which appears to mediate the binding of TSP-1 to some tumor cell types (Tuszynski and Nicosia, Bioessays 18(1): 71-76, 1996). These results suggest that CSVTCG, or related sequences, can be used to target other moieties to tumor cells.' Taken together, the available data indicate that TSP-1 plays a role in the growth and vascularization of tumors. Subfragments of TSP-1, then, may be useful as antiangiogenic components of chimeras and/or in targeting other proteins to specific tumor cells. Subfragments may be generated by standard procedures (such as proteolytic fragmentation, or by DNA amplification, cloning, expression, and purification of specific TSP-1 domains or subdomains) and tested for antiangiogenic or anti-tumor activities by methods known in the art (Tolsma et al, J Cell Biol 122(2): 497-511, 199-3; Tuszynski and Nicosia, Bioessays 18(1): 71-76, 1996).

The phrase "integrin antagonist" includes agents that impair endothelial cell adhesion via the various integrins. Integrin antagonists induce improperly proliferating endothelial cells to die, by interfering with molecules that blood vessel cells use to bridge between a parent blood vessel and a tumor.

-32- Adhesion forces are critical for many normal physiological functions. Disruptions in these forces, through alterations in cell adhesion factors, are implicated in a variety of disorders, including cancer, stroke, osteoporosis, restenosis, and rheumatoid arthritis F. Horwitz, Scientific American, 276:(5): 68-75, 1997).

Integrins are a large family of cell surface glycoproteins which mediate cell adhesion and play central roles in many adhesion phenomena. Integrins are heterodimers composed of noncovalently linked a and b polypeptide subunits. Currently eleven different a subunits have been identified and six different 0 subunits have been identified. The various a subunits can combine with various b subunits to form distinct integrins.

One integrin known as avb, (or the vitronectin receptor) is normally associated with endothelial cells and smooth muscle cells. A b, integrins can promote the formation of blood vessels (angiogenesis) in tumors.

These vessels nourish the tumors and provide access routes into the bloodstream for metastatic cells.

The a b, integrin is also known to play a role in various other disease states or conditions including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, and smooth muscle cell migration restenosis).

-33- Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.

The a b, integrin and a variety of other avcontaining integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands and bind to cell surface receptors. Fibronectin and vitronectin are among the major binding partners of a)b, integrin. Other proteins and peptides also bind the ab, ligand. These include the disintegrins Pfaff et al., Cell Adhes. Commun. 491-501, 1994), peptides derived from phage display libraries (Healy, J.M. et al., Protein Pept. Lett. 23-30, 1996; Hart, S.L.

et al., J. Biol. Chem. 269(17): 12468-12474, 1994) and small cyclic RGD peptides Pfaff et al., J. Biol.

Chem., 269(32): 20233-20238, 1994). The monoclonal antibody LM609 is also an a)b, integrin antagonist (D.A.

Cheresh et al., J. Biol. Chem., 262(36): 17703-17711, 1987).

Ab, inhibitors are being developed as potential anti-cancer agents. Compounds that impair endothelial cell adhesion via the ab, integrin induce improperly proliferating endothelial cells to die.

The ab 3 integrin has been shown to play a role in melanoma cell invasion (Seftor et al., Proc. Natl. Acad.

Sci. USA, 89: 1557-1561, 1992). The ab, 3 integrin expressed on human melanoma cells has also been shown to

I

-34promote a survival signal, protecting the cells from apoptosis (Montgomery et al., Proc. Natl. Acad. Sci.

USA, 91: 8856-8860, 1994).

Mediation of the tumor cell metastatic pathway by interference with the ab, integrin cell adhesion receptor to impede tumor metastasis would be beneficial.

Antagonists of ab, 3 have been shown to provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) because systemic administration of a b, antagonists causes dramatic regression of various histologically distinct human tumors (Brooks et al., Cell, 79: 1157-1164, 1994).

The adhesion receptor identified as integrin ab 3 is a marker of angiogenic blood vessels in chick and man.

This receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells by new blood vessels.

Antagonists of ab, inhibit this process by selectively promoting apoptosis of cells in the neovasculature. The growth of new blood vessels, also contributes to pathological conditions such as diabetic retinopathy (Adonis et al., Amer. J. Ophthal., 118: 445-450, 1994) and rheumatoid arthritis (Peacock et al., J. Exp. Med., 175:, 1135-1138, 1992). Therefore, ab, antagonists can be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, 264: 569-571, 1994).

The a)b, cell surface receptor is also the major integrin on osteoclasts responsible for the attachment to the matrix of bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity, osteoporosis (a loss of bone) results, which leads to an increased number of bone fractures, incapacitation and increased mortality.

Antagonists of ab, have been shown to be potent inhibitors of osteoclastic activity both in vitro (Sato et al., J. Cell. Biol., 111: 1713-1723, 1990) and in vivo (Fisher et al., Endocrinology, 132: 1411-1413, 1993). Antagonism of avb, leads to decreased bone resorption and therefore assists in restoring a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast ab 3 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.

PCT Int. Appl. WO 97/08145 by Sikorski et al., discloses meta-guanidine, urea, thiourea or azacyclic amino benzoic acid derivatives as highly specific ab 3 integrin antagonists.

PCT Int. Appl. WO 96/00574 Al 960111 by Cousins, R.D. et. al., describe preparation of 3-oxo-2,3, 4 tetrahydro-1H-1,4-benzodiazepine and -2-benzazepine derivatives and analogs as vitronectin receptor antagonists.

PCT Int. Appl. WO 97/23480 Al 970703 by Jadhav, P.K. et. al. describe annelated pyrazoles as novel integrin receptor antagonists. Novel heterocycles including 3-[1-[3-(imidazolin-2-ylamino)propyl]indazol- 5-ylcarbonylamino]-2-(benzyl oxycarbonylamino)propionic acid, which are useful as antagonists of the avb3 integrin and related cell surface adhesive protein

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-36receptors.

PCT Int. Appl. WO 97/26250 Al 970724 by Hartman, G.D. et al., describe the preparation of arginine dipeptide mimics as integrin receptor antagonists.

Selected compounds were shown to bind to human integrin ab 3 with EIB <1000 nM and claimed as compounds, useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.

PCT Int. Appl. WO 97/23451 by Diefenbach, B. et.

al. describe a series of tyrosine-derivatives used as alpha v-integrin inhibitors for treating tumors, osteoporosis, osteolytic disorder and for suppressing angiogenesis.

PCT Int. Appl. WO 96/16983 Al 960606. by Vuori, K.

and Ruoslahti, E. describe cooperative combinations of ab 3 integrin ligand and second ligand contained within a matrix, and use in wound healing and tissue regeneration. The compounds contain a ligand for the ab, integrin and a ligand for the insulin receptor, the PDGF receptor, the IL-4 receptor, or the IGF receptor, combined in a biodegradable polymeric hyaluronic acid) matrix.

PCT Int. Appl. WO 97/10507 Al 970320 by Ruoslahti, E; and Pasqualini, R. describe peptides that home to a selected organ or tissue in vivo, and methods of identifying them. A brain-homing peptide, nine amino acid residues long, for example, directs red blood cells to the brain. Also described is use of in vivo panning to identify peptides homing to a breast tumor or a melanoma.

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-37- PCT Int. Appl. WO 96/01653 Al 960125 by Thorpe, Philip Edgington, Thomas S. describes bifunctional ligands for specific tumor inhibition by blood coagulation in tumor vasculature. The disclosed bispecific binding ligands bind through a first binding region to a disease-related target cell, e.g. a tumor cell or tumor vasculature; the second region has coagulation-promoting activity or is a binding region for a coagulation factor. The disclosed bispecific binding ligand may be a bispecific (monoclonal) antibody, or the two ligands may be connected by a (selectively cleavable) covalent bond, a chemical linking agent, an avidin-biotin linkage, and the like.

The target of the first binding region can be a cytokine-inducible component, and the cytokine can be released in response to a leukocyte-activating antibody; this may be a bispecific antibody which crosslinks activated leukocytes with tumor cells.

The phrase "matrix metalloproteinase inhibitor" or "MMP inhibitor" includes agents that specifically inhibit a class of enzymes, the zinc metalloproteinases (metalloproteases). The zinc metalloproteinases are involved in the degradation of connective tissue or connective tissue components. These enzymes are released from resident tissue cells and/or invading inflammatory or tumor cells. Blocking the action of zinc metalloproteinases interferes with the creation of paths for newly forming blood vessels to follow.

Examples of MMP inhibitors are described in Golub, LM, Inhibition of Matrix Metalloproteinases: Therapeutic Applications (Annals of the New York Academy of Science,

I

Vol 878). Robert A. Greenwald and Stanley Zucker (Eds.), June 1999), and is hereby incorporated by reference.

Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.

Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.

Degradation of connective tissue or connectivetissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major -39class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).

The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are:' collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.i7), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.

The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimer's Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur.

This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.

Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF) and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-a, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large integer of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobactefial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal.

TNF-a convertase is a metalloproteinase involved in the formation of active TNF-a. Inhibition of TNF-a convertase inhibits production of active TNF-a.

Compounds that inhibit both MMPs activity have been disclosed in, for example PCT Publication WO 94/24140.

Other compounds that inhibit both MMPs activity have also been disclosed in WO 94/02466. Still other compounds that inhibit both MMPs activity have been disclosed in WO 97/20824.

-41- There remains a need for effective MMP and TNF-a convertase inhibiting agents. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994)). McGeehan et al., Nature 376, 558-561 (1994) also reports such findings.

MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (-Amyloid Precursor Protein) to the amyloid plaque and inactivation of al-protease inhibitor (a3 Iphibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as a i-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.

Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the-selective inhibition of stromelysin (MMP-3), gelatinase (MMP-2), or collagenase III (MMP-13) are the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile.

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-42- Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP), a2-macroglobulin and their analogs or derivatives. These are high molecular weight protein molecules that form inactive complexes with metalloproteases. An integer of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.

Thiol group-containing amide or peptidyl amidebased metalloprotease (MMP) inhibitors are known as is shown in, for example, WO 95/12389. Thiol groupcontaining amide or peptidyl amide-based metalloprotease (MMP) inhibitors are also shown in WO 96/11209. Still further Thiol group-containing amide or peptidyl amidebased metalloprotease (MMP) inhibitors are shown in U.S.

Patent No. 4,595,700. Hydroxamate group-containing

MMP

inhibitors are disclosed in a number of published patent applications that disclose carbon back-boned compounds, such as in WO 95/29892. Other published patents include WO 97/24117. Additionally, EP 0 780 386 further discloses hydroxamate group-containing MMP inhibitors.

WO 90/05719 disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones. WO 93/20047 also discloses hydroxamates that have a peptidyl backbones or peptidomimetic back-bones. Additionally, WO 95/09841 discloses disclose hydroxamates that have

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-43peptidyl back-bones or peptidomimetic back-bones. And WO 96/06074 further discloses hydroxamates that have peptidyl back-bones or peptidomimetic back-bones.

Schwartz et al., Progr. Med. Chem., 29:271-334(1992) also discloses disclose hydroxamates that have peptidyl back-bones or peptidomimetic back-bones. Furthermore, Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) discloses hydroxamates that have peptidyl back-bones or peptidomimetic back-bones. Also, Denis et al., Invest.

New Drugs, 15(3): 175-185 (1997) discloses hydroxamates that have a peptidyl back-bones or peptidomimetic backbones as well.

One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC 5 0 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC 50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69- 75 (1997).

Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate), indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological

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-44activity. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder.

A

short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.

In view of the importance of hydroxamate

MMP

inhibitor compounds in the treatment of several diseases and the lack of enzyme specificity exhibited by two of the more potent drugs now in clinical trials, it would be beneficial to use hydroxamates of greater enzyme specificity. This would be particularly the case if the hydroxamate inhibitors exhibited limited inhibition of MMP-1 that is relatively ubiquitous and as yet not associated with any pathological condition, while exhibiting quite high inhibitory activity against one or more of MMP-2, MMP-9 or MMP-13 that are associated with several pathological conditions.

Non-limiting examples of matrix metalloproteinase inhibitors that may be used in the present invention are identified in Table No. 1, below.

Table No. 1. Miatrix metalloproteilase inhibitors.

Compound Trade N~ame Reference Dosage Biphenyl WO 97/18188 hydroxamate AG-3067 Winter Conf.

(Agouron Med. Bio- Pharm. organic Inc.) Chem. 1997 January, 26- 31 AG-3340 WO 97/20824 50 mg/kg (Agouron treatment Pharm. of Lewis Inc.) lung carcinomas in test animal s AG-2024 (Agouron Pharm.

Inc.) AG -3365 (Agouron Phanu.

Inc.) 3(S)-N-hydroxy- WO 97/20824. In female FEEBS (1992) Lewis rats, (imidazol-1- 296 :263 arthritis yl) phenoxy] benze model: dose nesulfonyl) of Compound Trade Namie Referenlce Dosage dimethyl mg/kg/day tetrahydro-2H- gave 97.5% 1, 4-thiazine-3 weight loss carboxamide, and inhibition derivatives thereof Heteroaryl WO 98/17643 succ inamides derivatives AG -3296 (Agouron Pharm.

Inc.)

AG-

3287 (Agouir on Pharm.

Inc.) AG- 3293 (Agouron Pharm.

Inc.) AG-3294 (Agouron Pharmn.

Inc.) AG-3 067 Winter Conf (Agouron Med Bio- Pharm. organic Chem Inc.) 1997 January 26-31 -47- Compound Trade Name Ref erence Dosage 2R 4S)-4- EP 0818443 hydroxy-2 i sobutyl merc apt 0-N- 2dimethyl-lmethyl carbaincyip ropyll Pentanamide N-alkyl, N- WO 98/16520 Phenylsulfonyl- N' -hydroxanic acid derivatives of heteroaryl carboxylic acids Novel N-alkyl, WO 98/16514

N-

phenylsul fonyl N' -hydroxanic acid derivatives of-heteroaryl carboxylic acids Novel N-alkyl, WO 98/16506

N-

phenyl sul fonyl N'-hydroxaric acid derivatives of cycloalkane carboxylic acids Novel N-alkyl, WO 98/16503 -48- Compound Trade Name Reference Dosage

N-

phenylsulfonyl- N'-hydroxaic acid derivatives of anthranilic acid sulfonamido- EP 03/98753 hydroxamic acid derivatives TIMP-3: WO 95/09918 polynucleotides encoding endogenous (human) peptides (3alpha, wo 93/23075 5beta,6alpha,7al phabeta) (hexahydro-2,2dimethyl-1, 3- 6-diyl)bis(2,6piperazinedione) and derivatives thereof BE-16627B wO 91/08222.

Int. J.

Cancer 1994 58 5 730 735 wO 96/15096 -49cmwound Trade Name Reference Dosage chiorophenyl )phe nyl)-4-oxo- 2- (2phthal iidoethyl )butanoic acid Bay-12- WO 96/15096 10 to 400 9566 mg/day 4-oxo-2- WO -97/43238 phthalimidoethyl alkanoic acid derivatives Novel WO 97/43237 Alkynyiphenyl) 4-oxobutanoic acid derivatives substituted 4- WO 96/15096 biarylbutyric or biarylpentanoic acids and derivatives Substituted 4- WO 98/22436 biphenyl -4hydroxybu Lyric acid derivatives 2R,S)-HONH-CO- J Med Chem CH(i-Bu)-CO-Ala- 1998 41 3 Gly-NH2, 339 -345 batimastat; BB- WO 90/05719 15 to 135 94; Hydroxam~ic mg/rn2 compound acid based col lagenase inhibitors HydroXamric acid based collagenase inhibitors WO 90/05719 marimastat BE- WO 94/02447 5 to 800 mg 2516; Hydroxamic daily acid derivatives alpha-cycJloalkyl Bio-orgalic analogs of Med Chemn niarimastat Lett 1998 8 11 1359 1364 GI-245402 (BB-2983) Hyclroxamfic acid WO 94/21625 derivatives Succinyl WO 95/32944 hydroxaxnic acid, N- formyl -Nbydroxy amino carboxylic acid and succinic acid amnide derivatives hydroxaxnic acid, WO 97/19053 N-f orinyl-Nhydroxyamino and -51compound Trade Name Reference Dosage carboxylic acid pseudopeptide WO 97/19050 hydroxainic and carboxylic acid derivatives from the corresponding lactone and alpha-amino acid Succinic acid WO 97/03966.

amide GB 95/00111.

derivatives GB 95/00121.

Hydroxamic acid WO 97/02239 derivatives Succinainidyl WO 96/33165 (alpha substituted) hydroxamic acid derivatives WO 96/25156 dimethyl-isthiazol-2ylcarbarnoyl propylcarbanoy-] methyl-2- (prop- 2 -enyl) hexanohydroxanic acid and derivatives thereof~ -52compound Trade Name Reference DoSage Hydroxamic or WO 96/16931 carboxylic acid derivatives hydroxainic and carboxylic acids WO 96/06074 2-f (iR)biphenyll -4ylmethylthio] -1- (lS)-2,2dimethyl-l- (methylcarbamoyl propylcarbamoyl I ethylcarbamoyl) 3-dioxo- 1,3dihydroisoindo- 2-yl)butylthio) acetate, and derivatives thereof SWO .98/23588 I HydroxaiiC derivatives inhibitors cytokine production ac id as of -t iWO 95/0.9841 1 Iydroxamic acid WO 94/24140 derivatives Aromatic or WO 95/19956 he teroaryl -53- Compound Trade Name Reference Dosage substituted hydroxamic or carboxylic acid derivatives Hydroxamic acid WO 95/19957 Doses are derivatives preferably 1 to 100 mg/kg.

Hydroxamic acid WO 95/19961 Doses are and carboxylic preferably acid derivatives 1 to 100 mg/kg.

Butanediamide, BB-1433 At 50 mg/kg N1- bid. p.o.

[l(cyclohexyl- inhibited methyl)-2 bone (methylamino)-2- mineral oxoethyl]-N4,3- density dihydroxy-2-(2- loss methylpropyl)-, [2R[N1(S*),2R*,3 tetracycline EP 733369 D-penicillanalogs and D- amine penicillamine reduced allergic encephaliti s symptom scores in a dose -54compound Trade Name Reference .Dosage dependent manner at 27, 125 and 375 mug with complete inhibition CDP-845 Biochem Pharmacol 1990 39 12 2041-2049 succinamide derivatives WO 95/04033 oral bioavail ability by murine pleural cavity assay in the presence of gelatiflase: Between 73% and lciO1% inihibiti on was displayed at 10 mg/kg for six of the compounds- Compound Trade N~ame Reference Dosage The seventh displayed 10.0% inhibition at mg/kg.

Bept idyl derivatives Mercaptoalkylpeptidyl compounds having an imidazole.

subs tituent 7mercaptoalkyl pept ide derivatives Mercaptoalkylamide derivatives arylsulEonylhydrazime derivatives N-acetylthiolacetyl.-N- (3phthal1imnidopropY 1) -L-leucyl-Lphenylalalife

N-

methylamide 2 -acetylsul fanywo 94/25435.

WO 94/25434 WO 97/19075 WO 97/38007.

WO 95/12389.

WO 96/11209.

WO 97/37974 0O 97/37973.

WO 9 5/112389 WO 96/35714

I

-56- Compound Trade Name Reference Dosage pentanoy. mg to 3.5 g leucineN- per day for phenylethyl)- the amide treatment of inflammat ion WO 96/35711 pentanoyl-Lleucyl-LphenylalanineNmethylamide peptidyl WO 98/06696 derivatives WO 98/05635 (methoxycarbony dimethyiphenyl]- 2-methyl-i (2 H) phthalazinone, and hydroxanic and carboxylic acid derivatives thio-substituted WO 97/12902 peptides Mercaptoamides WO 97/12861 Peptidyl WO 96/35687 derivatives having SH or acylo groups which are -57- D- 5410 (Chiroscience Group plc) CH-104, (Chiroscience Group plc) D- 2163 (Chiro Science Ltd.) D-1927 (Chiro Science Ltd.) Dermastat (Colla- Genex Pharmaceutical Inc.) -58- Compound Trade Name Reference Dosage Os teostat (Colla- Genex Phar- Maceutical Inc.) doxy- Gingival cyc line; crevicular Roche; fluid- Periostat collagenase is reported to be inhibited at concentrations of microg /ml or microM 2S, 5R, 6S-3- WO 97/18207 aza-4-oxo-10- 2- (Nmethyl carboxainido) paracyclopha ne-6-Nhydroxycarboxami de -59- Do sage Compound hydrcxamic acid and amidnoc arboxyl ate compounds N -hydroxami c derivatives of succinamide Macrocyclic amino carboxylates Trade Name Reference I1 WO 96/33176 WO 96/33166 j med Chemn 1998 41 11 1749-1751 SE-205 (Du Pont Merck Pharm Co.) Bjo-organic Med Chemr Lett 1998 8 7 837-842.

J Med Chemn 1998 41 11 1745 -1748 macrocyclic matrix metalloprotease- 8 inhibitors iydroxamic acid and carboxylic acid derivatives I o95/22966 succinainid derivatives mercaptosulfide derivatives sulfoximine and sul fodiimine US 5256657 WO 95/09833 IWO 95/09620 I J Compound Trade Name Reference Dlosage derivatised pept ides water soluble WO 96/33968 MMP inhibitors hydantoin EP 06/40594 derivatives Piperazine, WO 98/27069 derivatives GI-155704A J Med Chem 1994 37 674.

Bioorganic Med Chemn Lett 1996 6 16 1905 1910 Cyclic imide EP 05/20573 derivatives.

3-Cinercapto- WO 97/48685 methyl) hexahyciro-2, pyrazinedione derivatives beta- WO 96/40738 mer captoke tone and betamnercaptoalcohol derivatives ilomastat US 5114953. eye drops MPI; GM- Cancer Res containing -61- Cyclic and WO VI heterocyclic Nsubstituted alphaiminohydroxanic and carboxylic acids Arainomethyl- EP 703239 phosphonic and aauinotnethyl phosphinic acids derivatives 3-Mercapto- WO 98/12211 acetylamino-l, qubstituted-2oxo-azepan derivatives 2-substituted WO 94/04531 indane-2 mnercaptoacetylamide tricyclic derivatives Ro -2756 (Roche Holding

AG)

Ro-26 -43 -62- Compound Trade Nqame Reference Dosage (Roche Holding

AG)

RO-26-5726.

(Roche Holding

AG)

Ro -26-6307 (Roche Holding

AG)

Ro-31-9790 J Am Soc mono- (Roche Nephrol 1995 arthritis Holding 6 3 904. in rat: 100 AG) Inflanim Res mg/kg/day 1995 44 8 345 -349 substituted and WO 92/09556 unsubstituted hydroxamates (specifically N- ED, L-2-isobutyl- 3 -hydroxycarbonyl-amido) propanoyl] trypto, phaniethylaznide) GM6001, WO 95/24921 2 (hydroxyaiuinoc ar bonylnethyl.) 4- -63- ICompoun11d methylpentanoyl) -L-tryptophal methylamide.

Oligonucleotice (c-jun) sulfated polysaccharides Fas ligand solubilization inhibitor gelastatin

AB,

KRIBB

Trade Name

I

RefeGrenC-e Dosage 98/ 1114 1 KB-R7785; KB-R83 01; KB-R8845 1997 61 8 795-803 -Wo 97/09066 -12 (Kotobuki Seiyaku Co Ltd.) Faseb J 1998 12 5 A773 (4482) GB' 23418789 2- (N2- (2R) -2- (2 -hydroxyamin~fo- 2-oxoethyl) (4methoytyphefloxy) p entanoyl]

-L-

phenylalanylanin o) ethanesulfonaa ide, and carboxylic acid derivatives -64thereof Chromone derivatives IEP 75a649 Pyrolylthio -chromone in a murine melanoma model produced 37% inhibition at 100 Smg-/kg Esculetin EP 719770 derivatives, substituted and WO 92/09563 unsubstituted hyroxyureas and reverse hydroxantates Synthetic MHP inhibitors (ex.

N- (D,L-2isobutyl-3- hydroxyc arbonyl a tnido)propanoyl) t ryptophan methylamide) 94/22309 Reverse hydroxamates and hydroxyureas Compound Trade Name Ref erenice Dosage w/rnurine melanomainit. 80 mu g followed by 150 mg/kg/day N- US 5629343 (mercaptoacy.) aryl derivatives of, leucine and phenylalanine N-carboxyalkyl WO 95/29689 derivatives Substituted GB 22/82598 Inflamnratio cyclic n is stated derivatives to be effectively treated by oral admini strat.

ion of 0.01 to 50 mg/kg Substituted n- GB 22/72441 carboxyalkyldi peptides (2S,4R)-2- WO 97/11936 methyl-4- (phenylaminocarbonylmethyaminocarbonyl)

I

compounid ITrade N~ae Reference DoSWge 6- (4-propylphenyl )hexanoic acid, and carboxylic acid derivatives Substituted cycl1ic derivatives -t tiUS 5403952 Thiol WO 98103166 sulfonamide metalloprotease inhibitors Thiol sulfone Wo 98/03164 metal loproteinase inhibitors formulations WO 97/47296 containing vanadium compounds and NacetylcyS teine

NSC-

683551; COL- 3 (National Cancer Institute) BB-3 644 (Neures Ltd.) Arylsulfonamido- CGS- mElt -Congr 600 Ii i -67- Compound ]Trade Name Reference Dosage substituted 27023A; Inflanmm Res (Ph I hydroxamic acids CGS-25966 Assoc 1994 colorectal.

7th ZAbs 73. and EP-00606046 melanoma patients); 100 mg/kg in food in osteoarthri tis model rabbits alpha- WO 97/22587 Substituted arylsulfonainido hydroxamic acid derivatives Arylsulfonamido- US 5455258 active at substituted 30 mg/kg in hydroxamic acids in vivo as say Arylsulfonainido- WO 96/00214 substituted hydroxainic acids 2s,3S)-N- WO 98/14424 hydroxy- inethyl-2- [12- (2methoxyethoxy) et hoxymnethyll1-3methylcarbamoyl) -2- -68- Compound Trade Name Reference DosEage phenylethy. 3carb amoyl) hexanamnide and Hydroxaxnic acid derivatives arylsulfonamido- WO 96/40101 in tumor substituted model mice: hydroxamic acids administere d for 7 to 17 days at a dosage of mg/kg twice daily Aryl (sulfide, WO 97/49679 sulfoxide and suif one) derivatives Phenylsulfon- WO 97/45402 amide derivatives Arylsulfonamido- EP 757037 aininoacid derivative A1PDX (Oregon Health Sciences University) futoenone Bia-organic analogs Med Chem Lett 1995 1637 -69debromohymeni aldisine and related compounds WO 96/40147 preferred 1-30 mg/day I 1 i amide derivatives of 5-axnino-1, 3,4thiadiazolones WO 96/40745 4 t 3S- (Nhydroxylamino) isobutylsuccinyl amino-imethoxymethyl 3,4dihydrocarbos tyr ii and derivi atives therof WO 94/21612 Carbostyryl JP 8325232 derivatives OPB-3206 (Otsuka Pharmaceutical Co, Ltd.) Arylsulfonyl WO 96/33172 hydroxamic acid derivatives Cyclic sulfone EP 818442 derivatives Compound Trade Name Reference Dosage arylsulfonamido WO 96/27583 N-hydroxamic acid derivatives of butyric acid Arylsulfonyl- WO 98/07697 amino hydroxamic acid derivatives phosphinate- WO 98/03516 based derivatives cyclopentyl- ,WO 92/14706 substituted glutaramide derivatives N-hydroxamic WO 97/49674 acid succinamide derivatives Thiadiazole WO 97/48688 amide MMP inhibitors.

WO 97/40031 5-thioxo-1,3,4thiadiazol-2yl)amino]carbonyl)amino]- I-oxo-3- (pentafluorophenyl)propyl)- 4-(2-pyridinyl)- -72.compound piperazilne hydroxamic acid derivatives of pyrrolidone-3 [acetamide.

T

WO 98/17645 alphaarylsulfonainido- N-hydroxamfiC acid derivatives Hydroxamic acid derivatives WO 98/13340 II US 5712300 PNU- 99533 (Pharnac-ia Upjohn Tnc.) PNU-1243 677 (Pharinacia &Upjohn Inc.) I

T-

I -4 T PoL -641 (Polif arina) Peptidomimeti WO 96/20,18.

inhibitors WO 96/29313.

wo 98/08814.

WO 98/08815.

Wa 98/08850.

-72comp~ound Trade Name Reference Dosage WO 98/08822.

WO 98/08823.

WO 98/08825.

WO 98/08827.

2R) -Nhydroxyc arboxami demethyldecanoic acid amnide of 1N- (carbomethoxymethyl) -caprolactam- (3S) -amine WO 96/29313 rheumnato id arthritis: female subject 50 mg po for 2 yrs; male subject mg po daily for yrs; corneal ulcer: male subject 0 mng in saline soln for 2 months, 2 times/day WO 96/20918 Hydroxyaminocarb onyl) methyl -Nisobutylaminocar bonyl) isobutylpro- -73- Compo'und Trade Namn Reference Dosage panoyl -Lphenylalanine amnide N-hydroxy- WO 98/08853 phosphinic acid amnides N'-arylsulfonyl WO 98/08850 derivatives of spirocyclic-Nhydroxyc arboxamides N'-arylsulfonyl WO 98105827 derivatives of thiazepinone and az epinone -Nhydroxyc arboxam ides Substituted WO 98/08825 pipera zine derivatives N'-arylsulfonyl WO 98/08823 derivatives of pyrimidine, thiazepine and di azepine -Nhydroxycarboxamides Substituted, WO 98/08815 pyrrol idine derivatives -74compound Trade NIame Reference Dosage Substituted WO 98/08814 heterocyc les Substituted 1,3- wo 09/08822 diheterocyCliC derivatives substituted 5- WO 98125949 amno- 1, 2 4 thiadiazoJle-2thi ones Hydroxamfic acid WO 97/24117 derivatives which inhibit TNF production.

6-methoxy- WO 97/37658 1,2,3,4tetrahydronorharman -1carboxylic acid RS-130830 Arthritis Rheumn 1997 9 SUPPL.

S 128 Aralkyl NMP WO 96/16027 inhibitors (ex.

N- (2Rc arboxymethyl (biphera-4yl)pentanoyl)

-L-

t-butylgjlycine- N' (pyridin-4compounid Trade Name Reference Dosage yl) carboxainide) Ro-32-3 555 (Roche Holding

AG)

Ro -32-1278 (Roche Holding

AG)

Ro -32 -1541 (Roche Holding

AG)

Ro-31-3790 Arthritic (Roch e model rats: Holding Protection AG) of cartilage degradation following oral administrat ion; mg/kg po (3R,11S)-N- WO 95/04735 rethyl-3- oxo-l, 9diazatricyclo- (11.6.1.014, 19)e -76- Campound Trade Name Reference Dosage icosa- 13(20) ,14(19) ,17-tetraen- 11ylcarbamoyl) hexa namide and derivatives thereof Bridged indoles WO 96/23791 (Roche Holding

AG)

substituted EP 780386 phenyl sul.fonyl acetainide, propionainide and carboxamide compounds 5-(4'--bipheflyl)- WO 97/23465 (4nitrophenyl) pip eraz inyl] barbituric acid Malonic acid based matrix metal loproteiflas e inhibitors phenyl.

carboxamide derivatives Malonic acid based rnimp EP 716086

I

-77- Coapound Trade Name Reference Dosage inhibitors (specifically 2- (4-acetylaminobenzoyl)-4methylpentanoic acid) Hydroxyl amine Ro-31- EP 236872 derivatives 4724; Ro- 31-7467; The following individual patent references listed in Table No. 2 below, hereby individually incorporated by reference, describe various MMP inhibitors suitable for use in the present invention described herein, and processes for Table No. 2.

their manufacture.

MMP inhibitors EP 189784 US 4609667 WO 98/25949 WO 98/25580 JP 10130257 WO 98/17655 WO 98/17645 US 5760027 US 5756545 WO 98/22436 WO 98/16514 WO 98/16506 WO 98/13340 WO 98/16520 WO 98/16503 WO 98/12211 WO 98/11908 WO 98/15525 WO 98/14424 WO 98/09958 WO 98/09957 GB 23/18789 WO 98/09940 WO 98/09934 JP 10045699 WO 98/08853 WO 98/06711 WO 98/05635 WO 98/07742 WO 98/07697 WO 98/03516 WO 98/03166 WO 98/03164 GB 23/17182 WO 98/05353 WO 98/04572 WO 98/04287 WO 98/02578 WO 97/48688 WO 97/48685 -78wo 97/49679 WO 97/47599 WO 97/43247_(WO 97/43240 WO 97/43238 EP 818443 EP 818442 WO 97/45402 WO 97/40031 WO 97/44315 WO 97/38705 US 5679700 WO 97/43245 WO 97/43239 WO 97/43237 JP 09227539 WO 97/42168 US 5686419 WO 97/37974 WO 97/36580 Wa 97/25981 WO 97/24117 US 5646316 WO 97/23459 Wa 97/22587 EP 780386 DE 19548624 WO 97/19068 Wa 97/19075 WO 97/19050 WO 97/18188 WO 97/18194 Wa 97/18183 WO 97/17088 DE 19542189 WO 97/15553 WO 97/12902 WO 97/12861 WO 97/11936 Wa 97/11693 WO 97/09066 JP 09025293 EP 75/8649 WO 97/039661 Wa 97/03783 EP 75/7984 WO 97/02239 WO 96/40745 WO 96/40738 WO 96/40737 JP 08/311096 WO 96/40204 Wa 96/40147 WO 96/38434 WO 96/35714 Wa 96/35712 Wa 96/35711 WO 96/35687 EP 74,3,070 WO 96/33968 WO 96/33165 WO 96/33176 WO 96/33172 Wa 96/33166 Wa 96/33161 GB 23/00190 WO 96/29313 EP 73/6302 Wa 96/29307 EP 733369 WO 96/26223 WO 96/27583 WO 96/25156 GB 22/98423 WO 96/23791 WO 96/23505 GB 22/97324 DE 19501032 WO 96/20918 US 5532265 EP 719770 Wa 96/17838 WO 96/16931 Wa 96/16648 WO 96/16027 EP 716086 WO 96/15096 JP 08104628 WO 96/13523 JP 08081443 WO 96/11209 EP 703239 Wa 96/06074 Wa 95/35276 WO 96/00214 Wa 95/33731 WO 95/33709 WO 95/32944 WO 95/29,892 WO 95/29689 CA 21/16924 Wa 95/24921 WO 95/24199 WO 95/23790 WO 95/22966 GB 22/87023 WO 95/19965 WO 95/19961 WO 95/19956 WO 9S/19.957 WO 95/13,289 WO 95/13380 WO 95/12603 WO 95/09918 WO 95/09841 Wa 95/ 0983 3 WO 95/09620 WO 95/08327 GB 22/82598 WO 95/07695 -79wo 95/05478 WD 95/D4735 WO 95/04033 WO 95/02603 WO 95/02045 EP 626378 WO 94/25435 WO 94/25434 WO 94/21612 WO 94/24140 WO 94/24140 EP 622079 WO 94/22309 JP 06256209 WO 94/21625 FR 27/03053 EP 606046 WO 94/12169 WO 94/11395 GB 22/72441 WO 94/07481 Wa 94/04190 WO 94/00119 GB 22/68934 WO 94/02446 EP 575844 WO 93/24475 WO 93/24449 US 5270326 US 5256657 Wa 93/20047 WO 93/18794 WO 93/14199 WO 93/14096 WO 93/13741 WO 93/09090 EP 53/2465 EP 532156 WO 93/00427 WO 92/21360 WO 92/09563 WO 92/09556 EP 48/9579 EP 489577 Us 5114953 EP 45/5818 US 5010062 AU 90/53158 WO 97/19075 US 7488460 US 7494796 US 7317407 EP 277428 EP 23/2027 WO 96/15096 WO 97/20824 US 5837696 The Marimastat used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 94/02,447.

The Bay-12-956 6 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 96/15,096.

The AG-3340 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 97/20,824.

The Metastat used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,837,696.

The D-2163 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 97/19,075.

More preferred zinc matrix metalloproteinase inhibitors include those described in the individual U.S. Patent applications, PCT publications and U.S.

Patents listed below in Table No. 3, and are hereby individually incorporated by reference.

Table No. 3. More preferred zinc matrix metalloproteinase inhibitors U.S. Patent Application Serial Number 97/12,873 U.S. Patent Application Serial Number 97/12,874 U.S. Patent Application Serial Number 98/04,299 U.S. Patent Application Serial Number 98/04,273 U.S. Patent Application Serial Number 98/04,297 U.S. Patent Application Serial Number 98/04,300 U.S. Patent Application Serial Number 60/119,181 WO 94/02447 WO 96/15096 WO 97/20824 WO 97/19075 US 5837696 Even more preferred zinc matrix metalloproteinase inhibitors that may be used in the present invention include: -81- M41)

HCI

N-hydroxy-1- (4-methylpheny-) [4- (trifluoroinethyl) phenoxy] phenyl) sulfonyl] -4piper idinecarboxamide monohydrochloride; M2) HCd N 1-cyclopropyl-N-hydroxy-4- [4- (trifauoroinethoxy) phenoxy] pheriyl) sulfonyl] -4piperidinec'arboxamide monohycdrochloride; -82- 143) 0 00 Ur3 H N1 HT NX HCI N N-hydroxy-i1- (phenylmethyl) 4- [4 4 (trifluoromethoxy) phenoxy) -1piperidinyll suitonyl) -4-piperidineCarbOXamide monohydrochioride; M4)

ECI

H 3

C'

N-hydroxy--(4-PYridinyirnethyl) (tritluoromethyl) phenoxy) phenyl] suit onyl] -4piperidinecarboxaiide dihydrochioride;

MS)

N-hydroxy-2, 3-dimethoxy-6-E 4- [4- (trifluoromethyl) phenoxy) -1piperidinyl] sulfonyl] benzanide; M6)

HCI

N-hydroxy-l- (4-pyridinylmethYl) -4-il 4- [4- (trif luoromethyl)pheloxy) phenyl] sulf onyl 1 -4piperidinecarboxamide aihydxochloride; -84- M7)

HCI

.HCI

N-hydroxy-1- (3-pyridinylmethyl) (trif luoromethYJ-) phenoxy] phenyl I sulf onyl]1 -4piperidinecarboxamide dihydrochioride;

MS)

,CF

3

HOHN

N-hydroxy-1-.(2-pyridiflmethyl) [4- (trifluoromethy-) phenoxylphel]sulfonyl] -4piperidinecarboxamide nonohydrochioride; N CH3

H

un Ii British Biotech BB-2516 (Mariinastat), N4-[2,2dimethyl- 1- [(methylamrino) carbonyl] propyl] N1,2 -dihydroxy-3 (2-methylpropyl)-, [2S- Bayer Ag Bay-12--9566, 4-[(41-chloro[1,1'iphenyll- 4-yl)xY]-2- [(phenylthio)methyllbutaloic acid; Ml 1) Agouron Pharmaceuticals AG-3340, N-hYdroxy-2,2 dimethyl- 4- (4-pyridinyloxy)phenyl] suit onyl] 3-thiomorpholinecarboxamide; M12) CollaGeriex Pharmaceuticals cMT-3 (Metastat), 6- dernethyl-6-deoxy-4 dedimethylaxninotetracycl ire; -86- M13) Chiroscience D-2163, 2- [IS- acetylmercapto- 5- phthalimido]peltalOY-

L-

leucyl) amino- 3- methylbutyl] imidazole; M14) HCI NXC N-hydroxy- 4- (Phenylthio)phel.sulfonyil]- 1- (2 -propynyl) -4-piperidinecarboxamide monohydrochioride; mis)

HOHN'

CC

N-hydroxy-1- (2-methoxyethy-) [14- [4 (trif2.uoromethoxy) phenoxy] phenyl) sulfonyl) -4piperidinecarboxamide monohydrochloride; -87- M1 6) MOHN"~Kj

N

nNN N-hydroxy-1- (2-methoxyethyl) [4- (trif luoroiethyl) phenoxy) phenyl]I sulf onyl) 1-4piperidinearboxamide; HOHN .F.

IHCI

1-cyclopropyl-N-hydroxy-4- [4- (trifluoromethyl)phenoxy]phenyl] sulfonyll -4piper idinecarboxamide monohycirochioride; M17) -88- M18) 1419)

HCI

4- (cyclohexylthio)phelyl]sulfflY1]

-N-

hydroxy-1- (2 -propynyl) -4-piperidinecarboxanide inonohydrochi or ide; HOHN

N

chiorophenoxy) phenyl] sulfonyl] tetrahydro-Nhydroxy-2H-pyran-4 -carboxamide; Ooo 1420) N-hydroxy-4- (4nethoxyphenoxy)phenyl) sulfonyl] propynyl) -4-p iperidinecarboxanide; -89- M1421)

A

1-cyclopropyl-4-[E 4- (4fluorophenyl) thio) phenyilsulfonyl] -N-hydroxcy- 4 -piperidinec arboxamide; M22) 1-cyclopropyl-N-hydroxy-4- [14- (phenylthio) phenyl] sulfonyl) -4piperidinecarboxamide; X23)

HOHN

j:

N

tetrahydro-N-hydroxy-4-[[4- (4pyridinylthio)phenyl] sulfonyl] -2H-pyran-4carboxamide; M2 4)

HOW-I

tetrahydxo-N-hydroxy- 4 [4- (trifluoromethYl)PheloxyIIphenYl] sulfonyl) -2Hpyran-4-carboxamide.

Still more preferred IMThP inhib itors include: Ml)

HCI

CH

3 N-hydroxy-l- (4-methyiphelyl) [[4-IA- (trifluoromfethyl)phenolO]phenYfl sulfonyl] -4piperidinecarboxamride monohydrochioride; -91-

MZ)

HCI N 1-cyclopropyl1N-hydr~oxy- 4 I4- 4- (trifluoromethoxy) phenoxyl phenyl) sulfoflyl) -4piperidinecarboxamide monohydrochloride; H-CJ N N-hydroxy--l- (pheflylmethYl) [4- (trifluoromethOXY)phenoxY] -1piperidiny-J ulfony1) 4 -piperidinecarboxamide monohydrochi oride; -92- M4) H Io, HCl

H

3 C 1 N-hydroxy---(4-pyridinylmethyl) [4- (trifluoromethyl) pbenoxyl phenyl) sulfonyil -4piperidinecarboxanide dihycirochioride; N-hydroxy-2,3-dimethoxy-6- [4- (trifluoromethyl) phenoxy] -1piperidinyll sulfonyl] benzamide; -93- M46) HOHN Jr

HCI

HCI I N-hydroxy-i- (4-PyridiriylmethYl) [4- (tri fluoromethyl) phenoxyl phenyl]I suit oayl 3-4 piperidinecarboxamide dihydrochioride; N47)

HOH-N

HOI

HCI

N-hydroxy-1- (3-pyridirlylmethyl) [4- (trif luoromethyl) phenoxy] phenyl] sulfonyl) -4piperidinecarboxamfide dihydrochioride; -94- X8) SOH 0"

CF

3

N

N MCI N-bydroxy-l-,(2-pyridinylmethyl) [4- (trifluoromethy.) phenoxyjphenyl] sulfonyl) -4piperidinecarboxamide monohydrochioride; M.9 0H 0 HOHN

N

OH H British Biotech BB-2516 (Narimastat), N4-112,2dime thyl.- 1- [(methylainino) carbonyl Ipropyl] Ni,2 -dihydroxy-3 methyipropyl)-, [2S- Ml 1)

NN

Agourori Pharmaceuticals AG-3340, N-hydzoxy- 2,2- dimethyl- pyridinyloxy)phelyl] sulfonylj 3thioinorpholiziec arboxamide; M12) CollaGenex Pharmaceuticals CMT-3 (Metastat), 6- deiethyl-6-deoxy- 4 dedimethylamfifotetracYc line; M13) Chiroscience D-2163, 2- [IS- acetylmercapto- 5- phthalimidolpentaloyl-

L-

leucyl) amino- 3- methyilbutyl) imidazole.

-96- The phrase f cyclooxygenase-2 inhibitor" or "COX-2 inhibitor" or "cyclooxygenase-II inhibitor" includes agents that specifically inhibit a class of enzymes, cyclooxygenase-2, with less significant inhibition of cyclooxygenase-1. Preferably, it includes compounds which have a cyclooxygenase-2 IC50 of less than about 0.2 pM, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC50 of greater than about 1 uM, and more preferably of greater than 10 pM.

Studies indicate that prostaglandins synthesized by cyclooxygenases -play a critical role in the initiation and promotion of cancer. Moreover, COX-2 is overexpressed in neoplastic lesions of the colon, breast, lung, prostate, esophagus, pancreas, intestine, cervix, ovaries, urinary bladder, and head neck. In several in vitro and animal models, COX-2 inhibitors have inhibited tumorgrowth and metastasis.

In addition to cancers per se, COX-2 is also expressed in the angiogenic vasculature within and adjacent to hyperplastic and neoplastic lesions indicating that COX-2 plays a role in angiogenesis. In both the mouse and rat, COX-2 inhibitors markedly inhibited bFGF-induced neovascularization. The utility of COX-2 inhibitors as chemopreventive, antiangiogenic and chemotherapeutic agents is described in the literature (Koki et al., Potential utility of COX-2 inhibitors in chemoprevention and chemotherapy. Exp.

Opin. Invest. Drugs (1999) 8(10) pp. 1623-1638, hereby -97incorporated by reference). Amplification and/or overexpression of HER-2/nue (ErbB2) occurs in 20-30% of human breast and ovarian cancers as well as in 5-15% of gastric and esophageal cancers and is associated with poor prognosis. Additionally, it has been recently discovered in vitro that COX-2 expression is upregulated in cells overexpressing the HER-2/neu oncogene.

(Subbaramaiah et al., Increased expression of cyclooxygenase-2 in HER-2/neu-overexpressing breast cancer. Cancer Research (submitted 1999), hereby incorporated by reference). In this study, markedly increased levels of PGE, production, COX-2 protein and mRNA were detected in HER-2/neu transformed mammary epithelial cells compared to a non-transformed partner cell line. Products of COX-2 activity, i.e., prostaglandins, stimulate proliferation, increase invasiveness of malignant cells, and enhance the production of vascular endothelial growth factor, which promotes angiogenesis. Further, HER-2/neu induces the production of angiogenic factors such as vascular endothelial growth factor.

Consequently, the administration of a COX-2 inhibitor in combination with an anti HER-2/neu antibodies such as trastuzumab (Herceptin®) and other therapies directed at inhibiting HER-2/neu is contemplated to treat cancers in which HER-2/neu is overexpressed.

Also, it is contemplated that COX-2 levels are elevated in tumors with amplification and/or overexpression of other oncogenes including but not limited to c-myc, N-myc, L-myc, K-ras, H-ras, N-ras.

-98- Products of COX-2 activity stimulate cell proliferation, inhibit immune surveillance, increase invasiveness of malignant cells, and promote angiogenesis. Consequently, the administration of a COX-2 inhibitor in combination with an agent or agents that inhibits or suppresses oncogenes is contemplated to prevent or treat cancers in which oncogenes are overexpressed.

Accordingly, there is a need for a method of treating or preventing cancer in a patient that overexpresses COX-2 and/or an oncogene. Methods for the production of anti- ErbB2 antibodies are described in WO 99/31140.

Specific COX-2 inhibitors are useful for the treatment of cancer (W098/16227) and in several animal models reduce angiogenesis driven by various growth factors (W098/22101). Anti-angiogenesis was achieved with a COX-2 inhibitor in rats implanted with bFGF, vascular endothelium growth factor (VEGF) or carrageenan, proteins with well-known angiogenic properties. (Masferrer, et al., 89 t Annual Meeting of the American Association for Cancer Research, March 1998.) Pyrazoles can be prepared by methods described in WO 95/15,316. Pyrozoles can further be prepared by methods described in WO 95/15315. Pyrozoles can also be prepared by methods described in WO 96/03385. Thiophene analogs can be prepared by methods described in WO 95/00501. Preparation of thiophene analogs is also described in WO 94/15932. Oxazoles can be prepared by the methods described in WO 95/00501. Preparation of oxazoles is also described in WO 94/27980. Isoxazoles -99can be prepared by the methods described in WO 96/25405.

Imidazoles can be prepared by the methods described in WO 96/03388. Preparation of imidazoles is also described in WO 96/03387. Cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent No. 5,344,991. Preparation of cyclopentane Cox-2 inhibitors is also described in WO 95/00501. Terphenyl compounds can be prepared by the methods described in WO 96/16934. Thiazole compounds can be prepared by the methods described in WO 96/03,392. Pyridine compounds can be prepared by the methods described in WO 96/03392.

Preparation of pyridine compounds is also described in WO 96/24,585.

Nonlimiting examples of COX-2 inhibitors that may be used in the present invention are identified in Table No. 4 below.

Table No. 4. Cyclooxygenase-2 Inhibitors Ccm~pud Trade/ Reference Dosage Research Name 1,5-Diphenyl-3- WO 97/13755 substituted pyrazoles radicicol WO 96/25928.

Kwon et al (Cancer Res(1992) 52 6296) GB-02283745 TP-72 Cancer Res 1998 58 4 -100cczoudTrade/ R :e ece Msage Research Name 717 -723 A-183827.O0 chlorobenzoyl) -3- (4-f luoropheriyl tiliazol- 2-ylmiethyl] methoxy-2 -iethy lindole GR-253035 4- (4-cyclohexyl- im-522 JP 9052882 2 yl) -2fluorobenzeriesulf onarnide 5-chloro-3- (4- (methylsulforiyl) P heriyl) (mnethylpyridine 2- phenyl) -3-4- (methylsuif onyl) phenyl) -2 cyclopenten--re L-768277 L-783 003 DK-966; US 5968974 12.5-100 ng po VIOXXo indcmethacin- WO9613746791 200 mng/kg/day -101- Ccziwound Trade/ Reference Dosage Reseamch NaE derived indolalkanoic acid 1-Methylsu-foflyl- WO 95/30656.

1-dimethYl- wo 95/30652.

4-(4-WO 96/38418.

fluorophenyl)cycl WO 96/38442.

open ta-2, 4--dien- 3 -yl 3berizene 4, 4-dimethyl-2pheny1-3- [4- (methylsulfofll) p henyl) cyclobutenone 2-(4-EP 799823 methoxyphenyl) -4methyl-i- (4sulfamoylphenyl) pyrrole N-[5-(4-RwJ-63556 f luoro) phpnoxy] th iophene-2methanesulf onamide 5-di- S-2474 E? 595546 tert-butyl-4hydroxy) benzyi ide ne-2-ethyl-l, 2isothiazolidinfe- -102c~pu ~Trade/ Ref ezu2we Dosage R-seardh Nbrn F r'amiflo-7- T-614 DE 38/34204 xneth-ylsulf onylami no- 6.-p1encvy- 4

H-

1-benzopyrafl-4one Bezenesulfoflamid celecoxib US 5466823 e, 4 5 4 rethylpeiy) -3- (trifluoromethyl) -1H-pyrazol-1- CS 502 (Sankyo) MK 633 (Merck) nieloxicam US 4233299 15-3 0 rrg/day ninesulide US 3840597 The following references listed i.n Iallo below, hereby individually incorporated by reference, describe various COX-2 inhibitors suitable for use in the present invention described herein, and processes for their manufacture.

Table No. 5 COX-2 inhibitors WO 99/30721 WO 9.9/25695 Wo 99/30729 wa 99/24404 US 5760068 WO 99/23087

I

wo 98115528 FR 27/71005 WO 99/15505 WO 99/14194 EP 921119 wo 99/15S03 FR 27/70131 Wa 99/14205 wa 99/18960 WO 99/14195

I

wa 99/13799 GB 23/30833 1US 5859036 wa 99/12930 WO 99/11605 WO 99/10332 Wa99/10331 wo 99/09988 -103- US 5869524 WO 99/05104 US 5859257 WO 98/4780 Wa 98/47871 US 5830911 US 5824699 WO 98/45294 wo 98143966 WO 98/41511 WO 98/41864 WO 98/41516.

Wa 98/37235 EP 86/3134 JP 10/175861 US 5776967 Wa 98/29382 WO 98/25896 ZA 97/04806 EP 84/6,689 Wa 98/21195 GB 23/19772 Wa 98/11080 WO 98/06715 Wa 98/06708 Wa 98/07425 Wa 98/04527 WO 98/03484 FR 27/51966 WO 97/38986 WO 97/46524 WO 97/44027 Wa 97/34882 US 5681842 :Wa 97/37984 us 5686460 WO 97/36863 WO 97/40012 WO 97/36497 Wa 97/29776 WO 97/29775 WO 97/29774 WO 97/28121 WO 97/28120 WO 97/27181 Wa 95/11883 WO 97/14691 WO 97/13755 WO 97/13755 CA 21/80624 WO 97/11701 WO 96/41645 Wa 96/41626 WO 96/41625 WO 96/38418 WO 96/37467 Wa 96/37469 WO 96/36623 WO 96/36617 Wa 96/31509 Wa 96/25405 Wa 96/24584 WO 96/23786 Wa 96/19469 WO 96/16934 Wa 96/13483 WO 96/03385 US 5510368 WO 96/09304 WO 96/06840 WO, 96/06840 Wa 96/03387 WO, 95/21817 GB 22/83745 WO -94/27980 WO 94/26731 Wa 94/20480 Wa 94/13635 FR 27/70,131 US 5859036 Wa 99/01131 Wa 99/01455 WO 99/01452 WO, 99/01130 Wa 98/57966 Wa 98/53814 WO 98/53818 Wa 98/53817 WO 98/47890 US 5830911 US 5776967 Wa 98/22101 DYE 19/753463 Wa 98/21195 WO 98/16227 US 5733909 Wa 98/05639 WO 97/44028 Wa 97/44027 Wa 97/40012 Wa 97/38986 US 5677318 Wa, 97/34882 WO 97/16435 WO 97/03678 :WO 97/03667 WO 96/36623 Wa 96/31509 Wa 96/25928 Wa 96/06840 Wa 96/21667 WO, 96/19469 US 5510368 Wa 96/09304 GB 22/83745 WO 96/03392 Wa 94/25431 Wa 94/20480 WO 94/13635 JP09052882 104 GB 22/94879 WO 95/15316 WO 95/15315 WO 96/03388 WO 96/24585 US 5344991 WO 95/00501 US 5968974 US 5945539 US 5994381 WO 99/11605 discloses compounds of formula (I) R CCOOH i0 7 R4 R3 wherein R is methyl or ethyl; R' is chloro or fluoro; R 2 is hydrogen or fluoro; R 3 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R 4 is 15 hydrogen or fluoro; and R 5 is chloro, fluoro, trifluoromethyl or methyl; pharmaceutically acceptable salts thereof and pharmaceutically acceptable prodrug esters thereof.

Such compounds inhibit cyclooxygenase-2 without significantly inhibiting cyclooxygenase-l, and are therefore cyclooxygenase-2 selective inhibitors.

The celecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,466,823.

The valdecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,633,272.

The parecoxib used in the therapeutic combinations' of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,932,598.

The rofecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,968,974.

The Japan Tobacco JTE-522 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in JP 90/52,882.

Preferred COX-2 inhibitors that may be used in the present invention include, but are not limited to: -105- Cl) N~ 0 0 0 F JTE-522, 4- (4-cyclohexyl-2-methyloxazol-S-y-) 2 -fluorobenzenesulfonamide; C2) -chloro-3- (methyl su f nyl) phenyl1) -2 (rethyl- pyridinyl) pyridine; C3) 2- (3 5-difluorophenyl) (methylsulfanyl)phenyl) -2cyr-lopenten-1-one; is C4)

H

2

NO

2

S

CH

3

N

N

CF

3 4- (4-methyiphenyl) (trifluoromethyl) -1Hpyrazol-1-yl) -benzenesulfonamide; -106rofecoxib, 4- (methylsulfonyl)phenyl] -3phenyl-2 (5H) -furanone; C6) 4- (S-methyl-3-phenylisoxazol,-4yl benz enesul fonamide; N- (5-methyl-3-phenylisoxazol- 4y1] phenyl] sul fonyl ]propaiaiide; -107c8) (4-chorOPhelyl) (trif luoronethyl) -1Hpyrazole-1-yl] benzenesulfcinamfide; C9) 0 cI N OH 0. CF 3 cI dlO) Cil) 0 N.j r

N

N

NH

0 6- [5 (4 -cbiorobenzoyJl) 1, 4-dimethyl -ilpyrroJ.-2-ylJ methyl] -3 (2H) -pyridazinone; -108- C12)

NO

2 N- (4-nitro-2-pheloxyphelyl )methanesulf onamide; C13) 0 N. 0C 2

H

N 0 CF, 3

CI

C14) 3- 4-dif luorophenoxy) -5,5-dimethyl-4- [4- (methylsulf onyl) phenyl]1 -2 (5H) -furaflone; -109-

NHSO

2

CH

3

F

K- F 0 N- C2.4-difluorophenyl)thio] -2,3-dihydrooxo-1H-ildefl-5-y1 ]methanesulfonanide; 016) 3- (4-chiorophelyl) [4- (methylsulfonyl)phell-2 (3H) -oxazolone; 017) 4- (4-f luorophenyl) 3-dihydro-2-oxo-4oxazolyl] benzenesulfonanide; -110- C18) 3- (methylsulfonyl)phenyl) -2--phenyl--2cyclopenten-1-one; C19) 4- (2-methyl-4-phenyl-5oxazolyl )benzenesulfonamide; C2 0) F,_a 0 3- (4-f luorophenyl) [4- (methylsulfonyl)phenyl3 -2 (3H)-oxazolone; -111- C2 1) CHi 3 o zi

CF

3

F

(4-fluorophenyl) (methylsulfonyl)phelyl] (trifluoromethyl) JH-pyrazole; C22)

NH

2 os

A

4- [5-phenyl) (trifluoromethyl) -1H-pyrazol-1l) benzenesulfonanide; C23)

CF

3

H

2

NN,

0 0 4- [1-phenyl-3- (trifluoromethyl) yl~benzenesulfolaide; -112- C24) 4- (4-f luorophenyl) (trifluoromethyl) -lHpyrazol-1-yl]I benzenesulf onanide; N0 2 N- (cyclohexyloxy) -4nitrophenyl )methanesulfonamide; C2 6) N- C[6- 4 -di fluorophenoxy) 3 -dihydro-1 -oxo- 111- inden- 5 -ylJ ethanesulf onanide; -113- C27) N HSO 2

CH

3 3- (4-chiorophenoxy) -4- [(methylsulfolyl) aminolbenzenesulfocifide; C28)

NHSO

2

C-

3

H

2 N 3- (4-f luorophenoxy) -4- [(methylsulfonl)aio]belzeelUfoflide; C2 9)

NHSO

2

CH

3

CH

3- E(1-methyl-lH-imida~zol-2-Yl) thiol -4 [(methylsulfonly) aininolbenzenesu-folamtide; -114-

CH

3

H

3

CCH

47~ 0 o 5-dimethyl-4- (methylsulfonyl)phenl -3phenoxy-2 (511)-furanone; C3 1) N HSO 2 C H 3

CH

3 0 (4-ethy-2thiazoly)thioV-1,3dihydrOmethanesulfolaide; C32)

NHSO

2

CH

3

CI

0 (2.4-dichlorophenyl)thiol- 4 [(methylsulfonyl) aminolbenzelesulfoflaide; -115- C3 3) 1-fluoro-4- [4- (methyl suif onyl) phenyl] cyclopentel-lylJ benzene; C3 4) 4- (4-chlorophenly) (difluoromethyl) -1Hpyrazol -1 -yl Ibenzenesul fonainide; -116- C3 3- (rethylsulfonyl)phell-4- (trifluoromethyl) -1H-imidazol-2-yl]pyridile; C3 6) 4- (3-Dyridinyl1) (trifluoromethYl) -11imidazol-l-yl Ibenzenesulfoamfide; -117- C37) N 0 HA,

CH

2 0H 0 0 4- (hydroxymethyl) -3-phenylisoxazol-4yl) benzeraesulfonamide; C3 8)

H

2

NN,

4- (4-chiorophenyl) 3-dihydro-2-oxo-4oxazoly. benzenesulfonanide; C39) 0 I2

CF

2

H

0 0 4- (di fluoromethyl) 3-phenyli soxazol -4yl] benzenesulfonlide; -118- C4 0) ,1m-terpheiy3-4-sufflfaide; C4 1) 4-(methylsulfonyl)-1,1' ,1"-terphenyl; C42) 4- (2 -phenyl-3 -pyridinyl) benzenesulfonanide; -119- C43)

NHSO

2

CH

3 0 N- 3 -dihydro-1, 1-dioxido-6 -phenoxy-1, 2 methanesulfonamide; and C44)

N~N

b0 N- (formylamino) -4-oxo-6-phenoxy-4H-1benzopyran-7- yl) methanesulfonamide; 0 0-Na+ 0 CF 3 cI 46) 0 Il

NH

2 0 CF 3 cI -120- More preferred COX-2 inhibitors that may be used in the present invention are selected from the group consisting of: Cl) JTE-522, 4- (4-cyclol'exyl-2-methyloxazol-5-yl) 2 -fluorobenzenesulfonamide; -121- -chl oro -3 (4 (methyl sul f orn4) phenyl) 2- (me thyl -5 pyridiny1) pyridine; 2- 5-difluorophenyl) (rethylsulfoflYl)PhelYl) -2cyclopenten--ofle; C4) 4- (4-methyiphenyl) (trif luoromethyl) -1Hpyrazol -1-yl] -benzenesulfolamfide; rofecoxib, 4- (methylsulfonlY) phenyl] -3phenyl-2 (5H) -furanone; -122- C6)

H

2

NO

2

S

H

3

C

4- (5-methyl-3 -phenylisoxazol-4 yl) benzenesulfonamide; C7) N- (5-methyl-3-phenylisoxazol- 4yl] phenyl] sulforayl] propanamide; C8)

NK

2

CF

3 C1 4- (4-cho rophenyl) -3 (trif luoromethyl) -lHpyrazole-1-yl ]benzenesulfonamide; Still more preferably, the COX-2 inhibitors that may be used in the present invention include, but are not limited to celecoxib, valdecoxib, parecoxib, rofecoxib, and Japan Tobacco JTE-522.

I

-123- Dosage of MMP and COX-2 Inhibitors Dosage levels of MMP and COX-2 inhibitors on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 1.0 mg to about 1,000 mg. The amount of active ingredient that may be combined with other anticancer agents to produce a single dosage form will vary depending upon the host treated and the particular mode of administration- It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated and form of administration.

Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro initially can provide useful guidance on the proper doses for patient administration.

Studies in animal models also generally may be used for guidance regarding effective dosages for treatment of cancers in accordance with the present invention. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular patient, etc. Generally speaking, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with

I

-124the concentrations found to be effective in vitro. Thus, where an compound is found to demonstrate in vitro activity at, 10 pM, one will desire to administer an amount of the drug that is effective to provide about a 10 pM concentration in vivo. Determination of these parameters are well within the skill of the art.

These considerations, as well as.effective formulations and administration procedures are well known in the art and are described in standard textbooks.

Administration Regimen Any effective treatment regimen can be utilized and readily determined and repeated as necessary to effect treatment. In clinical practice, the compositions containing a MMP and COX-2 inhibitor alone or in combination with other therapeutic agents are administered in specific cycles until a response is obtained.

For patients who initially present without advanced or metastatic cancer, a MMP and COX-2 inhibitor in 'combination with radiation therapy, is used as a continuous post-treatment therapy in patients at risk for recurrence or metastasis (for example, in adenocarcinoma of the prostate, risk for metastasis is based upon high PSA, high Gleason's score, locally extensive disease, and/or pathological evidence of tumor invasion in the surgical specimen). The goal in these patients is to inhibit the growth of potentially metastatic cells from the primary tumor during surgery

I

-125and inhibit the growth of tumor cells from undetectable residual primary tumor.

For patients who initially present with advanced or metastatic cancer, a MMP and COX-2 inhibitor in combination with radiation therapy of the present invention is used as a continuous supplement to, or possible replacement for hormonal ablation. The goal in these patients is to slow or prevent tumor cell growth from both the untreated primary tumor and from the existing metastatic lesions.

Also included in the combination of the invention are the isomeric forms, prodrugs and tautomers of the described compounds and the pharmaceutically-acceptable salts thereof. Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.

Suitable pharmaceutically-acceptable base addition salts of compounds of the present invention include metallic ion salts and organic ion salts. More preferred metallic ion salts include, but are not limited to appropriate alkali metal (group la) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metal ions. Such salts can be made from the ions of -126aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part,, trimethylamine, diethylamine,

N,N'-

dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine

(N-

methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.

A MMP or COX-2 inhibitor of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975. Another discussion of drug formulations can be found in Liberman, H.A. and Lachman, Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, 1980.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be -127formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules.

In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, a contemplated -128aromatic suif one hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidole, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.

Such capsules or tablets can contain a controlledrelease formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In, the case of capsules, tablets, and pills, the dosage forms can also compri~e buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate.

-Tablets and pills can additionally be prepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. A contemplated MMP or COX-2 inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions,

I

-129solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.

Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.

The phrase "antineoplastic agents" includes agents that exert antineoplastic effects, prevent the development, maturation, or spread of neoplastic cells, directly on the tumor cell, by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification. There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in preclinical development, which could be included in the present invention for treatment of neoplasia by combination drug chemotherapy. For convenience of discussion, antineoplastic agents are classified into the following classes, subtypes and species: ACE inhibitors, alkylating agents, angiogenesis inhibitors, angiostatin, anthracyclines/DNA intercalators, anti-cancer antibiotics or antibiotic-type agents, antimetabolites, antimetastatic compounds, asparaginases, -130bisphosphonates, cGMP phosphodiesterase inhibitors, calcium carbonate, cyclooxygeflase- 2 inhibitors DHA derivatives, DNA topoisomerase, endostatin, epipodophylotoxlfls, genistein, hormonal anticancer agents, hydrophilic bile acids (URSO), immunomodulators or immunological agents, integrin antagonists interferon antagonists or agents, MM? inhibitors, miscellaneous antineoplastic agents, monoclonal antibodies, nitrosoureas, NSAIDs, ornithine decarboxylase inhibitors, pBATTs, radjo/chemo sensitizers/protectors, retinoids *selective inhibitors of proliferation and migration of endothelial cells, *selenium, stromelysin inhibitors, taxanes, vaccines, and ymnca alkaloids.

I

-131- The major categories that some preferred antineoplastic agents fall into include antimetabolite agents, alkylating agents, antibiotic-type agents, hormonal anticancer agents, irmunological agents, interferon-type agents, and a category of miscellaneous antineoplastic agents. Some antineoplastic agents operate through multiple or unknown mechanisms and can thus be classified into more than one category.

A first family of antineoplastic agents which may be used in combination with the present invention consists of antimetabolite-type antineoplastic agents. Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids. Suitable antimetabolite antineoplastic agents that may be used in the present invention include, but are not limited to acanthifolic acid, aminothiadiazole, anastrozole, bicalutanide, brequinar sodium, capecitabine, carmofur, Ciba-Geigy CGP-30694, cladribine, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, cytarabine ocfosfate, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck Co. EX-015, fazarabine, finasteride, floxuridine, fludarabine phosphate, Daiichi Seiyaku FO-152, fluorouracil fibrinogen, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, nafarelin, norspermidine, nolvadex, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical -132- PL-AC, stearate; Takeda TAC-788, thioguanine, tiazofurin, Erbainont TIF, trirnetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho tJFT, toremifene, and uricytin.

Preferred antimetabolite agents that may be used in the present invention include, but are not limited to, those identified in Table No. 6, below.

Table No. G6.

Antimetabolite agents capomd CCC=C~ azW Referen~e Dosage ____rade Name_ 1,3- anastrozole Zeneca EP 296749 1-np/day Benzeneiaceto ;ARMl'EXD nitrile, alpha, alpha, alphar a (1H-l,2,4triazol-l-ylMe thyl) Propanarnide, bicalutamnd Zeneca EP 100172 50 ing once N-[4-cyano-3- e; CASQDEK daily (trif luorometh yl) phenyl] -3 (4f luorcphenyl) sulfonyl] -2hydroxy-2methyl-, cape citabin Roche US 5472949 e Adenosine, 2- cladribine; Johnson &EP 173059 0.09 chloro-2 2-CdA; Johnson rag/kgf/day deoxy-; 2- LEtJSTAT; f or 7 chloro-2 LEtJSTA- days.deoxy- (beta) TIM; D-adenosine) LEEJSTA-TINM in-jection;

LEUSTATINBV

RWJ -133- CcZrpc~md CM cciapazy Reference Dosage Naml~ Trade Name 26251; 2 (iH) cytarabine Yamasa, EP 239015 100 300 Pyrimidinone, ocf osf ate; Corp mrg/day f or ara C42 2 weeks 0- stearyl (hydroxy(octad ester; Cecyloxy) phosph 18-PCA; inyl] -beta-D- cytarabine arabinofuranos phosphate Y11-1stearate; monosodium Starasid; salt YNK-01; CYTOSAR-TJ 4-Azaandrost- f inasteride Merc=k EP 155096 1-ene- 17- ;PROPCI& Co carboxamL.e, N- (1,1dimethylethyl) l7beta fluorouraci 'S 4336381 1 (5-FJ) Fludarabine ~fludarabine Southern US 4357324 25 rgm2/ phosphate. phosphate; Research TVoe 9H-Purin-6- 2-F-araA4P; institutepeido amine, 2- Fludara; ;Berlex prx Fluxdara iv; imately phosphono- Fludara. minutes beta- D- oral; NSC- daily for arabinofuranos 312887; SE- 5 on yl) 573; SH- secutive 584; SH days, 586; cnced every 28 days.

gemcitabi Eli Lily US 4526988 ne methotrexat Hiyal JS 2512572 trcphcdiamino- 6- e iv, Hyal; Pharma- blastic pteridinyl )met HA ceutical; diseases: hyl)metwylamifl rrethotreat Arterican 15 to o) benzoyl) e, 3ya; IHme g/d -134- Cctpacud CCU== Cczzpai Referezce Dosage Hame/ Txade !N glutaric acid methotrexat Products; orally or e iv, =rr Lederle intra- Technolog; muscularly in a fiveday course (repeated 3 to times as needed) Luteinizing nafarelin Roche EP 21234 hormonereleasing factor (pig), naphthalenyl) D-alaninel pentostatin Warner- US 3923785 CI-825; Laibert deoxycoform ycln; Nipent; NSC-218321; _Oncopent; Ethanamine, 2- toremifene; Orion EP 95875 60 rg/d (4-chloro- FARESINS) Phaxna 1, 2-diphenyl 1butenyl) pheno y] Ndimethyl-, A second family of antineoplastic agents which may be used in combination with the present invention consists of alkylating-type antineoplastic agents. The alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases in DNA, arresting cell division. Typical alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas. A -13 disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestiflal mucosa, and fetal tissue. Suitable alkylating-type antineoplastic agents that may be used.

in the present invention include, but are not limited to, shionogi 2,54-S, aldo-phosphamfide analogues, altretamfifle, anaxirone, Boehringer MNannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine (BiCNU), Chinoin-139, Chinoin-153, chiorainbucil, cisplatil, cyclophosphamfide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, dacarbazine, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiroDustine, diplatinum ctsai, Erba distalnycin derivatives, Chugai DWA-2114R, ITI E09, elmustile, Erbamont FCE-24517, estramustine phosphate sodium, etoposide phosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfainide, iproplatin, lomnustine, mafosfainide, mitolactol, mycophenolate, Nippon Kayaku NK-121, NCI NSC-26439 5 NCI NSC-34 2215 oxaliplati', Upjohn PCNU, precdnimustine, Proter PTT-119, ranjjnustifle, semustine, SmithKline SK&F-1017 72 thiotepa, Yakult Honsha SN-22, spiromus-tile, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirole, tetraplatin and trimelamol.

Preferred alkylating agents that may be used in the present invention include, but are not limited to, those identified in Table No. 7, below.

Table No. 7. 30 Tale N. 7. Alkylating agents -136- Cwpo~Hd Ccpazn Ref ermcxe Dosage ?0zrw/ Trade Platinum, carboplatin; Johnson US 4657927. 360 rg/rn( dialrrnne 1, 1 pARAPLA.T2N a matthey US 4140707. squared) -cyclobu- INV. on tanedicarbox dayl1 ylato every 4 (SP-4-2) weeks.

Caxnaustine, BiCNU= Ben Venue JP MA 1985; Preferred: 1, 3-bis Labora- 253 150 to 200 chloroethyl) tories, 1590-1592. Mg/ m2 -1-nitro- Inc. every 6 sourea etoposide Bristol- US 4564675 phosphate Myers thiotepa Platimin, cisplatin; Bristol- US 4177263 dianmiinedi- PLATINOL-AQ Myers chioro-, Squibb (SP-4-2) dacarbazine DrIC D~re ]Bayer 2 to ay for days; square meter body surface! day I.V.

for 5 days every 3 weeks ifosfanide iFXBristol- 4-5 g/m Meyers (square) Squibb single bolus dose, or 1. 2 -2 g/m (square) INV. over days.

cyclophosph US 4537883 amide__ cis- Platinol Bristol- 20 mgM -137- Ccqpound cmcny Ref erence IDsage Nm/Tr~ade Name_ dianinedichl Cisplatin Myers IV daily oroplatinum Squibb for a clay cycle.

A third family of antineoplastic agents which may be used in comibination with the present invention consists of antibiotic-type antineoplastic agents.

Suitable antibiotic-type antineoplastic agents that may be used in the present invention include, but are not limited to Taiho 4161-A, aclarubicin, actinomycin D, actinoplanone, Erbarnont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY- 25067, Bristol-M~yers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BlAY-28-438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chroinoximycii, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Iiakko DC-79, Kyowa Rakko DC- 88A, Kyowa Hakko DC89-Al, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperainicin-Al, esperaxnicin-Alb, Erbaznont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincainycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KJA-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT- 5594, Kyowa Hakko KT-6149, American Cyanamnid LL-D49194, Meiji Seika ME 2303, ienogaril, mitomycin, Initoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, -138- Nippon Kayaku NKT-O1, SRI International NSC-357704, oxalysine, oxaunomlycin, peploinycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA- I, rapaxnycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand.SN-07, sorangicin-A, sparsoniycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A:, F'ujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

Preferred antibiotic anticancer agents that may be used in the present invention incluae, but are not limited to, those agents identified in Table No. 8, below.

Table No. 8. Antibiotic anticancer agents Ccupouzid CazM~zn ?Na r/ C~na=Y Reference Dosage Trade Naue_ 4-Hexenoic imycopheno- Roche WO 91/19498 1 to 3 acid, 6- 3- late mofetil grn/d hydroqr-6methaxy-7 isobenzofurarryl -4-methyl-, 2- (4morpholinyl) eth yl ester, mitoxan- US 4310666 trone __________doxorubicin 3590028 Mitomycin Miitamycin Bristol- After and/or Myers full mitarm'cin-C Squibb hernato- Oncology! logical Immiun- recovery ology from any -139- Cmpound Ccannon Name/ Ocupany Reference Dosage Trade Name chemotherapy: 2 rg/m intravenously as a single dose via a functioning intravenous catheter.

A fourth family of antineoplastic agents which may be used in combination with the present invention consists of synthetic nucleosides. Several synthetic nucleosides have been identified that exhibit anticancer activity. A well known nucleoside derivative with strong anticancer activity is 5-fluorouracil Fluorouracil has been used clinically in the treatment of malignant tumors, including, for example, carcinomas, sarcomas, skin cancer, cancer of the digestive organs, and breast cancer. 5-Fluorouracil, however, causes serious adverse reactions such as nausea, alopecia, diarrhea, stomatitis, leukocytic thrombocytopenia, anorexia, pigmentation, and edema. Derivatives of fluorouracil with anti-cancer activity have been described in U.S. Pat. No. 4,336,381. Further derivatives have been described in the following patents listed in Table No. 9, hereby individually incorporated by reference herein.

Table No. 9. 5-Fu derivatives JP 50-50383 JP 50-50384 JP 50-64281 -140- JP 51-146482 JP 53-84981 U.S. Pat. No. 4,000,137 discloses that the peroxidate oxidation product of inosine, adenosine, or cytidine with methanol or ethanol has activity against lymphocytic leukemia. Cytosine arabinoside (also referred to as Cytarabin, araC, and Cytosar) is a nucleoside analog of deoxycytidine that was first synthesized in 1950 and introduced into clinical medicine in 1963. It is currently an important drug in the treatment of acute myeloid leukemia. It is also active against acute lymphocytic leukemia, and to a lesser extent, is useful in chronic myelocytic leukemia and non-Hodgkin's lymphoma. The primary action of araC is inhibition of nuclear DNA synthesis. Handschumacher, R. and Cheng, "Purine and Pyrimidine Antimetabolites", Cancer Medicine, Chapter XV-1, 3rd Edition, Edited by J. Holland, et al., Lea and Febigol, publishers.

is a cytidine analog that is primarily used in the treatment of acute myelocytic leukemia and myelodysplastic syndrome.

(Fludara, also referred to as FaraA) is one of the most active agents in the treatment of chronic lymphocytic leukemia. The compound acts by inhibiting DNA synthesis. Treatment of cells with F-araA is associated with the accumulation of cells at the G1/S phase boundary and in S phase; thus, it is a cell cycle S phase-specific drug. InCorp of the active metabolite, F-araATP, retards DNA chain elongation. F-araA is also a potent inhibitor of

I

-141ribonucleotide reductase, the key enzyme responsible for the formation of dATP. 2-Chlorodeoxyadenosine is useful in the treatment of low grade B-cell neoplasms such as chronic lymphocytic leukemia, non-Hodgkins' lymphoma, and hairy-cell leukemia. The spectrum of activity is similar to that of Fludara. The compound inhibits DNA synthesis in growing cells and inhibits DNA repair in resting cells.

A fifth family of antineoplastic agents which may be used in combination with the present invention consists of hormonal agents. Suitable hormonal-type antineoplastic agents that may be used in the present invention include, but are not limited to Abarelix; Abbott A-84861; Abiraterone acetate; Aminoglutethimide; anastrozole; Asta Medica AN-207; Antide; Chugai AG-041R; Avorelin; aseranox; Sensus B2036-PEG; Bicalutamide; buserelin; BTG CB-7598; BTG CB-7630; Casodex; cetrolix; clastroban; clodronate disodium; Cosudex; Rotta Research CR-1505; cytadren; crinone; deslorelin; droloxifene; dutasteride; Elimina; Laval University EM-800; Laval University EM-652; epitiostanol; epristeride; Mediolanum EP-23904; EntreMed 2-ME; exemestane; fadrozole; finasteride; flutamide; formestane; Pharmacia Upjohn FCE-243047 ganirelix; goserelin; Shire gonadorelin agonist; Glaxo Wellcome GW-5638; Hoechst Marion Roussel Hoe-766; NCI hCG; idoxifene; isocordoin; Zeneca ICI- 182780; Zeneca ICI-118630; Tulane University J015X; Schering Ag J96; ketanserin; lanreotide; Milkhaus LDI-200; letrozol; leuprolide; leuprorelin; liarozole; lisuride hydrogen maleate; loxiglumide; mepitiostane; Leuprorelin; Ligand Pharmaceuticals LG-1127; LG-1447; LG-2293; LG-2527; LG- -142- 2716; Bone Care international LR-103; Lilly LY-326315; Lilly LY-353381-HCl; Lilly LY-326391; Lilly LY-353381; Lilly LY-357489; miproxifene phosphate; Orion Pharma MPV-22l3ad; Tulane University MZ-4-71; nafarelin; nilutainide; Snow Brand NKS0l; octreotide; Azko Nobel OI~R- 31710; Azko Nobel ORG-31806; orimeten; orimetene; orimetine; ormeloxifene; osaterone; Smithkline Beecham SKB-105657; Tokyo University 0SW-l1; Peptech PTL-03001; Pharmacia Upjohn PNU-156765, quinagolide; ramorelix; Raloxifene; statin; sandostatin LAR; Shionogi S-10364; Novartis SMT- 487; somavert; somatostatin; tamoxif en; tainoxifen methiodide; teverelix; toremifene; triptorelin; TT-232; vapreotide; vorozole; Yamanouchi YM-l16; Yamanouchi YM- 511; Vainanouchi YM-55208; Yamanouchi YM-53789; Schering AG ZK-1911703; Schering AG ZK-230211; and Zeneca ZD- 182780.

Preferred hormonal agents that may be used in the present invention include, but are not limited to, those identified in Table No. 10, below.

Table No. 10. Hormonal agents Ccxnpoumd CcIETVD Cbcmpany Refewenie D~osage Trade 2- EntreMed; Entre~e methoxyestradiol 2-M d N-CS)- A-84861 Abbott tetrahydrofurcyl -Gly-D2Nal- D4ClPhe-D3Pal- Ser-Meyr- DMys (Nic) -Leu- LYS (Isp -Protraloxi -143- Ccupouzd uMcc Caipany Refereice Dosage Nqame/ Trade f fene_____ A~G-041R Ca-ugai WO 94/19322 Dimethoxyethyl) methyiphenyl) ai noca-boylmithyr1 (4-me thylp-hezyl) ureid o) -indoline-2one]__ AN-207 Asta WO 97/19954 medica Ethanainine, 2 toreinif- Orion EP 95875 60 ng/d (4-chloro- ene; Phannm 1, 2 dipherryl-1- FA1RESTCMN butenyl) phenoxyrI N-dimethyl- Ethananine, 2- tartoxifen zeneca US 4536516 For NOLVADEX( patients diphenyl-l- R) with butenyl )phenoxy] breast N-dixnethyl-, cancer, WZ- the recamende d. daily dose is 20-40 inx.

Dosages greater than 2 0 ing per dlay should be divided (Mmrning and D-Alaninamide N- Antide; Ares- VJ0 89/01944 25 or acetylL-3- ORF-23541 Serono naphthalenlyl) kg sc alanryl-4-chloro- D-phenylalanyl- 13-(3_ -144- ZCmpmnd Ccpmwz~ JWerence Dosage Mqaze/ wZade N pyric3inyl) -Dalanyl-L-seryl- N6- (3pyridinylcarbony 1) L-lysyl-N6- (3 -pyridinylca rhonyl) -D-lysyl- L-leucylI-NG- (1methylethyl) -LlYyl-L-prolyl B2 03 6-

PEG;

Samaver; Trovert Sensus 4-methyl-2- EM-800; Laval EMv-652 Univers.

piperidiriyl) etb~o ity xyl phenyl)3 -7 (pivaloyloxy) -3- (pivalcylox y)phenyl] -2H-1benzopyran letrozol 4749346 US 4100274 GW-5638 Glaxo Dipheriyl- I Weilcam butenyl]I pheny 22 llI e 2 (B)-propenoic acid Estra-1, 3, 5(10) ICI- Zeneca EP 34/6014 250nrjlmth triene-3,17- 182780; diol, Faslodex; ZD-182780 pentafluoropentyl) Sulfinyll nonyllI (7alpba, 17beta) muiane Univers WG-11.27; Ligatid LG-1447 Pharmac -145- Comd ci Cc~va Ref erm Dosage Name/ Trade eutical, LG-2293 Ligand Phaxmac eutical

S

LG-2527; Ligand LG-2716 Pban-ac eutical

S

buser- Peptech elin,.

Peptech; deslorelin, Peptech;

FIL_-

03001; triptorelin, Peptech LR-103 Bone Care Iriterna LY-326315 Lilly WO 9609039 hydrcxjphenyl) 6hydraxynaphthale n-1-y1j (1piperdinyl) ethox y) pheny l1methane hydrochloride LY- Lilly 353381- HCJ. LY-326391 Lilly LY-353381 Lilly LY-3 57489 Lilly MPV- Ori on EP 476944 0.3-300 mg 1Pharma -146- C=P=MO Um1 CbmIwW Reference Dosage Trade Isabutyzy].-Ty~r- JY-4-71 'b.l1ae D-Arg-App-Ala- tUnivers le- (4-Cl) -Phe- ity rfhr-1Asn-Ser-Tyr- Arg-Lys-Val-Ljeu- (2miindbutyry1) Gln-Leu-Ser-Ala- Arg-Lys-Leu-Leu.- Gin-Asp- Ile-Nie- Ser 4gjanidinobu tylamride 7Androst-4-ene- NKS01; snow EP 300062 3,6,17-trione, l4alpha.- Brand 14-hydroxy- HT 3beta, l6beta, 17a iphatrihydroxytholes t-S-en-22-one- 16-0- (2-0-4methoxybenzoyrlbeta.-D-xy lopyranosyl) (1- 3) alpha-Larabinopyranosid e) Spiro [estra-4, 9- Org- Akzo EP 289073 diene- 31710; Nobel Org-31806 furani -3-one, 11-[4- (dirnethylaTmino) p dihxydro-6methyl-, (Gbeta, llbeta, 17 (22RS) 1, 1- PN-Phanuac trifluoro-2- 156765; ja. phenyiprop-2- FCE-28260 Upjohn -147czpwdckm Coan~y Reere DOSAge yl) -3-axo-4-aza- 1-eae-17beta carboxamide 1- [(benzofuzan- Menarin 2yl)-4- i ch:lorophenylmeth yl] inidazole Tryptamine Rhone- M 96/35686 derivatives Poulenc Rorer Permanently Phannos M) 95/26720 ionic deriva.tives of steroid hormones and their antagonists Novel Meiji MO 97/30040 tetrahydronaph Seika tho furanone derivatives S~ff-487; Novarti s octreo- D-Phe-Cys-Tyr-D- TT-232 Ttp-Lys-Cys-Thr- 2 (H-imidazol- YM-116 Yalnanou 4-ylmethyl) -9H- -chi carbazole nonhyclrochiorid e monohydrate 4-N-4-YM-511 Yamanou bromobenzyl) -chi (4cyanophenyl) axnin ol -4H-l,2, 4triazole J2-(1H-irnidazol- 1_YM-55208; IYainanou -148- Cm~pwtd Q~m ccuzmy Reference 1Dzmage Tade 4-ylmethyl) -9H- YM-53789 -ci carbazole rronohydroch]lorid e monohdrate ZK- Scherin g AG ZK-23 0211 Scherin g AG_ abarelix Praecis Pharma~c euticals Androsta-5,16- abira- B'IG dien-3-ol, 17- terone Q3-pyridiflyl) acetate; acetate (ester), CB-7598; (3beta.)- CB-7630 2,6- mninoglut Novarti. US 3944671 Piperidinedione, ethirnide; s 3-(4-Cibaarinophenyl) 16038; ethyl- Cytadren; Elimina; Orimeten; Orimetene; 1,3- anastro- Zeneca EP 296749 1rrg/day Benzenediacetorli zole; trile, alpha, aiph Arimidex; a,a2lpha' alpha'- iCI- D1033; (1H- 1, 2, 4- ZD-1033 triazol-1-ylne thyl) avorelin; Medi- EP 23904 L-histidyl-L- meterelin olanumn tryptophyl-Lseryl-L-tyrosyl- 2 -retbyl-Dtryptophyl- Lleucyl-Largmnyl -N-ethyl- -149r~sage L-prolinaide Namre/ Trade Qbmany Ref erence i Dosage I ~P lrJUi12 propanamide, N- [4-cyano-3- (trifuorofletl phenyl -3 (4fluorophenlyl) sulfonyl) -2hjydroxy- 2 mty'l-, bicalutam ide; Casodex; Cosudex;

ICI-

176334 Zeneca EP 100172 4 t I

I

Luteaflizing hormonereleasing factor (pig), 6-[0- 1dimnthylethyl) D-seririe)

(N-

ethyl-Lprolinamide) -10deglycinarnide- D-AlaniJnaUde, N-acety1-3- (2naphtha]lenyl) -Dalanyl-4-chloro- D- phenyla]l&iyl- 3- (3-pyridiny-) D-aJlafyl-Lseryl-L-tyrosYl- (amrinocarbanyl) D-ol-L-leucyl-Larginyl-L- Iprolylbusereliii; Hoe- 766; Prof act Receptal; S-74 6766; Suprecor; Suprecur; Suprefact; Suprefakt Hoechst Marion Roussel

CB

15/23 623 200-600 maicrog/ day

T

EP 29/9402 cetrorelix; SB-075; Asta Medica EP 29/9402 -4 1 I Schern.fl phosphonic acid, (dichbloromethyle ne) bis disodiizn salt- Luteiniziflg hormoneclodronate disodium, Leiras; Bonef os; Clastoban; KCX)- 692 deslorelin; g AG !Roberts US4034082 -150- Namre/ Trade Naum mnamv I Pef exlce 4 1 releasing factor (pig), G-Dtryptophan-.9-

(N-

ethyl-Lprolinamide) -10deglycinan-ide- Phenol, 3-[l144- [2- (dimethylaiino) e thoxy] phenyilI -2 phenyl-1butenyl]-, ICA S) 4-Azaandrost-lene-17carbamide,

N-

bis (trifluoranet hyl)phenyl) -3oxo-, Sai2 pha, i~heta) gonadorelin analogue, Roberts;

LHRH

analogue, Roberts; Somagard droloxifene; FK- 435; K- .060; K- 21060E; RE' 60850 dutasteride; GG- 745; GI- 198745 Klinge IEP 54168 Glaxo wellcon e 4. 1- I i Androstan-17--ol, 2, 3-epit-i-o-, (2alpha,3alpha' 1 alpha, l7beta) Androsta-3, 5diene-3 carboxylic acid, 17-( dimethylethyl) am ino) carbonyl) (l7beta)epitiostanol; 10275-S; epithioan drostan- 01; s- 10275; Thiobrestin; Thiodrol epristeride; ONO -93 02; 105657; SKE 105657 Shionog Smith- Kline Beecham us 3230215 EP 289327 0.4- 16Oiq/ day 4 1 estrone 3-0sulfarnate estrone sulfainate i i -151- C -VU C-i Trade 19 -Norpreglna- 1, 3,5 (10) -triex- 20-yne-3, 17diol, 3- (2propanesu fonate ),(17alpha) ?Androsta-1, 4diene-3, 17dimne, 6inetlrjleneethirn'1 estradiosulfonate; J96; Turisteron schierin g AG DE 1949095 -J i I e.xcmestane; BtE-243 04 Pharnac ia Upjohn DE 3622841 Smg/kg IP I bU ~p Benzonitrile, 4- (5,6,7,8tetraiydroinm2idaz mo~nohydrochlorid e 4-Azaandrost-lene-17carbcammide, N- (1,1dimethylethfyl) 3-oxofadrozole; ZAfemi; Arensin;

CG~S-

16949;

CGS-

1694 9A;

CGS-

20287; fadrozole monohytdro chloride finasteride; Andozac; ChibroPro scar, Finastid; MK-0906; MK-906; Procure; Prodel; propecia; Proscar; Proskar; Prostide; ym-152 Novarti

S

Ey 165904 EP 155096 bid I Us 4329364 1 propariamide, 2 methyl-N- t I nitro-3 (trif luorcim~thyl phenyl]I f lutamide Dogenil; Euf lex; Eulexin; Scherin g Plough IUS 4399364 1

L-

-152- Cmwvound m m cupay Ref erence Dosage Trade Eulecine; Flucinom Flutanida Fugerel; NK- 601; Odne; Prostogen at; Sch- Androst-4-ene- formest- Novarti EP 346953 250 or 3,17-dione, 4- ane; 4- s 600mrg/day hydroxy- HAD; 4 PO OHA; CGP- 32349;

CGRC-

82 /01; Depot; [N-AC-D-Nal, D- ganirel- Roche EP 312052 pci-The, D-Pa1,D- ix; OrghArg(Et)2,bArg(E 37462; t) 2,D-AlaGnRH- RS-26306 gonadore- Shire 2-in agonist, Luteinizing goserel- Zeneca US 4100274 hormone- in; ICireleasing factor 118630; (pig), 6- [O0- Zoladex; Zoladex diinethylethyl) LA D-serine) deglycinamide-, 2- (aminocarbonyl) h ydrazide_____ hCG; Milkhau gonadotro s phin; LDI-200 I_ Ihuman I -153- Ccuzvouzd cCEM CMW Rference Dosage Name! Trade chorionic gonadotro hCG Pyrrolidine, 1- idoxifene BMI( EP 260066

;CB-

iodopheuyl) 7386; CBphErxy1-1- 7432; SBbutenyll3phenoy) 223030 et hylI isocord- Indena c 2,4(lH,3H)- ketanse- Johnson EP 13612 Quinazolinedione rin; Aseranox; Johnson fluorobenzoyl) Ketensin; 1- YJK-945; piperidinyllIethy ketanselii- rine; Perketan; R-41468; Serefrex; Serepress; Sufrexal; Taseron L-Threoninamide, lanreot- Beaufou EP 215171 3(-ide; r-Ipsen naphtbalenyl) A 7 ngiopept alanyl-L- in; BIMcysteixyl-L- 23014; tyrosyl-D- Dentppept tryptophyl-L- in; lysyl-L-valyl-L- Ipstyl; cysteinyl-, Sanatulcyclic ie disulfide Sanatuline Benzonitrile, betroz- Novarti EP 236940 ole; CGS- s triazol-1- 20267; ylrmthylene) bis- Femara Luteinizing leuprol- Atrix hormne- -154- Cm~anx1cmo CwPw Reference Dosage Name releasing factor Atrigel; (pig), leuprolleucine-9- ide, ethyl-L- Atr2ax prolinamid e) deglycinanide Luteinizing leupror- Abbott US 4005063 3. honnmie- elin; sc q 28 releasing factor Abbott- days (pig), 6-D- 43818; leucine-9- Carcinil; ethyl-L- Enantone; prolinamide) -10 Leuplin; deglycinamide- Lucrmn; Lupron; Lupron Depot; leuprolide, Ahbott; leuprolide, Taikeda; leuproreli, Takeda; Procren Depot;' Procrin; Prostap; Prostap SR; TAP- 144-SR Luteinizing leupror- Aiza hormo~ne- elmn, releasing factor DtJRDS; (pig) 6-D- leuprolid leucine-9- e, DUROS; etbyl-L- leuprorprolinatnid e) elin deglycinamide Comounda Cmn Ccuparn' Refemvce D=Me 1H-liaro- Johnson EP 260744 3 00mrg bid Be=zanidazole, zole; 5-[3-Liazal; Johnson chiorophenyl) Liazol; m-iinidazol-1- liaroylmethyl) zole fumrarate; R-7 5251; R-85246; Ro-85264 Urea, lisuride vuFB [(8alpba) -9,10- hydrogen didehydro-6- raleate; metfrflergolin-8- Cuva1~it; yl) N-diethyl- Dopergin; Dopergine butenedioate Euna1; (1:1)Lysenyl; Lysenyl Forte; Revanil Pentanoic acid, loxiglumi Rotta. M 87103869 3,4- de; CR- Researc dichlorobenzoyl) 1505 h axino]-5-[(3methoxypropyl) pentylanino] OX- Androstane, 2, 3- rnepitio'st shionog US 3567713 epithio-17- ane; S- i nethoxycyclopent 10364; yl) oxyl rThioderon (2alpha, 3alpha, alpa17beta) Phenol, 4- niproxif e Taiho WO 87/07609 ne (dimethylaxnino) e phosphate thoxy] phenryl 1 DP-TAT- 59; TATmthylethyl) 59 phenyl I -1Ibutenyl) dihydrogen -156c F ud Ccmi caxnaz Ref exence Dsg phosphate (ester), Luteinizing nafarelin Roche EP 21/23 4 horrrne- NAG releasing factor Syntex; (pig), Nasanyl; naphthalenyl) RS-94991; alanine]- RS-94991- 298; Synarel; Synarela; Synrelina 2,4- nilutam- Hoechst US 4472382 imidazolidinedio ide; Marion ne, 5,5- AnanTdron; Roussel dimethyl-3- IA- Nilandnitro-3- ron; (trifluoromepthyl Notost- )phenyl] ran; RU- 23908 obesity Lilly wo 96/24670 gene; diabetes gene; L-Cysteinamide, octreot- Novarti EP 29/579 D-phenylalagyl- ide; s L-cysteinyl-L- Longastphenylalanyl-D- atina,; tryptophyl-L- octreotlysyl-L- ide tbreoniyl-N- pamoate; hydroxy-1l- Sandost- (1rdronethy1 )p atin; ropylJ-, cyclic Sandostat in ILAR; disulfide, Sandost- R*)J atina; Sandostatine; SMS-201- 995 Pyrrolidine, 1- ormelox- Central Th 329201 -157- Ocuoomd CCzum CCUxPaW Ref ~eve DOmg Namrn (2-(-(7-ifene; Drug methoxy-2,2- 6720- Researc dimethyl-3- CDRI; h Inst.

phenyl-4- Centron; chroanyl) Choice-7; phenoxy) ethryl I, ceritcbrom trans- an; Saheli 2-Cxcapregna-4, 6- osaterone Teikoku EP 193871 di.&xe-3, 20- acetate; Hozinone dione, 17- Iiipros; (acetyloxy) TZP-4238 -chioro Pregn-4-ene- progeste37 Colurabi 3,20-dione one, a Crinone, Laborat Sulfarnide, N, N- quinagol- Novarti EP 77754 dietlyl-N'I- ide; CV- S (1,2,3,4,4a,5,10 205-502; ,l0a-octabydro- Nor- 6-hydroxy-1- prolac; propylbenzo [glqu SIJZ-205inolin-3-yl) 502 (3alpha, 4aalpha, l0abeta)- L-Proline, 1- ramore- Hoechst EP 451791 (N2- lix; Hoe- Marion (N-acetyl- 013; Hoe- Roussel 3-(2-013C; naphtbalenyl) Hoe-2 013 alanyl) -4-chi oro-Dphenxylalanyl) -Dtryptcphyl) -Lseryl) -Ltyrosyl) deoxy-al1pha-Linannopyra nosyl) -D-seryl) L-leucyl) -Larginyl) 2- (aminocarbonyl -158- CCSTUpold CCUMxz CCEmnpn Ref ezrece DOsg Trad1e ydrazide--____ soiratosta Tulane tin tUnivers analogues ity Ethanmin, 2 tamoxi- Zeneca US 4536516 fen; diphenyl-l- Ceadan; butenyl) phenoxy) ICI- N-dimethyl-, 46474; 'Kessar; Nolgen; Nolvadex; Taf oxen, Tamof en; Tamoplex; Tamoxasta; Tainoxen; Toiaxen tamoxif en Phanns inethiodide__ Ethanamine, 2 tamoxif en Douglas dliplhenl-1buteyl phenoxyl N-dimethyl-, D-Alaninainide, tevere- Asta, N-acetyl-3- lix; Medica naphthalenyl) Antarelix alanyl-d-chloro- D-pheny lalanyl- 3- (3-pyridinyl) D-alanyl-Lsexyl-L-tyrosyl- N6- (miinocarbonyl) D-lysyl-L leucyl-N6- (1methylet1hrl) -Llysyl-L-prolyl- Etianiamine, 2- toremif Orion E-P 95875 6 Orrq po -159- Dosage 0cnw~ (4-cbloro- .1,2-diphenyl-lbutenyl) phenoxy) MZ Luteiniz2-ng hormonereleasing factor (pig) 6-Dtryptophan- Tzude COazMW Ref erewe Dosage 4 1 ene; Estrimex; Farestofl; FC-1157; FC-1157a; NK- 622 triptorelin;

ARVEKAP;

AY-25650; 21003; BN-52 104; Decap- Ky 4 2 4 2 2 Pharma Debiopbarm US 4010125 -t t EP 203031 ~uurnicrog vapreot- Debio- EP 203031 Tryptophanaflude, ide; EW- pbann sc rn D-pherylaJ-afyl- 41606; L-cysteinyl-L- Octastatyrosyl-D- tin; RCtryptphyl-L- 160 L-cystelinyl-, cyclic -disulfide 1H vorozole; Johnson EP 293978 Benzotriazole, R-76713; R-83842; Johnson chiorophenyl) Rivizor 1H-i, 2, 4triazol-lmet1hj1-_____ A Sixth family of antineoplastic agents which may be used in combination with the present invention consists of a miscellaneous family of antineoplastic agents including, but not limited to alpha-carotene, alpha-difluoroethyl-argiie, acitretin, Biotec Kyorin AHC-52, alstonine, amonafide, amphethinile, -160amsacrine, Angiostat, ankinomycin, anti-neoplaston antineoplaston A2, antineoplaston A3, antineoplaston antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparagilase, Ava-rol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM~-23O15, bisantrele, Bristo-Myers BI4Y-40481, Vestar boron-lO, brornofosfamide, Wellcome BW-502, Wellcome BW-773, calciumn carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane calcium carbonate tablets, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquiloxale, Chemes CHX-2053, Chemex CHX-100, Warner-Lamnbert CI-921, Warner-Lambert CI-937, Warner-Lamnbert CI-941, Warner-Lamnbert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Cell Pathways CP-461, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin

B,

cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinun, DFI4O, dideinf-B, dihaematoporphyril ether, dihydrolenperole, dinaline, distanycil, Toyo Pharmar DM-341, Toyo Pharmar Dajichi Seiyaku DN-9693, docetaxel, Encore Pharmaceuticals E78G9, elliprabin, elliptiniumf acetate, Tsumura EPMTC, ergotamile, etoposide, etretinate, Bnlexin®, Cell Pathways Exisulind®D (sulindac suiphone or CP-246), fenretinide, M4erck Research Labs Finasteride, Filorical, Fujisawa FR-57704, gallium nitrate, gemcitabine, genkwadaphnin, Gerimed, Chugai GLA-43, Glaxo GR-63178, grifolan hexadecylphosphOcholine, Green Cross HO-221, homoharriigtoflie, hydroxyurea, BTG ICRF-187, ilmofosine, irinotecan, isoglutamine, isotretinoin, Otsuka JI-36, Raxnot K-477, ketoconazole, Otsuak K- -161- 76COONa, Kureha chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leucovorin, levainisole, leukoregulin, lonidamne, Lundbeck LU-23-2.12, Lilly LY- 186641, Materna, NCI (US) MAP, marycin, Merrel Dow MDL- 27048, Medco MF.DR-340, megestrol, merbarone, merocyanine derivatives, methylanililoacridile, Molecular Genetics MGI-136, minnactivin, mitonafide, mitoquidone, Monocal, mopidanol, motretinide, Zenyaku Kogyo MST- 16, Mylanta, N- (retinoyl) amino acd, Nilandron; Nisshin Flour Milling N-021, N-acylated-dehydroalaniles, nafazatron, Taisho NCU-190, Nephro-Calci tablets, nocodazole derivative, Normosaig, NCI NSC-145813, NCI NSC-361456, NCI NSC-60478 2 NCI NSC-95 580, octreotide, Ono ONO-112, oquizanocile, Akzo Org-10172, paclitaxel, pancratistatin'. pazelliptine, Warner-Lamnbert PD-111707, Warner-Lambert PD-115934, Warner-Lamtbert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrole, polyhaematoporphyril. polypreic acid, Efainol porphyrin, probimane, procarbazile, proglumide, Invitron protease nexin 1, Tobishi RA-700, razoxane, retinoids, Encore Pharmaceuticals R-flurbiprof en, Sandostatin; Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenic RP-49532, Rhone-Poul~enc RP-56976, Scherring-Plough SC-57050, Scherring-Plough SC-57068, seleniuin(seleflite and selenomethioline), SmithKline SK&F-104864,,Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogemaliuml Unimed, SS Pharmaceutical SS-554, strypoldinole, Stypoldione, Suntory SUN 0237,'Suntory SUN 2071, Sugen SU-101, Sugen 513-5416, Sugen SU-6668, sulindac, sulindac sulf one; superoxide disinutase, Toyamna -162- T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinbiastine sulfate, vincris tine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides, Yaxnanouchi YM-534, Zileuton, ursodeoxycholic acid, and Zanosar.

Preferred miscellaneous agents that may be used in the present invention include, but are not limited to, those identified in Table No. 11, below.

Table No.- 11. M~iscellaneous agents Cmzxund CXzuivM Ccupazm RefereD~e Dosage Trade Nam Flutamide; 2- EfL~m Schering 750 rrg/d in methyl N- (4 Corp 3 8-br nitro-3 doses.

(triflucrozethyl) pheryl) propanamide Ketocon- US 4144346 azole leucovo- US 4148999 rin__ irinote- US 4604463 can__ levamis- GB 11/20406 Ole__ meg US 4696949 paclita- US 5641803 xel Nilutainide Nilandron Hoechst A total ,5-dimethyl Marion daily dose' 3-(4-nitro 3- Roussel of 300 rag (trifluorometh f or 30 days y) phernyl) followed 2,4- thereafter iindazolidined he -163-- Ccunpound ccmo capxany iRaf ere' Dsaae Trade Nam ione tablets mg each) once a day for a total daily dosage of 150 rg.

Vinorel- EP 0010458 bine__ vinbias tine vincris- Octreotide Sandosta- Sandoz S *c or acetate L- tin Phazra-, iv.

cysteinam'ide, ceuticals admiistrat D- ion phenylalanyl- Acrcsmegaly: L-cysteirnyl-L- 50 300 phenylalanryl- mncgm tid.

D-tryptophyl- Carcinoid L-lysyl-L- tumors: 100 threonryl- -600 (2 mcgm/d hydroxy-1- (mean 300 (hydroxyrnethyl mcgm/d) )propyl) Viparas.

cyclic- 200-300 disulfide; mcgm in first two acetate salt weeks of therapy Streptozocin Zanosa~r Pharmacia, i 1000 Streptozocin Upjohn n-g/142 of 2 -deoxy-2- body ((metliylnitro surface per samrino) carboriy week f or 1) amino) two weeks.

alpha (and beta) -Dglucoprnse) topteanUS 5004758 SeleniumEP842 cczvound CcEMc Oaspavw Reference Dosage Name/ Trade Name ACES& J.R.

selenomethioni Carlson ne Laboratcalcium carbonate sulindac ExisulandM US 5858694 sulfone ursodeoxycho US 5843929 lic acid Cell Pathways CP-461 Some additional preferred antineoplastic agents include those described in the individual patents listed in Table No. 12 below, and are hereby individually incorporated by reference.

Table No. 12.

Antineoplastic agents EP 0296749 EP 0882734 EP 00253738 GB 02/135425 WO 09/832762 EP 0236940 US 5338732 US 4418068 US 4692434 US 5464826 US 5061793 EP 0702961 EP 0702961 EP 0702962 EP 0095875 EP 0010458 EP 0321122 US 5041424 JP 60019790 WO 09/512606 US 4,808614 US 4526988 CA 2128644 US 5455270 WO 99/25344 WO 96/27014 US 5695966 DE 19547958 WO 95/16693 WO 82/03395 US 5789000 US 5902610 EP 189990 US 4500711 FR 24/74032 US 5925699 WO 99/25344 US 4537883 US 4808614 US 5464826 US 5366734 US 4767628 US 4100274 US 4584305 US 4336381 JP 5050383 JP 5050384 JP 5064281 JP 51146482 JP 5384981 US 5472949 US 5455270 US 4140704 US 4537883 US 4814470 US 3590028

I

-165- US 4564675 US 4526988 US 4100274 US 4604463 US 4144346 US 4749713 US 4148999 GB 11/20406 US 4696949 US 4310666 US 5641803 US 4418068 US 5,004758 EP 0095875 EP 0010458 US 4935437 US 4,278689 US 4820738 US 4413141 US 5843917 US 5,858694 US 4330559 US 5851537 US 4499072 US 5,217886 WO 98/25603 WO 98/14188 Table No. 13 provides illustrative examples of median dosages for selected cancer agents that may be used in combination with an antiangiogenic agent.-it should be noted that specific dose,regimen for the chemotherapeutic agents below depends upon dosing considerations based upon a variety of factors including the type of neoplasia; the stage of the neoplasm; the.

age, weight, sex, and medical condition of the patient; the route of administration; the renal and hepatic function of the patient; and the particular combination employed.

Table No. 13. Median dosages for selected cancer agents.

NAME OF CHEMOTHERAPEUTIC

AZ,(NP

MrnDIAr nnSAGtPE uJur~ul uvu~~uu

AGENT

Asparaginase Bleomycin Sulfate Carboplatin Carmustine Cisplatin 10,000 units 15 units 50-450 mg.

100 mg.

10-50 mg.

-166- Cladribine Cyc lopho sphami de (lyophilized) Cyc lophosphanide (nonlyophilized) Cytarabine (lyophilized powder) Dac arbazime Dac tinomyc in Daunorubicin Diethylstilbestrol Doxorubi cin Etidronate Etopos ide Floxuridine Fludarabine Phosphate Fliorourac il Goserelin Granisetron Hydrochloride Idarubicin Ifosfainide Leucovorin calcium Leuprolide Mechlorethamine Medroxyproges terone Meiphalan Methotrexate Mi tomyc in Mi toxan trone Ondansetron Hydrochloride Paclitaxel 10 rag.

100 mg.-2 gmn.

100 rag.-2 gmn.

100 mg.-2 gin.

100 mg. -200 Mag.

0.5 Mng.

20 mag.

250 mg.

10-150 Mug.

300 mag.

100 Mag.

500 Mag.

50 Mug.

500 mg.-5 gmn.

3.6 mag.

1 rag.

5-10 rMg.

1-3 gmn.

50-350 mag.

3.75-7.5 rng.

10 Mg.

1 gin.

50 gmn.

20 mg.-1 gmn.

5-40 mag.

20-30 rag.

40 rag.

30 rag.

I

-167- Pamidronate Disodium Pegaspargase Plicamycin Streptozocin Thiotepa Teniposide Vinblastine Vincristine Aldesleukin Epoetin Alfa Filgrastim Immune Globulin Interferon Alpha-2a Interferon Alpha-2b Levamisole Octreotide Sararamostim 30-90 mg.

750 units 2,500 mcgm.

1 gm.

15 mg.

50 mg.

10 mg.

1-5 mg.

22 million units 2,000-10,000 units 300-480 mcgm.

500 mg.-10 gm.

3-36 million units 3-50 million units 50 mg.

1,000-5,000 mcgm.

250-500 mcqm.

The anastrozole used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,935,437.

The capecitabine used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,472,949.

The carboplatin used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,-455,270.

The Cisplatin used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,140,704.

I

-168- The cyclophosphamide used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,537,883.

The eflornithine (DFMO) used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,413,141.

The docetaxel used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,814,470.

The doxorubicin used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 3,590,028.

The etoposide used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,564,675- The fluorouricil used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,336,381.

The gemcitabine used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,526,988.

The goserelin used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No- 4,100,274- The irinotecan used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,604,463.

The ketoconazole used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,144,346.

I

-169- The letrozole used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No- 4,749,713.

The leucovorin used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,148,999.

The levamisole used in the therapeutic combinations of the present invention can be prepared in the manner set forth in GB 11/20,406.

The megestrol used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,696,949.

The mitoxantrone used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,310,666.

The paclitaxel used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,641,803.

The Retinoic acid used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,843,096.

The tamoxifen used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,418,068.

The topotecan used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,004,758.

The toremifene used in the therapeutic combinations of the present invention can be prepared in the manner set forth in EP 00/095,875.

I

-170- The vinorelbine used in the therapeutic combinations of the present invention can be prepared in the manner set forth in EP 00/010,458.

The sulindac sulfone used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,858,694.

The selenium (selenomethionine) used in the therapeutic combinations of the present invention can be prepared in the manner set forth in EP 08/04,927.

The ursodeoxycholic acid used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 97/34,608. Ursodeoxycholic acid can also be prepared according to the manner set forth in EP 05/99,282. Finally, ursodeoxycholic acid can be prepared according to the manner set forth in U.S.

Patent No. 5,843,929.

Still more preferred antineoplastic agents include: anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461, cyclophosphamide, docetaxel, doxorubicin, etoposide, Exisulind®, fluorouracil fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone and eflornithine

(DFMO).

The phrase "taxane" includes a family of diterpene alkaloids all of which contain a particular eight (8) member "taxane" ring structure. Taxanes such as -171paclitaxel prevent the normal post division breakdown of microtubules which form to pull and separate the newly duplicated chromosome pairs to opposite poles of the cell prior to cell division. In cancer cells which are rapidly dividing, taxane therapy causes the microtubules to accumulate which ultimately prevents further division of the cancer cell. Taxane therapy also affects other cell processes dependant on microtubules such as cell motility, cell shape and intracellular transport. The major adverse side-effects associated with taxane therapy can be classified into cardiac effects, neurotoxicity, haematological toxicity, and hypersensitivity reactions. (See Exp. Opin. Thera.

Patents (1998) hereby incorporated by reference).

Specific adverse side-effects include neutropenia, alopecia, bradycardia, cardiac conduction defects, acute hypersensitivity reactions, neuropathy, mucositis, dermatitis, extravascular fluid accumulation, arthralgias, and myalgias. Various treatment regimens have been developed in an effort to minimize the side effects of taxane therapy, but adverse side-effects remain the limiting factor in taxane therapy.

It has been recently discovered in vitro that COX-2 expression is elevated in cells treated with taxanes.

Elevated levels of COX-2 expression are associated with inflammation and generation of other COX-2 derived prostaglandin side effects. Consequently, when taxane therapy is provided to a patient, the administration of a COX-2 inhibitor is contemplated to reduce the inflammatory and other COX-2 derived prostaglandin side effects associated with taxane therapy.

-172- Taxane derivatives have been found to be useful in treating refractory ovarian carcinoma, urothelial cancer, breast carcinoma, melanoma, non-small-cell lung carcinoma, gastric, and colon carcinomas, squamous carcinoma of the head and neck, lymphoblastic, myeloblastic leukemia, and carcinoma of the esophagus.

Paclitaxel is typically administered in a 15-420 2 mg/m dose over a 6 to 24 hour infusion. For renal cell carcinoma, squamous carcinoma of head and neck, carcinoma of esophagus, small and non-small cell lung cancer, and breast cancer, paclitaxel is typically 2 administered as a 250 mg/m 24 hour infusion every 3 weeks. For refractory ovarian cancer paclitaxel is 2 typically dose escalated starting at 110 mg/m 2 Docetaxel is typically administered in a 60 100 mg/M i.v. over 1 hour, every three weeks. It should be noted, however, that specific dose regimen depends upon dosing considerations based upon a variety of factors including the type of neoplasia; the stage of the neoplasm; the age, weight, sex, and medical condition of the patient; the route of administration; the renal and hepatic function of the patient; and the particular agents and combination employed.

In one embodiment, paclitaxel is used in the present invention in combination with a cyclooxygenase-2 inhibitor and a MMP inhibitor and with cisplatin, cyclophosphamide, or doxorubicin for the treatment of breast cancer. In another embodiment paciltaxel is used in combination with a cyclooxygenase-2 inhibitor and a -173- MMP inhibitor, cisplatin or carboplatin, and ifosfamide for the treatment of ovarian cancer.

In another embodiment docetaxal is used in the present invention in combination with a cyclooxygenase-2 inhibitor and a MMP inhibitor and in combination with cisplatin, cyclophosphamide, or doxorubicin for the treatment of ovary and breast cancer and for patients with locally advanced or metastatic breast cancer who have progressed during anthracycline based therapy.

The following references listed in Table No. 14 below, hereby individually incorporated by reference herein, describe various taxanes and taxane derivatives suitable for use in the present invention, and processes for their manufacture.

Table No.

Taxanes and taxane derivatives EP 694539 EP 683232 EP 639577 EP 627418 EP 604910 EP 797988 EP 727492 EP 767786 EP 767376 US 5886026 US 5880131 US 5879929 US 5871979 US 5869680 US '5871979 US 5854278 US 5840930 US 5840748 US 5827831 US 5824701 US 5821363 US 5821263 US 5811292 US 5808113 US 5808102 US 5807888 US 5780653 US 5773461 US 5770745 US 5767282 US 5763628 US 5760252 US 5760251 US 5756776 US 5750737 US 5744592 US 5739362 US 5728850 US 5-728725 US 5723634 US 5721268 US 5717115 US 5716981 US 5714513 US 5710287 US 5705508 US 5703247 US 5703117 US 5700669 US 5693666 US 5688977 US 5684175 US 5683715 US 5679807 US 5677462 us 5675025 US 5670673 US 5654448 US 5654447 US 5646176 US 5637732 US 5637484 US 5635531 US 5631278 -174- US 5629433 US 5622986 US 5618952 US 5616740 US 5616739 US 5614645 US 5614549 US 5608102 US 5599820 US 5594157 US 5587489 US 5580899 US 5574156 US 5567614 US 5565478 US 5560872 US 5556878 US 5547981 US 5539103 US 5532363 US 5530020 US 5508447 us 5489601 US 5484809 U S 5475011 US 5473055 US 5470866 US 5466834 US 5449790 US 5442065 US 5440056 US 5430160 US 5412116 US 5412092 US 5411984 US 5407816 US 5407674 US 5405972 US 5399726 US 5395850 US 5384399 US 5380916 US 5380751 US 5367086 us 5356928 US 5356927 US 5352806 US 5350866 US 5344775 US 5338872 US 5336785 us 5319112 US 5296506 US 5294737 US 5294637 US 5284865 US 5284864 US 5283253 US 5279949 US 5274137 US 5274124 US 5272171 US 5254703 US 5254580 US 5250683 US 5243045 US 5229526 US 5227400.

US 5200534 US 5194635 US 5175,315 US 5136060 US 5015744 WO 98/38862 Wo 95/24402 WO 93/21173 EP 681574 EP 681575 EP 568203 EP 642503 EP 667772 EP 668762 EP 679082 EP 681573 EP 688212 EP 690712 EP 690853 EP 710223 EP 534708 EP 534709 EP 605638 EP 669918 EP 855909 EP 605638 EP 428376 EP 428376 EP 534707 EP 605637 EP 679156 EP 689436 EP 690867 EP 605637 EP 690867 EP 687260 E? 690711 EP 400971 E? 690711 EP 400971 EP690711 EP 884314 EP 568203 EP 534706 EP 428376 EP 534707 EP 400971 EP 669918 EP 605637 LIS 5015744 US 5175315 US 5243045 -175iqn7 A 1 i')A US 5283253 US 5250b8 U DZD /Um U.-I L I *J US 528 US 522 Us 571 US 57 US 57 US 54 34864 US 5284865 US 5350866 US 5227400 29526 US 4876399 US 5136060 US 5336785 L0287 US 5714513 US 5717115 US 5721268 2634 US 5728725 US 5728850 US 5739362 60219 05972 US 5760252 US 5430160 US 5384399 US 5466834 US 5399726b US 5489601 US 5587489 1 1 US US 5532363 US 5539103 US 557156b US 5618952 US 5637732 US 5654447 US 4942184 US 5059699 US 5157149 US 5202488 US 5750736 US 5202488 US 5549830 US 5281727 US 5019504 US 4857653 US 4924011 us 5733388 US 5696153 WO 93/06093 WO 93/06094 WO 94/10996 WO 9/10997 WO 94/11362 WO 94/15599 wo 94/15929 WO 94/17050 WO 94/17051 WO 94/17052 WO 94/20088 WO 94/20485 WO 94/21250 WO 94/21251 WO 94/21252 WO 94/21623 Wa 94/21651 WO 95/03265 WO 97/09979 WO 97/42181 WO 99/08986 WO 99/09021 WO 93/06079 US 5202448 US 5019504 US 4857653 US 4924011 WO 97/15571 WO 96/38138 US 5489589 EP 781778 WO 96/11683 EP 639577 EP 747385 US 5422364 WO 95/11020 EP 747372 Wa 96/36622 US 5599820 WO 97/10234 WO 96/21658 WO 97/23472 US 5550261 WO 95/20582 WO 97/28156 WO 96/14309 Wa 97/32587 WO 96/28435 WQ 96/03394 WO 95/25728 WO 94/29288 WO 96/00724 wa 95/02400 EP 694539 WO 95/24402 Wa 93/10121 WO 97/19086 WO 97/20835 Wa 96/14745 WO 96/36335 U.S. Patent No. 5,019,504 describes the isolation of paclitaxel and related alkaloids from culture grown Taxus brevifolia cells.

-176- U.S. Patent No. 5,675,025 describes methods for synthesis of Taxol®, Taxol® analogues and intermediates from baccatin III.

U.S. Patent No. 5,688,977 describes the synthesis of Docetaxel from 10-deacetyl baccatin III.

U.S. Patent No. 5,202,488 describes the conversion of partially purified taxane mixture to baccatin III.

U.S. Patent No. 5,869,680 describes preparing taxane derivatives.

U.S. Patent No. 5,856,532 describes the production of Taxol®.

U.S. Patent No. 5,750,737 describes paclitaxel'synthesis.

U.S. Patent No. 6,688,977 describes docetaxel synthesis.

U.S. Patent No. 5,677,462 describes preparing taxane derivatives.

U.S. Patent No. 5,594,157 describes making Taxol® derivatives.

the process of the process of the method for methods for the process of the process of Some preferred taxanes and taxane derivatives are described in the patents listed in Table No. 15 below, and are hereby individually incorporated by reference herein.

Table No. 15. Some preferred taxanes and taxane derivatives -177- US 5015744 US 5136060 US 5175315 US 5200534 US 5194635 US 5227400 US 4924012 US 5641803 US 5059699 US 5157049 US 4942184 US 4960790 US 5202488 US 5675025 US 5688977 US 5750736 US 5684175 US 5019504 US 4814470 WO 95/01969 The phrase "retinoid" includes compounds which are natural and synthetic analogues of retinol (Vitamin A).

The retinoids bind to one or more retinoic acid receptors to initiate diverse processes such as reproduction, development, bone formation, cellular proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision. Retinoids are required to maintain normal differentiation and proliferation of almost all cells and have been shown to reverse/suppress carcinogenesis in a variety of in vitro and in vivo experimental models of cancer, see (Moon et al., Ch. 14 Retinoids and cancer. In The Retinoids, Vol.

2. Academic Press, Inc. 1984). Also see Roberts et al.

Cellular biology and biochemistry of the retinoids. In The Retinoids, Vol. Academic Press, Inc. 1984, hereby incorporated by reference) which also shows that vesanoid (tretinoid trans retinoic acid) is indicated for induction of remission in patients with acute promyelocytic leukemia (APL).

A synthetic description of retinoid compounds, hereby incorporated by reference, is described in: Dawson MI and Hobbs PD. The synthetic chemistry of -178retinoids: inThe retinoids, 2" edition. MB Sporn, AB Roberts, and DS Goodman(eds). New York: Raven Press, 1994, pp 5-178.

Lingen et al. describe the use of retinoic acid and interferon alpha against head and neck squamous cell carcinoma (Lingen, MW et al., Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma. Cancer Research 58 (23) 5551- 5558 (1998), hereby incorporated by reference).

lurlaro et al. describe the use of beta interferon and 13-cis retinoic acid to inhibit angiogenesis.

(Iurlaro, M et al., Beta interferon inhibits HIV-1 Tatinduced angiogenesis: synergism with 13-cis retinoic acid. European Journal of Cancer 34 570-576 (1998), hereby incorporated by reference).

Majewski et al. describe Vitamin D3 and retinoids in the inhibition of tumor cell-induced angiogenesis.

(Majewski, S et al., Vitamin D3 is a potent inhibitor of tumor cell-induced angiogenesis. J. Invest. Dermatology.

Symposium Proceedings, 1 97-101 (1996), hereby incorporated by reference.

Majewski et al. describe the role of retinoids and other factors in tumor angiogenesis. Majewski, S et al., Role of cytokines, retinoids and other factors in tumor angiogenesis. Central-European journal of Immunology 21 281-289 (1996), hereby incorporated by reference).

Bollag describes retinoids and alpha-interferon in the prevention and treatment of neoplastic disease.

(Bollag W. Retinoids and alpha-interferon in the prevention and treatment of preneoplastic and neoplastic

I

-179diseases. Chemotherapie Journal, (Suppl) 5 (10) 55-64 (1996), hereby incorporated by reference.

Bigg, HF et al. describe all-trans retinoic acid with basic fibroblast growth factor and epidermal growth factor to stimulate tissue inhibitor of metalloproteinases from fibroblasts. (Bigg, HF et al., All-trans-retoic acid interacts synergystically with basic fibroblast growth factor and epidermal growth factor to stimulate the production of tissue inhibitor of metalloproteinases from fibroblasts. Arch. Biochem.

Biophys. 319 74-83 (1995), hereby incorporated by reference).

Nonlimiting examples of retinoids that may be used in the present invention are identified in Table No. 16 below.

Table No. 16. Retinoids Compound CxmmUn Company Reference Dosage Nam/ Trade Name CD-271 Adapaline EP 199636 Tretinoin Vesanoid Roche trans Holdings mg/M 2 /day retinoic as two acid evenly divided doses until complete remission 2,4,6,8- etretinate Roche US .25 Nonatetraen isoetret- Holdings 4215215 mg/kg/day oic acid, in; -180methoxy- 2,3,6trimethyiph enyl) -3,7dimethylethyl ester, (all-E)- 9359; .Ro- 13-7652; Tegisoa; Tigason Retinoic isotret- Roche US 4843096 .5 to 2 acid, 13- mnom Holdings mg/kg/day cis- Accutane; Isotrex; Ro-4-37 Roaccutan; Roaccutane Roche Ro- Roche 40-0655 Holdings Roche Ro- Romhe 25-6760 Holdings Roche Ro- Roche 25-9022 Holdings Roche Ro- Roche 25-9716 Holdings Benz oi c acid, 4- [3,5bis (trixneth ylsilyl )ben zoyl] amino] TAC -101 Taiho Pharmace utical -181- Retinamide, fenretinid 50 400 e 4-HPR; mg/kg/day hyciroxyphen HPR; McNyl)- R-1967 (2E,4E,6E)- LGD-1550 Ligand ALRT-1550; Pharma- microg/m2 tert- AILRT-550; ceuticas /day to butyiphenyl LG-1550 ,400 )--Allergan microglxn2 methylocta- USA /day 2,4,6- administe trienoic red as a acid single daily oral dose Molecular us Design 4885311 MDI -101 molecular us Design 4677120 MDI-403 Benzoic bexarotene wo acid, LG-1064; 94/15901 LG-1069; tetrahydxo- LGD-1069; 3,5,5,8,8- Targretin; pentamethyl Targretin Oral; naphthaleny Targretin l)eth Topical -182enyl) Gel Benzoic bexarotene R P acid, soft gel Scherer bexarotene tetrahydro- Ligand; 3$5,8,8- bexaroten pentamethyl -2naphthaleny l)ethen yl)- (2E, 4E) WO 96/05165 [3- (5,5,8,8tetramrethyl -5,6,7,8tetrahydronaphthal en- 2-yl) thiopen-2 yll3-penta- 2, 4-dienoic acid SR-11262 Hoffmann F -La Roche Ltd BMS-181162 Bristol EP 476682 Myers Squibb N (4 IT hydroxyphen Research yl) retinafi Institute de AGN-19 3174 -183- Allergan

USA

Cancer Research 39, 1339- 1346 (1979) Wa 96/33716 The following individual patent references listed in Table No. 17 below, hereby individually incorpo~rated by reference, describe various retinoid and retinoid derivatives suitable for use in the present invention described herein, and processes for their manufacture.

Table No. 17. Retinoids U4215215 US 4885311 US 5260059 US 4503035 US 4843096 WO 96/05165 EP 19/9636 WO 96/33716 WO 98/36742 WO 97/25969 WO 97/241116 CHf 61/6134 US 5547947 EP 552624 US 4677120 US 4105681 US 5827836 US 3878202 Wa 97/34869 WO 97/49704 WO 97/24116 WO 97/09297 WO 96/11686 WO 94/15901 DE 2854354 EP 579915 EP 728742 EP 331983 EP 476682 Some preferred retinoids include Accutane; Adapalele; Allergan AGN-193174; Allergan AGN-19367 6

I

-184- Allergan AGN-193836; Allergan AGN-193109; Aronex AR-623; BMS-181162; Galderma CD-437; Eisai ER-34617; Etrinate; Fenretinide; Ligand LGD-1550; lexacalcitol; Maxia Pharmaceuticals MX-781; mofarotene; Molecular Design MDI-101; Molecular Design MDI-301; Molecular Design MDI- 403; Motretinide; Eisai 4-(2-[5-(4-methyl-7ethylbenzofuran-2-yl)pyrrolyl]) benzoic acid; Johnson Johnson N-[4-[2-thyl-- (1H-imidazol-1-yl)butyl]phenyl 2-benzothiazolamine; Soriatane; Roche SR- 11262; Tocoretinate; Advanced Polymer Systems trans-retinoic acid; UAB Research Foundation UAB-8; Tazorac; TopiCare; Taiho TAC-101; and Vesanoid.

cGMP phosphodiesterase inhibitors, including Sulindac sulfone (Exisuland®) and CP-461 for example, are apoptosis inducers and do not inhibit the cyclooxygenase pathways. cGMP phosphodiesterase inhibitors increase apoptosis in tumor cells without arresting the normal cycle of cell division or altering the cell's expression of the p53 gene.

Ornithine decarboxylase is a key enzyme in the polyamine synthesis pathway that is elevated in most tumors and premalignant lesions. Induction of cell growth and proliferation is associated with dramatic increases in ornithine decarboxylase activity and subsequent polyamine synthesis. Further, blocking the formation of polyamines slows or arrests growth in transformed cells. Consequently, polyamines are thought to play a role in tumor growth. Difluoromethylornithine (DFMO) is a potent inhibitor of ornithine decarboxylase that has been shown to inhibit carcinogen-induced cancer development in a variety of rodent models (Meyskens et -185al. Development of Difluoromethylornithine (DFMO) as a chemoprevention agent. Clin. Cancer Res. 1999 May, 5(%):945-951, hereby incorporated by reference, herein).

DFMO is also known as 2-difluoromethyl-2,5diaminopentanoic acid, or 2-difluoromethyl-2,5diaminovaleric acid, or a-(difluoromethyl) ornithine; DFMO is marketed under the tradename Elfornithine®.

Therefore, the use of DFMO in combination with COX-2 inhibitors is contemplated to treat or prevent cancer, including but not limited to colon cancer or colonic polyps.

Populations with high levels of dietary calcium have been reported to be protected from colon cancer. In vivo, calcium carbonate has been shown to inhibit colon cancer via a mechanism of action independent from COX-2 inhibition. Further, calcium carbonate is well tolerated. A combination therapy consisting of calcium carbonate and a selective COX-2 inhibitor is contemplated to treat or prevent cancer, including but not limited to colon cancer or colonic polyps.

Several studies have focused attention on bile acids as a potential mediator of the dietary influence on colorectal cancer risk. Bile acids are important detergents for fat solubilization and digestion in the proximal intestine. Specific transprot processes in the apical domain of the terminal ileal enterocyte and basolateral domain of the hepatocyte account for the efficient conservation in the enterohepatic circulation.

Only a small fraction of bile acids enter the colon; however, perturbations of the cycling rate of bile acids by diet fat) or surgery may increase the fecal

I

I

-186bile load and perhaps account for the associated increased risk of colon cancer. (Hill MJ, Bile flow and colon cancer. 238 Mutation Review, 313 (1990).

Ursodeoxycholate (URSO), the hydrophilic 7-beta epimer of chenodeoxycholate, is non cytotoxic in a variety of cell model systems including colonic epithelia. URSO is also virtually free of side effects. URSO, at doses of used primarily in biliary cirrhosis trials were extremely well tolerated and without toxicity.

(Pourpon et al., A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis.

324 New Engl. J. Med. 1548 (1991)). While the precise mechanism of URSO action is unknown, beneficial effects of URSO therapy are related to the enrichment of the hepatic bile acid pool with this hydrophilic bile acid.

It has thus been hypothesized that bile acids more hydrophilic than URSO will have even greater beneficial effects than URSO. For example, tauroursodeoxycholate (TURSO) the taurine conjugate of URSO. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the neoplastic transformation of colorectal epithelium. The likely mechanism to explain this chemopreventive effect is inhibition of prostaglandin synthesis. NSAIDs inhibit cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandins and thromboxanes. However, the potential chemopreventive benefits of NSAIDs such as sulindac or mesalamine are tempered by their well known toxicities and moderately high risk of intolerance.

Abdominal pain, dispepsia, nausea, diarrhea, constipation, rash, dizziness, or headaches have been reported in up to 9% of patients. The elderly appear to -187be particularly vulnerable as the incidence of NSAIDinduced gasttoduodenal ulcer disease, including gastrointestinal bleeding, is higher in those over the age of 60; this is also the age group most likely to develop colon cancer, and therefore most likely to benefit from chemoprevention. The gastrointestinal side effects associated with NSAID use result from the inhibition of cyclooxygenase-1, an enzyme responsible for maintenance of the gastric mucosa. Therefore, the use of COX-2 inhibitors in combination with URSO is contemplated to treat or prevent cancer, including but not limited to colon cancer or colonic polyps; it is contemplated that this treatment will result in lower gastrointestinal side effects than the combination of standard NSAIDs and URSO.

An additional class of antineoplastic agents that.

may be used in the present invention include nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase. (COX). However, for the purposes of the present invention the definition of an NSAID does not include the "cyclooxygenase- 2 inhibitors' described herein. Thus the phrase "nonsteroidal antiinflammatory drug" or "NSAID" includes agents that specifically inhibit cyclooxygenase-1, without significant inhibition of cyclooxygenase- 2 or inhibit cyclooxygenase-1 and cyclooxygenase-2 at substantially the same potency; or inhibit neither cyclooxygenase-1 or cyclooxygenase- 2 The potency and selectivity for the enzyme -188cyclooxygenase-1 and cyclooxygenase-2 can be determined by assays well known in the art, see for example, Cromlish and Kennedy, Biochemical Pharmacology, Vol. 52, pp 1777-1785, 1996.

Examples of NSAIDs that can be used in the combinations of the present invention include sulindac, indomethacin, naproxen, diclofenac, tolectin, fenoprofen, phenylbutazone, piroxicam, ibuprofen, ketophen, mefenamic acid, tolmetin, flufenamic acid, nimesulide, niflumic acid, piroxicam, tenoxicam, phenylbutazone, fenclofenac, flurbiprofen, ketoprofen, fenoprofen, acetaminophen, salicylate and aspirin.

The term "clinical tumor" includes neoplasms that are identifiable through clinical screening or diagnostic procedures including, but not limited to, palpation, biopsy, cell proliferation index, endoscopy, mammagraphy, digital mammography, ultrasonography, computed tomagraphy magnetic resonance imaging (MRI), positron emmission tomaagraphy (PET), radiography, radionuclide evaluation, CT- or MRI-guided aspiration cytology, and imaging-guided needle biopsy, among others. Such diagnostic techniques are well known to those skilled in the art and are described in Cancer Medicine 4t h Edition, Volume One. J.F. Holland, R.C.

Bast, D.L. Morton, E. Frei III, D.W. Kufe, and R.R.

Weichselbaum (Editors). Williams Wilkins, Baltimore (1997).

The term "tumor marker" or "tumor biomarker" encompasses a wide variety of molecules with divergent characteristics that appear in body fluids or tissue in association with a clinical tumor and also includes -189tumor-associated chromosomal changes. Tumor markers fall primarily into three categories: molecular or cellular markers, chromosomal markers, and serological or serum markers. Molecular and chromosomal markers complement standard parameters used to describe a tumor (i.e.

histopathology, grade, tumor size) and are used primarily in refining disease diagnosis and prognosis after clinical manifestation. Serum markers can often be measured many months before clinical tumor detection and are thus useful as an early diagnostic test, in patient monitoring, and in therapy evaluation.

Molecular Tumor Markers Molecular markers of cancer are products of cancer cells or molecular changes that take place in cells because of activation of cell division or inhibition of apoptosis. Expression of these markers can predict a cell's malignant potential. Because cellular markers are not secreted, tumor tissue samples are generally required for their detection. Non-limiting examples of molecular tumor markers that can be used in the present invention are listed in Table No. 1, below.

Table No. 1. Non-limiting Examples of Molecular Tumor Markers Tumor Marker Breast p53 Breast, ErbB-2/Her-2 Ovarian Breast S phase and ploidy Breast pS2 Breast MDR2 Breast urokinase plasminogen activator -190- Breast, myc family Colon, Lung Chromosomal Tumor Markers Somatic mutations and chromosomal aberrations have been associated with a variety of tumors. Since the identification of the Philadelphia Chromosome by Nowel and Hungerford, a wide effort to identify tumor-specific chromosomal alterations has ensued. Chromosomal cancer markers, like cellular markers, are can be used in the diagnosis and prognosis of cancer. In addition to the diagnostic and prognostic implications of chromosomal alterations, it is hypothesized that germ-line mutations can be used to predict the likelihood that a particular person will develop a given type of tumor. Non-limiting examples of chromosomal tumor markers that can be used in the present invention are listed in Table No. 2, below.

Table No. 2. Non-limiting Examples of Chromosomal Tumor Markers Tumor Marker Breast 1p 3 6 loss Breast 6q24-27 loss Breast 11q22-23 loss Breast 11ql3 amplification Breast TP53 mutation Colon Gain of chromosome 13 Colon Deletion of short arm of chromosome 1 Lung Loss of 3p Lung Loss of 13q Lung Loss of 17p

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-191- Lung Loss of 9p Serological Tumor Markers Serum markers including soluble antigens, enzymes and hormones comprise a third category of tumor markers.

Monitoring serum tumor marker concentrations during therapy provides an early indication of tumor recurrence and of therapy efficacy. Serum markers are advantageous for patient surveillance compared to chromosomal and cellular markers because serum samples are more easily obtainable than tissue samples, and because serum.assays can be performed serially and more rapidly. Serum tumor markers can be used to determine appropriate therapeutic doses within individual patients. For example, the efficacy of a combination regimen consisting of chemotherapeutic and antiangiogenic agents can be measured by monitoring the relevant serum cancer marker levels. Moreover, an efficacious therapy dose can be achieved by modulating the therapeutic dose so as to keep the particular serum tumor marker concentration stable or within the reference range, which may vary depending upon the indication. The amount of therapy can then be modulated specifically for each patient so as to minimize side effects while still maintaining stable, reference range tumor marker levels. Table No.

3 provides non-limiting examples of serological tumor markers that can be used in the present invention.

Table No. 3. Non-limiting Examples of Serum Tumor Markers Cancer Type Marker I l

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-192- Germ Cell Tumors a-fetoprotein (AFP) Germ Cell Tumors human chorionic gonadotrophin (hCG) Germ Cell Tumors placental alkaline phosphatase (PLAP) Germ Cell Tumors lactate dehydrogenase (LDH) Prostate prostate specific antigen

(PSA)

Breast carcinoembryonic antigen

(CEA)

Breast MUC-1 antigen (CA15-3) Breast tissue polypeptide antigen

(TPA)

Breast tissue polypeptide specific antigen (TPS) Breast CYFRA 21.1 Breast soluble erb-B-2 Ovarian CA125 Ovarian OVX1 Ovarian cancer antigen CA72-4 Ovarian

TPA

Ovarian

TPS

Gastrointestinal CD44v6 Gastrointestinal

CEA

Gastrointestinal cancer antigen CA19-9 Gastrointestinal NCC-ST-439 antigen (Dukes C) Gastrointestinal cancer antigen CA242 Gastrointestinal soluble erb-B-2 Gastrointestinal cancer antigen CA195

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-193- Gastrointestinal TPA Gastrointestinal Gastrointestinal TPS Esophageal CYFRA 21-1 Esophageal TPA Esophageal TPS Esophageal cancer antigen CA19-9 Gastric Cancer CEA Gastric Cancer cancer antigen CA19-9 Gastric Cancer cancer antigen CA72-4 Lung neruon specific enolase (NSE) Lung CEA \Lung CYFRA 21-1 Lung cancer antigen CA 125 Lung TPA Lung squamous cell carcinoma antigen (SCC) Pancreatic cancer cal9-9 Pancreatic cancer Pancreatic cancer call9 Pancreatic cancer Pancreatic cancer CEA Pancreatic cancer Renal Cancer CD44v6 Renal Cancer E-cadherin Renal Cancer PCNA (proliferating cell nuclear antigen) Examples -194- Germ Cell Cancers Non-limiting examples of tumor markers useful in the present invention for the detection of germ cell cancers include, but are not limited to, a-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and its beta subunit (hCGb), lactate dehydrogenase (LDH), and placental alkaline phosphatase (PLAP)'.

AFP has an upper reference limit of approximately kU/L after the first year of life and may be elevated in germ cell tumors, hepatocellular carcinoma and also in gastric, colon, biliary, pancreatic and lung cancers. AFP serum half life is approximately five days after orchidectomy. According to EGTM recommendations, AFP serum levels less than 1,000 kU/L correlate with a good prognosis, AFP levels between 1,000 and 10,000 kU/L, inclusive, correlate with intermediate prognosis, and AFP levels greater than 10,000 U/L correlate with a poor prognosis.

HCG is synthesized in the placenta and is also produced by malignant cells. Serum hCG concentrations may be increased in pancreatic adenocarcinomas, islet cell tumors, tumors of the small and large bowel, hepatoma, stomach, lung, ovaries, breast and kidney.

Because some tumors only hCGb, measurement of both hCG and hCGb is recommended. Normally, serum hCG in men and pre-menopausal women is as high as -5 U/L while postmenopausal women have levels up to -10 U/L. Serum half life of hCG ranges from 16-24 hours. According to the EGTM, hCG serum levels under 5000 U/L correlate with a good prognosis, levels between 5000 and 50000 U/L, inclusively correlate with an intermediate prognosis,

I

-195and hCG serum levels greater than 50000 U/L correlate with a poor prognosis. Further, normal hCG half lives correlate with good prognosis while prolonged half lives correlate with poor prognosis.

LDH is an enzyme expressed in cardiac and skeletal muscle as well as in other organs. The LDH-1 isoenzyme is most commonly found in testicular germ cell tumors but can also occur in a variety of benign conditions such as skeletal muscle disease and myocardial infarction. Total LDH is used to measure independent prognostic value in patients with advanced germ cell tumors. LDH levels less than 1.5 x the reference range are associated with a good prognosis, levels between and 10 x the reference range, inclusive, are associated with an intermediate prognosis, and levels more than x the reference range are associated with a poor prognosis.

PLAP is a enzyme of alkaline phosphatase normally expressed by placental syncytiotrophoblasts. Elevated serum concentrations of PLAP are found in seminomas, non-seminomatous tumors, and ovarian tumors, and may also provide a marker for testicular tumors. PLAP has a normal half life after surgical resection of between 0.6 and 2.8 days.

Prostate Cancer A nonlimiting example of a tumor marker useful in the present invention for the detection of prostate cancer is prostate specific antigen (PSA). PSA is a glycoprotein that is almost exclusively produced in the prostate. In human serum, uncomplexed f-PSA and a complex of f-PSA with al-anthichymotrypsin make up total -196- PSA (t-PSA). T-PSA is useful in determining prognosis in patients that are not currently undergoing anti-androgen treatment. Rising t-PSA levels via serial measurement indicate the presence of residual disease.

Breast Cancer Non-limiting examples of serum tumor markers useful in the present invention for the detection of breast cancer include, but is not limited to carcinoembryonic antigen (CEA) and MUC-1 (CA 15.3). Serum CEA an-d CA15.3 levels are elevated in patients with node involvement compared to patients without node involvement, and in patients with larger tumors compared to smaller tumors.

Normal range cutoff points (upper limit), are 5-10 mg/L for CEA and 35-60 u/ml for CAlS.3. Additional specificity is gained by confirming serum levels with two serial increases of more than Ovarian Cancer A non-limiting example of a tumor marker useful in the present invention for the detection of ovarian cancer is CA125. Normally, women have serum CA125 levels between 0-35 kU/L; 99% of post-menopausal women have levels below 20 kQ~i/L. Serum concentration of CA125 after chemotherapy is a strong predictor of outcome as elevated CA125 levels are found in roughly 80% of all patients with epithelial ovarian cancer. Further, prolonged CA125 half-life or a less than 7-fold decrease during early treatment is also a predictor of poor disease prognosis.

Gastrointestinal Cancers A non-limiting example of a tumor marker useful in the present invention for the detection of colon cancer -197is carcinoembryonic antigen (CEA). CEA is a glycoprotein produced during embryonal and fetal development and has a high sensitivity for advanced carcinomas including those of the colon, breast, stomach and lung. High preor postoperative concentrations ng/ml) of CEA are associated with worse prognosis than are low concentrations. Further, some studies in the literature report that slow rising CEA levels indicates local recurrence while rapidly increasing levels suggests hepatic metastasis.

Lung Cancer Examples of serum markers useful in the present invention to monitor lung cancer therapy include, but are not limited to, CEA, cytokeratin 19 fragments (CYFRA 21-1), and Neuron Specific Enolase (NSE).

NSE is a glycolytic isoenzyme of enolase produced in central and peripheral neurons and malignant tumors of neuroectodermal origin. At diagnosis, NSE concentrations greater than 25 ng/mL are suggestive of malignancy and lung cancer while concentrations greater than 100 ng/mL are suggestive of small cell lung cancer.

CYFRA 21-1 is a tumor marker test which uses two specific monoclonal antibodies against a cytokeratin 19 fragment. At diagnosis, CYFRA 21-1 concentrations greater than 10 ng/mL are suggestive of malignancy while concentrations greater than 30 ng/mL are suggestive of lung cancer.

Accordingly, dosing of the cyclooxygenase-2 inhibitor, matrix metalloproteinase inhibitor, and antineoplastic agent may be determined and adjusted based on measurement of tumor markers in body fluids or

I

-198tissues, particularly based on tumor markers in serum.

For example, a decrease in serum marker level relative to baseline serum marker prior to administration of the matrix metalloproteinase inhibitor, cyclooxygenase-2 inhibitor and antineoplastic agent indicates a decrease in cancer-associated changes and provides a correlation with inhibition of the cancer. In one embodiment, therefore, the method of the present invention comprises administering the cyclooxygenase-2 inhibitor, matrix metalloproteinase inhibitor, and antineoplastic agent at doses that in combination result in a decrease in one or more tumor markers, particularly a decrease in one or more serum tumor markers, in the mammal relative to baseline tumor marker levels.

Similarly, the rate of postoperative decrease of a particular marker predicts patient outcome. Decreasing tumor marker concentrations and half lives after surgery indicates a good prognosis, while tumor marker concentrations which decline slowly and don't reach the normal reference range predict residual tumor and poor prognosis. Further, during follow-up therapy, increases in tumor marker concentration predicts recurrent disease many months before clinical manifestation.

In addition to the above examples, Table No. 4, below, lists several references, hereby individually incorporated by reference herein, that describes tumor markers and their use in detecting and monitoring tumor growth and progression.

Table No. 4. Tumor marker references.

European Group on Tumor Markers Publications -199- Committee. Consensus Recommendations. Anticancer Research 19: 2785-2820 (1999) Human Cytogenetic Cancer Markers. Sandra R. Wolman and Stewart Sell Totowa, New Jersey: Humana Press.

1997 Cellular Markers of Cancer. Carleton Garrett and Stewart Sell Totowa, New Jersey: Human Press.

1995 Combinations with Other Treatments The COX- 2 inhibitors and MMP inhibitors of the present invention may be used in conjunction with other treatment modalities, including, but not limited to surgery and radiation, hormonal therapy, chemotherapy, immunotherapy, and cryotherapy. The present invention may be used in conjunction with any current or future therapy.

The following discussion highlights some agents in this respect, which are illustrative, not limitative. A wide variety of other effective agents also may be used.

-200- Surgerv and Radiation In general, surgery and radiation therapy are employed as potentially curative therapies for patients under 70 years of age who present with clinically localized disease and are expected to live at least years.

For example, approximately 70% of newly diagnosed prostate cancer patients fall into this category.

Approximately 90% of these patients (65% of total patients) undergo surgery, while approximately 10% of these patients of total patients) undergo radiation therapy. Histopathological examination of surgical specimens reveals that approximately 63% of patients undergoing surgery (40% of total patients) have locally extensive tumors or regional (lymph node) metastasis that was undetected at initial diagnosis. These patients are at a significantly greater risk of recurrence.

Approximately 40% of these patients will actually develop recurrence within five years after surgery.

Results after radiation are even less encouraging.

Approximately 80% of patients who have undergone radiation as their primary therapy have disease persistence or develop recurrence or metastasis within five years after treatment. Currently, most of these surgical and radiotherapy patients generally do not receive any immediate follow-up therapy. Rather, for example, they are monitored frequently for elevated Prostate Specific Antigen which is the primary indicator of recurrence or metastasis prostate cancer.

Thus, there is considerable opportunity to use the present invention in conjunction with surgical intervention.

-201- Hormonal Theray Hormonal ablation is the most effective palliative treatment for the 10% of patients presenting with metastatic prostate cancer at initial diagnosis.

Hormonal ablation by medication and/or orchiectomy is used to block hormones that support the further growth and metastasis of prostate cancer. With time, both the primary and metastatic tumors of virtually all of these patients become hormone-independent and resistant to therapy. Approximately 50% of patients presenting with metastatic disease die within three years after initial diagnosis, and 75% of such patients die within five years after diagnosis. Continuous supplementation with NAALADase inhibitor based drugs are used to prevent or reverse this potentially metastasis-permissive state.

Among hormones which may be used in combination with the present inventive compounds, diethylstilbestrol (DES), leuprolide, flutamide, cyproterone acetate, ketoconazole and amino glutethimide are preferred.

Immunotheraiy The COX-2 inhibitors and MMP inhibitors of the present invention may also be used in combination with monoclonal antibodies in treating cancer. For example monoclonal antibodies may be used in treating prostate cancer. A specific example of such an antibody includes cell membrane-specific anti-prostate antibody.

The present invention may also be used with immunotherapies based on polyclonal or monoclonal antibody-derived reagents, for instance. Monoclonal antibody-based reagents are most preferred in this

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-202regard. Such reagents are well known to persons of ordinary skill in the art. Radiolabelled monoclonal antibodies for cancer therapy, such as the recently approved use of monoclonal antibody conjugated with strontium-89, also are well known to persons of ordinary skill in the art.

Antianciocenic Thera=y The COX-2 inhibitors and MMP inhibitors may also be used in combination with other antiangiogenic agenst in treating cancer. Antiangiogenic agents include but are not'limited to MMP inhibitors, integrin antagonists, angiostatin, endostatin, thrombospondin-l, and interferon alpha. Examples of preferred antiangiogenic agents include, but are not limited to vitaxin, marimastat, Bay-12-95 6 6 AG-3340, metastat, celecoxib, rofecoxib, JTE-522, EMD-121974, and D-2163 (BMS-275291).

Crvotherapv Cryotherapy recently has been applied to the treatment of some cancers. Methods and compositions of the present invention also could be used in conjunction with an effective therapy of this type.

All of the various cell types of the body can be transformed into benign or malignant neoplasia or tumor cells and are contemplated as objects of the invention.

A "benign" tumor cell denotes the non-invasive and nonmetastasized state of a neoplasm. In man the most frequent neoplasia site is lung, followed by colorectal, breast, prostate, bladder, pancreas, and then ovary.

Other prevalent types of cancer include leukemia, -203central nervous system cancers, including brain cancer, melanoma, lymphoma, erythroleukemia, uterine cancer, and head and neck cancer. Examples 1 through 9 are provided to illustrate contemplated therapeutic combinations, and are not intended to iimit the scope of the invention.

Illustrations The following non-limiting illustrative examples describe various cancer diseases and therapeutic approaches that may be used in the present invention, and are for illustrative purposes only. Preferred antiangiogenic agents of the below non-limiting illustrations are MMP inhibitors and COX-2 inhibitors.

More preferably the MMP inhibitors include Compound Ml, Compound M2, Compound M3, Compound M4, Compound Compound M6, Compound M7, Compound M8, Marimastat, Bay- 12-9566, AG-3340, Metastat, and D-2163 (BMS-275291) and the COX-2 inhibitors include celecoxib, rofecoxib and JTE-522.

Examp~le I Lung Cancer In many countries including Japan, Europe and America, the number of patients with lung cancer is fairly large and continues to increase year after year and is the most frequent cause of cancer death in both men and women. Although there are many potential causes for lung cancer, tobacco use, and particularly cigarette smoking, is the most important. Additionally, etiologic factors such as exposure to asbestos, especially in smokers, or radon are contributory factors. Also

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-204occupational hazards such as exposure to uranium have been identified as an important factor. Finally, genetic factors have also been identified as another factor that increase the risk of cancer.

Lung cancers can be histologically classified into non-small cell lung cancers squamous cell carcinoma (epidermoid), adenocarcinoma, large cell carcinoma (large cell anaplastic), etc.) and small cell lung cancer (oat cell). Non-small cell lung cancer (NSCLC) has different biological properties and responses to chemotherapeutics from those of small cell lung cancer (SCLC). Thus, chemotherapeutic formulas and radiation therapy are different between these two types of lung cancer.

Non-Small Cell LunQ Cancer Where the location of the non-small cell lung cancer tumor can be easily excised (stage I and II disease) surgery is the first line of therapy and offers a relatively good chance for a cure. However, in more advanced disease (stage IIIa and greater), where the tumor has extended to tissue beyond the bronchopulmonary lymph nodes, surgery may not lead to complete excision of the tumor. In such cases, the patient's chance for a cure by surgery alone is greatly diminished. Where surgery will not provide complete removal of the NSCLC tumor, other types of therapies must be utilized.

Today radiation therapy is the standard treatment to control unresectable or inoperable NSCLC. Improved results have been seen when radiation therapy has been combined with chemotherapy, but gains have been modest -205and the search continues for improved methods of combining modalities.

Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues. The radiation dosage regimen is generally defined in terms of radiation absorbed dose (rad), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various consideration but the two most important considerations are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread. A prefered course of treatment for a patient undergoing radiation therapy for NSCLC will be a treatment schedule over a 5 to 6 week period, with a total dose of 50 to 60 Gy administered to the patient in a single daily fraction of 1.8 to 2.0 Gy, days a week. A Gy is an abbreviation for Gray and refers to 100 rad of dose.

However, as NSCLC is a systemic disease, and radiation therapy is a local modality, radiation therapy as a single line of therapy is unlikely to provide a cure for NSCLC, at least for those tumors that have metastasized distantly outside the zone of treatment.

Thus, the use of radiation therapy with other modality regimens have important beneficial effects for the treatment of NSCLC.

Generally, radiation therapy has been combined temporally with chemotherapy to improve the outcome of treatment. There are various terms to describe the temporal relationship of administering radiation therapy -2 06in combination with M~P inhibitors and coX-2 inhibitors and/or chemotherapy, and the following examples are the preferred treatment regimens and are provided for illustration only and are not intended to limit the use of other combinations. %Sequential" therapy refers to the administration of chemotherapy and/or MNP inhibitors and/or COX-2 inhibitors and/or radiation therapy separately in time in order to-allow the separate administration of either chemotherapy and/or NO4P inhibitors and/or coX-2 inhibitors, and/or radiation therapy. "Concomitant" therapy refers to the administration of chemotherapy and/or M? inhibitors, and/or cOX-2 inhibitors and/or radiation therapy on the same day. Final ly, ",alternating therapy 3 refers to the is administration of radiation therapy on the days in which chemotherapy and/or MMP inhibitors and/or COX-2 inhibitors would not have been administered if it was given alone.

It is reported that advanced non-small cell lung cancers do not respond favorably to single-agent chemotherapy and useful therapie s for advanced inoperable cancers have been limited. (journal of Clinical Oncology, vol. 10, pp. 829-838 (1992)).

Japanese Patent Kokai 5-163a293 refers to some specified antibiotics of 16 -membered- ring macrolides as a drug delivery carrier capable of transporting anthoracycline-type anticancer drugs into the lungs for the treatment of lung cancers. However, the macrolide antibiotics specified herein are disclosed to be only a drug carrier, and there is no reference to the therapeutic use of macrolides aga inst non-small cell lung cancers.

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-207- WO 93/18,652 refers to the effectiveness of the specified 16-membered-ring macrolides such as bafilomycin, etc. in treating non-small cell lung cancers, but they have not yet been clinically practicable.

Pharmacology, vol. 41, pp. 177-183 (1990) describes that a long-term use of erythromycin increases productions of interleukins 1, 2 and 4, all of which contribute to host immune responses, but there is no reference to the effect of this drug on non-small cell lung cancers.

Teratogenesis, Carcinogenesis, and Mutagenesis, vol. 10, pp. 477-501 (1990) describes that some of antimicrobial drugs can be used as an anticancer agent, but does not refer to their application to non-small cell lung cancers.

In addition, interleukins are known to have an antitumor effect, but have not been reported to be effective against non-small cell lung cancers.

Any 14 or 15-membered-ring macrolides have not been reported to be effective against non-small cell lung cancers.

However, several chemotherapeutic agents have been shown to be efficacious against NSCLC. Preferred chemotherapeutic agents that can be used in the present invention against NSCLC include etoposide, carboplatin, methotrexate, 5-Fluorouracil, epirubicin, doxorubicin, taxol, inhibitor of normal mitotic activity; and cyclophosphamide. Even more preferred chemotherapeutic agents active against NSCLC include cisplatin, ifosfamide, mitomycin C, epirubicin, vinblastine, and vindesine.

-208- Other agents that are under investigation for use against NSCLC include: camptothecins, a topoisomerase 1 inhibitor; navelbine (vinorelbine), a microtubule assebly inhibitor; gemcitabine, a deoxycytidine analogue; fotemustine, a nitrosourea compound; and edatrexate, a antifol.

The overall and complete response rates for NSCLC has been shown to increase with use of combination chemotherapy as compared to single-agent treatment.

Haskel CM: Chest. 99: 1325, 1991; Bakowski MT: Cancer Treat Rev 10:159, 1983; Joss RA: Cancer Treat Rev 11:205, 1984.

A preferred therapy for the treatment of NSCLC is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) itosfamide, cisplatin, etoposide; 2) cyclophoshamide, doxorubicin, cisplatin; 3) isofamide, carboplatin, etoposide; 4) bleomycin, etoposide, cisplatin; 5) isofamide, mitomycin, cisplatin; 6) cisplatin, vinblastine; 7) cisplatin, vindesine; 8) mitomycin C, vinblastine, cisplatin; 9) mitomycin C, vindesine, cisplatin; 10) isofamide, etoposide; 11) etoposide, cisplatin; 12) isofamide, mitomycin C; 13) flurouracil, cisplatin, vinblastine; 14) carboplatin, etoposide; or radiation therapy.

Accordingly, apart from the conventional concept of anticancer therapy, there is a strong need for the development of therapies practicably effective for the treatment of non-small cell lung cancers.

-209- Small Cell Lung Cancer Approximately 15 to 20 percent of all cases of lung cancer reported worldwide is small cell lung cancer (SCLC). Ihde DC: Cancer 54:2722, 1984. Currently, treatment of SCLC incorporates multi-modal therapy, including chemotherapy, radiation therapy and surgery.

Response rates of localized or disseminated SCLC remain high to systemic chemotherapy, however, persistence of the primary tumor and persistence of the tumor in the associated lymph nodes has led to the integration of several therapeutic modalities in the treatment of SCLC.

A preferred therapy for the treatment of lung cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following antineoplastic agents: vincristine, cisplatin, carboplatin, cyclophosphamide, epirubicin (high dose), etoposide (VP-16) etoposide (VP-16) oral, isofamide, teniposide (VM-26), and doxorubicin. Other preferred single-agents chemotherapeutic agents that may be used in the present invention include

BCNU

(carmustine), vindesine, hexamethylmelamine (altretamine), methotrexate, nitrogen mustard, and CCNU (lomustine). Other chemotherapeutic agents under investigation that have shown activity againe

SCLC

include iroplatin, gemcitabine, lonidamine, and taxol.

Single-agent chemotherapeutic agents that have not shown activity against SCLC include mitoguazone, mitomycin

C,

aclarubicin, diaziquone, bisantrene, cytarabine, idarubicin, mitomxantrone, vinblastine, PCNU and esorubicin.

-210- The poor results reported from single-agent chemotherapy has led to use of combination chemotherapy.

A preferred therapy for the treatment of NSCLC is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) etoposide (VP-16), cisplatin; 2) cyclophosphamide, adrianmycin [(doxorubicin), vincristine, etoposide 3) Cyclophosphamide, adrianmycin(doxorubicin), vincristine; 4) Etoposide (VP- 16), ifosfamide, cisplatin; 5) etoposide (VP-16), carboplatin; 6) cisplatin, vincristine (Oncovin), doxorubicin, etoposide.

Additionally, radiation therapy in conjunction with the preferred combinations of COX-2 inhibitors and MMP inhibitors and systemic chemotherapy is contemplated to be effective at increasing the response rate for SCLC patients. The typical dosage regimen for radiation therapy ranges from 40 to 55 Gy, in 15 to 30 fractions, 3 to 7 times week. The tissue volume to be irradiated is determined by several factors and generally the hilum and subcarnial nodes, and bialteral mdiastinal nodes up to the thoraic inlet are treated, as well as the primary tumor up to 1.5 to 2.0 cm of the margins.

Example 2 Colorectal Cancer Survival from colorectal cancer depends on the stage and grade of the tumor, for example precursor adenomas to metastatic adenocarcinoma. Generally, colorectal cancer can be treated by surgically removing -2 11the tumor, but overall survival rates remain between and 60 percent. Colonic excision morbidity rates are fairly low and is generally associated with the anastomosis and not the extent of the removal of the tumor and local tissue. In patients with a high risk of reoccurrence, however, chemotherapy has been incorporated into the treatment regimen in order to improve survival rates.

Tumor metastasis prior to surgery is generally believed to be the cause of surgical intervention failure and up to one year of chemotherapy is required to kill the non-excised. tumor cells. As severe toxicity is associated with the chemotherapeutic agents, only patients at high risk of recurrence are placed on chemotherapy following surgery. Thus, the incorporation of an antiangiogenesis inhibitor into the management of colorectal cancer will play an important role in the treatment of colorectal cancer and lead to overall improved survival rates for patients diagnosed with colorectal cancer.

A preferred combination therapy for the treatment of colorectal cancer is surgery, followed by a regimen of one or more chemotherapeutic agents and an MMP inhibitor and a COX-2 inhibitor cycled over a one year time period. A more preferred combination therapy for the treatment of colorectal cancer is a regimen of one or more MM~P inhibitors and/or COX-2 inhibitors, followed by surgical removal of the tumor from the colon or rectum and then followed be a regimen of one or more chemotherapeutic agents and one or more antiangiogenic agents, cycled over a one year time period. An even more preferred therapy for the treatment of colon cancer is a

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-212combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors.

A more preferred therapy for the treatment of colon cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following antineoplastic agents: fluorouracil, and Levamisole.

Preferably, fluorouracil and Levamisole are used in combination.

Example 3 Breast Cancer Today, among women in the United States, breast cancer remains the most frequent diagnosed cancer. One in 8 women in the United States are at risk of developing breast cancer in their lifetime. Age, family history, diet, and genetic factors have been identified as risk factors for breast cancer. Breast cancer is the second leading cause of death among women.

Different chemotherapeutic agents are known in art for treating breast cancer. Cytoxic agents used for treating breast cancer include doxorubicin,cyclophosphamide, methotrexate, fluorouracil, mitomycin C, mitoxantrone, taxol, and epirubicin. CANCER SURVEYS, Breast Cancer volume 18, Cold Spring Harbor Laboratory Press, 1993.

In the treatment of locally advanced noninflammatory breast cancer, MMP inhibitors and/or COX-2 inhibitors can be used to treat the disease in combination with other COX-2 inhibitors, other MMP inhibitors, antiangiogenic agents, or in combination

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-213with surgery, radiation therapy or with chemotherapeutic agents. Preferred combinations of chemotherapeutic agents, radiation therapy and surgery that can be used in combination with the present invention include, but are not limited to the following combinations: 1) doxorubicin, vincristine, radical mastectomy; 2) doxorubicin, vincristine, radiation therapy; 3) cyclophosphamide, doxorubicin, vincristine, prednisone, mastecomy; 4) cyclophosphamide, doxorubicin, 5-flourouracil, vincristine, prednisone, radiation therapy; 5) cyclophosphamide, doxorubicin, flourouracil, premarin, tamoxifen, radiation therapy for pathologic complete response; 6) cyclophosphamide, doxorubicin, 5-flourouracil, premarin, tamoxifen, mastectomy, radiation therapy for pathologic partial response; 7) mastectomy, radiation therapy, levamisole; 8) mastectomy, radiation therapy; 9) mastectomy, vincristine, doxorubicin, cyclophosphamide, levamisole; mastectomy, vincristine, doxorubicin, cyclophosphamide; 11) mastecomy, cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen, halotestin, radiation therapy; 12) mastecomy, cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen, halotestin.

In the treatment of locally advanced inflammatory breast cancer, MMP inhibitors and/or COX-2 inhibitors can be used to treat the disease in combination with other MMP inhibitors and/or COX-2 inhibitors, antiangiogenic agents, or in combination with surgery, radiation therapy or with chemotherapeutic agents.

Preferred combinations of chemotherapeutic agents, radiation therapy and surgery that can be used in combination with the present invention include, but or -214not limited to the following combinations: 1) cyclophosphanide, doxorubicin, 5-fluorouraci-, radiation therapy; 2) cyclophosphamfide, doxorubicin, fluorouracil, mastectomy, radiation therapy; 3) flurouracil, doxorubicin, clyclophosphamide, vincristile, prednisole, mastectomy, radiation therapy; 4) 5-flurouracil., doxorubicin, clyclophosphamfide, vincristile, mastectomy, radiation therapy; cyclophospharide, doxorubicin, vincristine, radiation therapy; 6) cyclophosphamide, doxorubicin, 5-fluorouracl, vincristine, mastectomy, radiation therapy; 7) doxorubicil, .vincristine, methotrexate, radiation therapy, followed by vincristine, cyclophosphamide, 5-fiorouracil; 8) doxorubicii, vincristine, cyclophosphafide, methotrexate, 5-florouracil, radiation therapy, followed by vincristile, cyclophosphamnide, 5-florouracil; 9) surgery, followed by cyclophosphanide, methotreXate, fluorouracil, predinsole, tamoxif en, followed by radiation therapy, followed by cyclophosphamide, methotrexate, S -fluorouracil, predinsone, tamoxif en, doxorubicin, vincristine, tamoxif en; 10) surgery, followed by cyclophosphanide, methotrexate, fluorouracil, followed by radiation therapy, followed by cyclophosphanide, methotrexate, predinsole, tamoxif en, doxorubicin, vincris tine, tamoxif en; 11) surgery, followed by cyclophosphafide, methotrexate, 5-fluorouracil, predinsone, tamoxif en, followed by radiation therapy, followed by cyclophosphamfide, methotrexate, 5-f luorouracil, doxorubicii, vincristile, tainoxifen;; 12) surgery, followed by cyclophosphafide, methotrexate,

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-215fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, predinsone, tamoxifen, doxorubicin, vincristine; 13) surgery, followed by cyclophosphamide, methotrexate, fluorouracil, predinsone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine, tamoxifen; 14) surgery, followed by cyclophosphamide, methotrexate, fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, predinsone, tamoxifen, doxorubicin, vincristine; surgery, followed by cyclophosphamide, methotrexate, fluorouracil, predinsone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, vincristine; 16) 5-florouracil, doxorubicin, cyclophosphamide followed by mastectomy, followed by doxorubicin, cyclophosphamide, followed by radtiation therapy.

In the treatment of metastatic breast cancer, MMP inhibitors and/or COX-2 inhibitors can be used to treat the disease in combination with other MMP inhibitors and/or COX-2 inhibitors, antiangiogenic agents, or in combination with surgery, radiation therapy or with chemotherapeutic agents. Preferred combinations of chemotherapeutic agents that can be used in combination with the angiogenesis inhibitors of the present invention include, but are not limited to the following combinations: 1) cyclosphosphamide, methotrexate, fluorouracil; 2) cyclophosphamide, adriamycin, fluorouracil; 3) cyclosphosphamide, methotrexate,

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flurouracil, vincristine, prednisone; 4) adriamycin, vincristine; 5) thiotepa, adriamycin, vinblastine; 6) mitomycin, vinblastine; 7) cisplatin, etoposide.

Example 4 Prostate Cancer Prostate cancer is now the leading form of cancer among men and the second most frequent cause of death from cancer in men. It is estimated that more than 165,000 new cases of prostate cancer were diagnosed in 1993, and more than 35,000 men died from prostate cancer in that year. Additionally, the incidence of prostate cancer has increased by 50% since 1981, and mortality from this disease has continued to increase. Previously, most men died of other illnesses or diseases before dying from their prostate cancer. We now face increasing morbidity from prostate cancer as men live longer and the disease has the opportunity to progress.

Current therapies for prostate cancer focus exclusively upon reducing levels of dihydrotestosterone to decrease or prevent growth of prostate cancer. In addition to the use of digital rectal examination and transrectal ultrasonography, prostate-specific antigen (PSA) concentration is frequently used in the diagnosis of prostate cancer.

A preferred therapy for the treatment of prostate cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors.

U.S. Pat. No. 4,472,382 discloses treatment of benign -217prostatic hyperplasia (BPH) with an antiandrogen and certain peptides which act as LH-RH agonists.

U.S. Pat. No. 4,596,797 discloses aromatase inhibitors as a method of prophylaxis and/or treatment of prostatic hyperplasia.

U.S. Pat. No. 4,760,053 describes a treatment of certain cancers which combines an LHRH agonist with an antiandrogen and/or an antiestrogen and/or at least one inhibitor of sex steroid biosynthesis.

U.S. Pat. No. 4,775,660 discloses a method of treating breast cancer with a combination therapy which may include surgical or chemical prevention of ovarian secretions and administering an antiandrogen.and an antiestrogen.

U.S. Pat. No. 4,659,695 discloses a method of treatment of prostate cancer in susceptible male animals including humans whose testicular hormonal secretions are blocked by surgical or chemical means, e.g. by use of an LHRH agonist, which comprises administering an antiandrogen, e.g. flutamide, in association with at least one inhibitor of sex steroid biosynthesis, e.g.

aminoglutethimide and/or ketoconazole.

Prostate Specific Antigen One well known prostate cancer marker is prostate Specific Antigen (PSA). PSA is a protein produced by prostate cells and is frequently present at elevated levels in the blood of men who have prostate cancer. PSA has been shown to correlate with tumor burden, serve as an indicator of metastatic involvement, and provide a parameter for following the response to surgery, irradiation, and androgen replacement therapy in -218prostate cancer patients. It should be noted that Prostate Specific Antigen (PSA) is a completely different protein from Prostate Specific Membrane Antigen (PSMA). The two proteins have different structures and functions and should not be confused because of their similar nomenclature.

Prostate Specific Membrane Antigen (PSMA) In 1993, the molecular cloning of a prostatespecific membrane antigen (PSMA) was reported as a potential prostate carcinoma marker and hypothesized to serve as a target for imaging and cytotoxic treatment modalities for prostate cancer. Antibodies against PSMA have been described and examined clinically for diagnosis and treatment of prostate cancer. In particular, Indium-111 labelled PSMA antibodies have been described and examined for diagnosis of prostate cancer and itrium-labelled PSMA antibodies have been described and examined for the treatment of prostate cancer.

Example Bladder Cancer The classification of bladder cancer is divided into three main classes: 1) superficial disease, 2) muscle-invasive disease, and 3) metastatic disease.

Currently, transurethral resection (TUR), or segmental resection, account for first line therapy of superficial bladder cancer, disease confined to the mucosa or the lamina propria. However, intravesical therapies are necessary, for example, for the treatment

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-219of high-grade tumors, carcinoma in situ, incomplete resections, recurrences, and multifocal papillary.

Recurrence rates range from up to 30 to 80 percent, depending on stage of cancer.

Therapies that are currently used as intravesical therapies include chemotherapy, immuontherapy, bacille Calmette-Guerin (BCG) and photodynamic therapy. The main objective of intravesical therapy is twofold: to prevent recurrence in high-risk patients and to treat disease that cannot by resected. The use of intravesical therapies must be balanced with its potentially toxic side effects. Additionally,

BCG

requires an unimpaired immune system to induce an antitumor effect. Chemotherapeutic agents that are knownto be inactive against superficial bladder cancer include Cisplatin, actinomycin D, bleomycin, and cyclophosphamide methotrxate.

In the treatment of superficial bladder cancer, MMP inhibitors and/or COX-2 inhibitors can be used to treat the disease in combination with other MMP inhibitors and/or COX-2 inhibitors, antiangiogenic agents, or in combination with surgery (TUR), chemotherapy and intravesical therapies.

A preferred therapy for the treatment of superficial bladder cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with: thiotepa (30 to 60 mg/day), mitomycin C (20 to mg/day), and doxorubicin (20 to 80 mg/day).

A preferred intravesicle immunotherapeutic agent that may be used in the present invention is BCG. A preferred daily dose ranges from 60 to 120 mg, depending -220on the strain of the live attenuated tuberculosis organism used.

A preferred photodynamic therapuetic agent that may be used with the present invention is Photofrin I, a photosensitizing agent, administered intravenously. It is taken up by the low-density lipoprotein receptors of the tumor cells and is activated by exposure to visible light. Additionally, neomydium YAG laser activation generates large amounts of cytotoxic free radicals and singlet oxygen.

In the treatment of muscle-invasive bladder cancer, MMP inhibitors and/or COX-2 inhibitors can be used to treat the disease,in combination with other MMP inhibitors and/or COX-2 inhibitors, antiangiogenic agents, or in combination with surgery (TUR), intravesical chemotherapy, radiation therapy, and radical cystectomy with pelvic lymph node dissection.

A preferred radiation dose for the treatment of bladder cancer is between 5,000 to 7,000 cGY in fractions of 180 to 200 cGY to the tumor. Additionally, 3,500 to 4,700 cGY total dose is administered to the normal bladder and pelvic contents in a four-field technique. Radiation therapy should be considered only if the patient is not a surgical candidate, but may be considered as preoperative therapy.

A preferred combination of surgery and chemotherapeutic agents that can be used in combination with the MMP inhibitors and/or COX-2 inhibitors of the present invention is cystectomy in conjunction with five cycles of cisplatin (70 to 100 mg/im(square)); doxorubicin (50 to 60 mg/m(square); and cyclophosphamide (500 to 600 mg/m(square).

-221- A more preferred therapy for the treatment of superficial bladder cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors.

An even more preferred combination for the treatment of superficial bladder cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; and 2) cisplatin, 5-fluorouracil. An even more preferred combination of chemotherapeutic agents that can be used in combination with radiation therapy and the MMP inhibitors and/or COX-2 inhibitors is a combination of cisplatin, methotrexate, vinblastine.

Currently no curative therapy exists for metastatic bladder cancer. The present invention contemplates an effective treatment of bladder cancer leading to improved tumor inhibition or regression, as compared to current therapies.

In the treatment of metastatic bladder cancer, MMP inhibitors and/or COX-2 inhibitors can be used to treat the disease in combination with other MMP inhibitors and/or COX-2 inhibitors, antiangiogenic agents, or in combination with surgery, radiation therapy or with chemotherapeutic agents.

A preferred therapy for the treatment of metastatic bladder cancer is a combination of therapeutically effective amounts of one or more NMP inhibitors and/or COX-2 inhibitors.

A more preferred combination for the treatment of metastatic bladder cancer is a combination of

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-222therapeutically effective amounts of one or more NMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplasitc agents: 1) cisplatin and methotrexate; 2) doxorubicin, vinblastine, cyclophoshamide, and 5-fluorouracil; 3) vinblastine, doxorubicin, cisplatin, methotrexate; 4) vinblastine, cisplatin, methotrexate; 5) cyclophosphamide, doxorubicin, cisplatin; 6) 5-fluorouracil, cisplatin.

Example 6 Pancreas Cancer Approximately 2% of new cancer cases diagnoses in the United States is pancreatic cancer. Pancreatic cancer is generally classified into two clinical types: 1) adenocarcinoma (metastatic and non-metastatic), and 2) cystic neoplasms (serous cystadenomas, mucinous cystic neoplasms, papilary cystic neoplasms, acinar cell systadenocarcinoma, cystic choriocarcinoma, cystic teratomas, angiomatous neoplasms).

Preferred combinations of therapy for the treatment of non-metastatic adenocarcinoma that may be used in the present invention include the use of MMP inhibitors and/or COX-2 inhibitors along with preoperative bilary tract decompression (patients presenting with obstructive jaundice); surgical resection, including standard resection, extended or radial resection and distal pancreatectomy (tumors of body and tail); adjuvant radiation; and chemotherapy.

For the treatment of metastatic adenocarcinoma, a preferred combination therapy consists of an antiangiogenesis inhibitor of the present invention in -223combination with continuous treatment of fluorouracil, followed by weekly cisplatin therapy.

A more preferred combination therapy for the treatment of cystic neoplasms is the use of MMP inhibitors and/or COX-2 inhibitors along with resection.

Examole 7 Ovary Cancer Celomic epithelial carcinoma accounts for approximately 90% of ovarian cancer cases. A preferred therapy for the treatment of ovary cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors.

Preferred single agents that can be used in combination with an antiangiogenesis agent include, but are not limited to: alkylating agents, ifosfamide, cisplatin, carboplatin, taxol, doxorubicin, fluorouracil, methotrexate, mitomycin, hexamethylmelamine, progestins, antiestrogens, prednimustine, dihydroxybusulfan, galactitol, interferon alpha, and interferon gama.

Preferred combinations for the treatment of celomic epithelial carcinoma is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2) hexamthylmelamine, cyclosphamide, doxorubicin, cisplatin; 3) cyclophosphamide, hexamehtylmelamine, cisplatin; 4) melphalan, hexamethylmelamine, cyclophosphamide; 5) melpha-lan, doxorubicin, -224cyclophosphamide; 6) cyclophosphamide, cisplatin, carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine, cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylmelamine, carboplatin; 9) cyclophosphamide, cisplatin; 10) hexamethylmelamine, doxorubicin, carboplatin; 11) cyclophosphamide, hexamethlmelamine, doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide.

Germ cell ovarian cancer accounts for approximately of ovarian cancer cases. Germ cell ovarian carcinomas are classified into two main groups: 1) dysgerminoma, and nondysgerminoma. Nondysgerminoma is further classified into teratoma, endodermal sinus tumor, embryonal carcinoma, chloricarcinoma, polyembryoma, and mixed cell tumors.

A preferred therapy for the treatment of germ cell carcinoma is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors.

A more preferred therapy for the treatment of germ cell carcinoma is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) vincristine, actinomycin D, cyclophosphamide; 2) bleomycin, etoposide, cisplatin; 3) vinblastine, bleomycin, cisplatin.

Cancer of the fallopian tube is the least common type of ovarian cancer, accounting for approximately 400 new cancer cases per year in the United States.

Papillary serous adenocarcinoma accounts for

I

-225approximately 90% of all malignancies of the ovarian tube.

A preferred therapy for the treatment of fallopian tube cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors.

A more preferred therapy for the treatment of fallopian tube cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplastic agents: alkylating agents, ifosfamide, cisplatin, carboplatin, taxol, doxorubicin, 5-fluorouracil, methotrexate, mitomycin, hexamethylmelamine, progestins, antiestrogens, prednimustine, dihydroxybusulfan, galactitol, interferon alpha, and interferon gama.

An even more preferred therapy for the treatment of fallopian tube cancer is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2) hexamthylmelamine, cyclosphamide, doxorubicin, cisplatin; 3) cyclophosphamide, hexamehtylmelamine, flurouracil, cisplatin; 4) melphalan, hexamethylmelamine, cyclophosphamide; 5) melphalan, doxorubicin, cyclophosphamide; 6) cyclophosphamide, cisplatin, carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine, cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylmelamine, carboplatin; 9) cyclophosphamide, cisplatin; hexamethylmelamine, doxorubicin, carboplatin; 11)

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-226cyclophosphamide, hexamethlmelamine, doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide.

Example 8 Central Nervous System Cancers Central nervous system cancer accounts for approximately 2% of new cancer cases in the United States. Common intracranial neoplasms include glioma, meninigioma, neurinoma, and adenoma.

A preferred therapy for the treatment of central nervous system cancers is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors.

A preferred therapy for the treatment of maligant glioma is a combination of therapeutically effective amounts of one or more MMP inhibitors and/or COX-2 inhibitors in combination with the following combinations of therapies and antineoplastic agents: 1) radiation therapy, BCNU (carmustine); 2) radiation therapy, methyl CCNU (lomustine); 3) radiation therapy, medol; 4) radiation therapy, procarbazine; 5) radiation therapy, BCNU, medrol; 6) hyperfraction radiation therapy, BCNU; 7) radiation therapy, misonidazole,

BCNU;

8) radiation therapy, streptozotocin; 9) radiation therapy, BCNU, procarbazine; 10) radiation therapy, BCNU, hydroxyurea, procarbazine, VM-26; 11) radiation therapy, BNCU, 5-flourouacil; 12) radiation therapy, Methyl CCNU, dacarbazine; 13) radiation therapy, misonidazole, BCNU; 14) diaziquone; 15) radiation therapy, PCNU; 16) procarbazine (matulane),

CCNU,

-227vincristile. A preferred dose of radiation therapy is about 5,500 to about 6,000 cGY. Preferred radiosensitiZers include misonidazole, intra-arterial Budz and intravenous iododeoxyuridile (IUdR) It is also contemplated that radiosurgery may be used in combinations with antiangiogenesis agents.

Exam-ple 9 Additional examples of combinations are listed in Table No 22.

Table No. 22., Therapy Combinations COX-2 1MB I-.ibitor inhibitor Celecoxib Compound M1 Celecoxib Compound M2 Celecoxib Compound M3 Celecoxib Compound M4 Celecoxib Compound Celecoxib Compound M7 Celecoxib Bay-12-9566 Celecoxib Metastat Celecoxib D-2163 Celecoxib D-1927 Rofecoxib Compound M1 Rofecoxib, Compound M2 Rofecoxib Compound M3 Rofecoxib Compound M4 Rofecoxib Compound Rofecoxib Compound M7 Rofecoxib Marimastat -228- Rofecoxib Bay-l2-9566 Rofecoxib AG-3340 Rofecoxib Metastat Rofecoxib D-2163 Rofecoxib D-1927 JTE-522 compound MI JTE-522 Compound M2 JTE-522 Compound M3 JTE-522 Compound M4 JTE-522 Compound JTE-522 Compound M7 JTE-522 Marimastat JTE-522 Bay-l2-956 6 JTE-522 AG-3340 JTE-522 Metastat JTE-522 D-2163, JTE-522 D-1927 Further additional examples of combinations are listed in Table No 23.

Table No. 23. Additional examples of combination therapies COX-2 beP Antineoplastic Indication Inhibitor Inhibitor Agent Celecoxib Compound M1 Anastrozole Breast Celecoxib Compound Ml Capecitabine Breast Celecoxib Compound Ml Docetaxel Breast Celecoxib Compound Ml Gemcitabine Breast, Pancreas Celecoxib Compound Ml Letrozole Breast

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-229- Celecoxib Compound Ml Megestrol Breast Celecoxib Compound M1 Paclitaxel Breast Celecoxib Compound M1 Tamoxif en Breast Celecoxib Compound MI Toremifene Breast Celecoxib Compound Ml Vinorelbile Breast, Lung Celecoxib Compound MI Topotecan Lung Ceecoxib Compound M1 Etoposide Lung Celecoxib Compound M1 Fluorouracil Colon Celecoxib Compound M1 Irinotecan Colon, (CPT-11) Bladder Celecoxib Compound M1 Retinoids Colon Celecoxib Compound M1 DFMO Colon Celecoxib Compound M1 Ursodeoxycholi Colon c acid Celecoxib Compound M1 calcium Colon carbonate Celecoxib Compound M1 selenium Colon Celecoxib Compound Ml sulindac Colon sulfone Celecoxib Compound M1 Carboplatin Brain Celecoxib Compound Ml Goserelin Prostate Acetate Celecoxib Compound Ml Ketoconazole Prostate Celecoxib Compound M1 Cisplatin Celecoxib Compound M2 Anastrozole Breast Celecoxib Compound M2 Capecitabie Breast Celecoxib Compound M2 Docetaxel Breast Celecoxib Compound M2 Gemcitabine Breast, Pancreas Celecoxib Compound M2 Letrozole Breast 1 -230- Celecoxib Compound 142 Megestrol Breast Celecoxib Compound M42 Paclitaxel Breast Celecoxib Compound M42 Tainoxif en Breast Celecoxib Compound M42 Toremifele Breast Celecoxib Compound M42 Vinorelbine Breast, Lung Celecoxib Compound 142 Topotec an Lung Celecoxib Compound 142 Etoposide Lung Celecoxib Compound M42 Fluorouracil Colon Celecoxib Compound 142 Irinotecan Colon, (CPT-1l) Bladder Celecoxib Compound M2 Ret inoids. Colon Celecoxib Compound M42 DFMO Colon Celecoxib Compound 142 Ursodeoxycholi Colon c acid Celecoxib Compound 142 calcium Colon carbonate Celecoxib Compound M42 selenium Colon Celecoxib Compound 142 sulindac Colon sul f one Celecoxib Compound M42 Carboplatin Brain Celecoxib Compound 142 Goserelin Prostate Acetate Celecoxib Compound M42 Ketoconazole Prostate Celecoxib Compound 142 Cisplatin Celecoxib Compound M43 Anastrozole Breast Celecoxib Compound M43 Capecitabine Breast Celecoxib Compound M43 Docetaxel Breast Celecoxib Compound M43 Gemcitabine Breast, Pancreas Celecoxib Compound X43 Letrozole Breast -23 1- Celecoxib Compound M3 bMegestrol Breast Celecoxib Compound M3 Paclitaxel Breast Celecoxib Compound M3 Tamoxif en Breast Celecoxib Compound M3 Toremifele Breaast Celecoxib Compound M3 Vinorelbile Breast, Lung Celecoxib Compound M3 Topotecai Lung Celecoxib Compound M3 Etoposide Lung Ceeoxib Compound M3 Fluorouracil Colon Celecoxib Compound M3 Irinotecan Colon, (CPT-11) Bladder Celecoxib Compound M3 Retinoids Colon Celecoxib Compound M43 DFMO Colon Celecoxib Compound M43 Ursodeoxycholi Colon c acid Celecoxib Compound M43 calcium Colon carbonate Celecoxib Compound M43 selenium Colon Celecoxib Compound M43 sulindac Colon sul fone Celecoxib Compound 143 Carboplatii Brain Celecoxib Compound M43 Goserelii Prostate Acetate Celecoxib Compound M44 Capecitabile Breast Celecoxib Compound 144 Docetaxel Breast, Pancreas Celecoxib Compound M44 Gemcitabile Breast Celecoxib Compound M44 Letrozole Breast

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-232- Celecoxib Compound M4 Megestrol Breast Celecoxib Compound M4 Paclitaxel Breast Celecoxib Compound M4 Tamoxifen Breiast Celecoxib Compound M4 Toremifee Breast, Lung Celecoxib Compound M4 Vinorelbine Lung Celecoxib Compound M4 Topotecan Lung Celecoxib Compound M4 Etoposide Colon Celecoxib Compound M4 Fluorouracil Colon, Bladder Celecoxib Compound M4 Irinotecan Colon.

(CPT-11) Celecoxib Compound M4 Retinoidt Colon Celecoxib Compound M4 DFMO Colon Celecoxib Compound M4 Ursodeoxycholi Colon c acid Celecoxib Compound M4 calcium Colon carbonate Celecoxib Compound M4 selenium Colon Celecoxib Compound M4 sulindac Colon sulfone Celecoxib Compound M4 Carboplatin Brain Celecoxib Compound M4 Goserein Prostate Acetate Celecoxib Compound 14 Ketocofazole Prostate Celecoxib Compound M4 Cisplatin Celecoxib Compound 145 Anastrozole Breast Celecoxib Compound M5 Capecitabine Breast Celecoxib Compound MS Docetaxel Breast, Pancreas Celecoxib Compound M5 Gemcitabine Breast -23 3- Celecoxib Compound M5 LTmoifen Breast Celecoxib Compound MS Toemefrle Breast 1 Celecoxib Compound MS Pacinoreln Breng Celecoxib Compound M5 Taooten Brung Celecoxib Compound M5 Etoposide Colon Celecoxib Compound M5 Fluorouracil Colon, Bladd~er Celecoxib Compound MS Irinotecan Colon (CPT-ll) Celecoxib Compound MS Retinoids Colon Celecoxib Compound MS DFMO Colon Celecoxib Compound MS Ursodeoxycholi Colon c acid Celecoxib Compound MS calcium Colon carbonate Celecoxib Compound MS selenium Colon Celecoxib Compound M5 sulindac Colon suif one Celecoxib Compound MS Carboplatin Brain Celecoxib Compound MS Goserel in Prostate Acetate Celecoxib Compound MS Ketoconazole Prostate Celecoxib Compound MS Cisplatin Celecoxib Compound M7 Anastrozole Breast Celecoxib Compound M7 Capecitabile Breast Celecoxib Compound M7 Docetaxel Breast, Pancreas

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-234- Celecoxib Compound M7 Gemcitabine Breast Celecoxib Compound M7 Letrozole Breast Celecoxib Compound M7 Megestrol Breast Celecoxib Compound M7 Paclitaxel Breast Celecoxib Compound M7 Tamox1fen Breast Celecoxib Compound M7 Toremifee Breast, Lung Celecoxib Compound M7 Vinorelbine Lung Celecoxib Compound M7 Topotecan Lung Celecoxib Compound M7 Etoposide Colon Celecoxib Compound M7 Fluorouracil Colon, Bladder Celecoxib Compound M7 Irinotecan Colon (CPT-11) Celecoxib Compound M7 Retinoids Colon Celecoxib Compound M7 DFMQ Colon Celecoxib Compound M7 Ursodeoxycholi Colon c acid Celecoxib Compound M7 calcium Colon carbonate Celecoxib Compound M7 selenium Colon Celecoxib Compound M7 sulindac Colon sulfone Celecoxib Compound M7 Carboplati Brain Celecoxib Compound M7 Goserelin Prostate Acetate Celecoxib Compound M7 Ketoconazole Prostate Celecoxib Compound M7 Cisplatin Celecoxib Bay-12-9566 Anastrozole Colon Celecoxib Bay-12-9566 Capecitabie Brain -235- Celecoxib Bay-12-956 6 Docetaxel Prostate Celecoxib Bay-12-956 6 Geincitabine Prostate Celecoxib Bay-12-9566 Letrozole Breast Celecoxib Bay-12-9566 Megestrol Breast Celecoxib Bay-l2-956 6 Paclitaxel Breast Celecoxib Bay-12-9566 Tamnoxif en Breast- Celecoxib Bay-12-9566 Toremifene Breast Celecoxib Bay-12-9566 Vinorelbine Breast, Lung Celecoxib Bay-12-9566 Topotecan Lung Celecoxib 'Bay-l2-9566 Etoposide Lung.

Celecoxib Bay-12-9566 Fluorouracil Colon Celecoxib Bay-12-9566 Irinotecan Colon, (CPT-11) Bladder Celecoxib Bay-12-9566 Retinoids Colon Celecoxib Bay-12-9566 selniu Colon Celecoxib Bay-12-9566 slidaoxchl Colon Celecoxib Bay-12-9566 calboiatm Brain Celecoxib Bay-12-956 6 Gseein Postat Celecoxib Bay-12-'9566 Ketocnazo Potat Celecoxib Bay-12-9566 CisbplatinBri Celecoxib Meastat956 Knatonzole Brestt Celecoxib Metastat Cnaectabie Breast Celecoxib Metastat Dopctaele Breast Celecoxib Metastat Gemcitabine Breast, Pancreas Celecoxib Metastat. Letrozo-e Breast Celecoxib Metastat MegestroJ. Breast celecoxib Metastat Paclitaxel Breast Celecoxib Metastat Taxnoxif en Breast Celecoxib Metastat Toremifele Breast Celecoxib Metastat Vinorelbine Breast, Lung Celecoxib Metastat Topotecan Lung Celecoxib Metastat Etoposide Lung- Celecoxib Metastat Fluorouracil Colon Celecoxib Metastat Irinotecan. Colon, (OPT-li) Bladder Celecoxib Metastat Retinoids Colon Celecoxib Metastat DFMO Colon Celecoxib Metastat Ursodeoxycholi Colon c acid Celecoxib Metastat calcium Colon carbonate Celecoxib Metastat selenium Colon Celecoxib Metastat sulindac Colon sulforie Celecoxib Metastat Carboplatin Brain Celecoxib Metastat Cisplatin Celecoxib D-2163 Anastrozole Breast Celecoxib D-2163 Capecitabile Breast Celecoxib D-2163 Docetaxel Breast -237- Celecoxib D-2163 Gemcitabine Breast, Pancreas Celecoxib D-2163 Letrozole Breast Celecoxib D-2163 Megestrol Breast Celecoxib D-2163 Paclitaxel Breast Celecoxib D-2163 Tamoxif en Breast Celecoxib D-2163 Toremifene Breast Celecoxib D-2163 Vinorelbine Breast, Lung Celecoxib, D-2163 Topotecan Lung Celecoxib D-2163 Etoposide Lung Celecoxib D-2163 Fluorouracil, Colon Celecoxib D-2163 Irinotecan Colon, (CPT-ll) Bladder Celecoxib D-2163 Retinoids Colon Celecoxib D-2163 DFMO. Colon Celecoxib D-2163 Ursodeoxycholi Colon c acid Celecoxib D-2163 calcium Colon carbonate Celecoxib D-2163 selenium Colon Celecoxib D-2163 sulindac Colon sulf one Celecoxib D-2163 Carboplatin Brain Celecoxib D3-2163 Goserelin Prostate Acetate Celecoxib D-2163 Ketoconazole Prostate Celecoxib D-2163 Cisplatin Celecoxib D-1927 Anastrozole Breast Celecoxib D-1927 Capecitabine Breast Celecoxib D3-1927 Docetaxel Breast -23 8- Celecoxib D-1927 Gemcitabine Breast, Pancreas Celecoxib D-1927- Letrozole Breast Celecoxib D-1927 Megestrol Breast Celecoxib D-1927 Paclitaxel Breast Celecoxib D-1927 Tamnoxif en Breast Celecoxib D-1927 Toremifene Breast Celecoxib D-1927 Vinorelbine Breast,.

Celecoxib D-1927 Fluorouracil Colon Celecoxib D-1927 Irinotecan Colon, (CPT-11) Bladder Celecoxib D-1927 Retinoids Colon Celecoxib D-1927 DFMO Colon Celecoxib D-1927 Ursodeoxycholi Colon c acid Celecoxib D-1927 calcium Colon carbonate Celecoxib D-1927 selenium Colon Celecoxib D-1927 sulindac Colon sul fone Celecoxib D-1927 Carboplatin Brain Celecoxib D-1927 Goserelin Prostate Acetate Celecoxib D-1927 Ketoconazole Prostate Celecoxib D-1927 Cisplatin Celecoxib Compound M1 Anastrozole Breast Celecoxib Compound Ml Capecitabine Breast -239- Celecoxib Compound M1 Loetozol Breast Celeco2Cib Compound M1 Gemestroln Breast, Celecoxib Compound M1 Laclitaxel Breast Celecoxib Compound M1 Tamoxif en. Breast Celecoxib -Compound MJ. Toremifefle Breast Celecoxib Compound MI Vinorelbirie Breast, Lung Celecoxib Compound X1 Topotecai Lung Celecoxib Compound NJ1 Etoposide Lung Celecoxib Compound M1 RtFluoui Colon Celecoxib Compound Ml DFNO Colon Celecoxib Compound Mi Ursodeoxycholi Colon c acid Celecoxib Compound M1 calcium Colon carbonate Celecoxib Compound Ni selenium Colon Celecoxib Compound Mi sulindac Colon suif one Celecoxib Compound Mi Carboplatin Brain Celecoxib Compound M1i Goserelin Prostate Acetate Celecoxib Compound M1 Ketoconazo-e Prostate Celecoxib Compound M1i Cisplatin Celecoxib Compound M2 Anastrozole Breast Celecoxib Compound M2 Capecitabirle Breast -240- Celecoxib Compound N2 Docetaxel Breast Celecoxib Compound M2 Gemcitabine Breast, Pancreas Celecoxib Compound N42 Letrozole -Breast.

Celecoxib Compound M2 Megestrol Breast Celecoxib Compound M42 Paclitaxel Breast Celecoxib Compound 142 Tamoxifen Breast Celecoxib Compound M42 Toremitene Breast Celecoxib Compound N42 Vinorelbine Breast, Lung Celecoxib Compound E42 Topotecan Lung Celecoxib Compound M42 Etoposide Lung Celecoxib Compound M42 Fluorouracil Colon Celecoxib Compound 142 Irinotecan Colon, (CPT-ll) Bladder Celecoxib Compound M42 Retinoids Colon Celecoxib Compound M42 DF14O Colon Celecoxib Compound 142 Ursodeoxycholi Colon c acid Celecoxib Compound 142 calcium Colon carbonate Celecoxib Compound M2 selenium Colon Celecoxib Compound M42 sulindac Colon Ulf one Celecoxib Compound M42 Carboplatin Brain Celecoxib Compound M42 Goserelin Prostate Acetate Celecoxib Compound M42 Ketoconazole Prostate Celecoxib Compound 142 Cisplatin Celecoxib Compound M3 Anastrozole Breast Celecoxib Compound M3 Capecitabine Breast

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-241- Celecoxib Compound M3 Docetaxel Breast Celecoxib Compound M3 Gemcitabie Breast, pancreas Celecoxib Compound M3 Letrozole Breast Celecoxib Compound M3 Megestrol Breast Celecoxib Compound M3 Paclitaxel Breast Celecoxib Compound M3 Tamoxifen Breast Celecoxib Compound M3 Toremifee Breast Celecoxib Compound M3 Vinorelbine Breast, Lung Celecoxib Compound M3 Topotecan Lung Celecoxib Compound M3 Etoposide Lung Celecoxib Compound M3 Fluorouracil Colon Celecoxib Compound M3 Irinotecan Colon, (CPT-l) Bladder Celecoxib Compound M3 Retinoids Colon Celecoxib compound M3 DFMO Colon Celecoxib Compound M3 Ursodeoxycholi Colon c acid Celecoxib Compound 43 calcium Colon carbonate Celecoxib Compound M3 selenium Colon Celecoxib Compound 143 sulindac Colon sulfone Celecoxib Compound M3 Carboplatin Brain Celecoxib Compound M3 Goserelin Prostate Acetate Celecoxib Compound 13 Ketoconazole Prostate Celecoxib Compound M3 Cisplatin Celecoxib Compound 14 Anastrozole Breast Celecoxib Compound M4 Capecitabine Breast

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-242- Celecoxib Compound M4 Docetaxel Breast, Pancreas Celecoxib Compound M4 Gemcitabine Breast Celecoxib Compound M4 Letrozole Breast Celecoxib Compound M4 Megestrol Breast Celecoxib Compound M4 Paclitaxel Breast Celecoxib Compound M4 Tamoxifen Breast Celecoxib Compound M4 Toremifene Breast, Lung Celecoxib Compound M4 Vinorelbine Lung Celecoxib Compound M4 Topotecan Lung Celecoxib Compound M4 Etoposide Colon Celecoxib Compound M4 Fluorouracil Colon, Bladder Celecoxib Compound M4 Irinotecan Colon (CPT-11) Celecoxib Compound M4 Retinoids Colon Celecoxib Compound M4. DFMO Colon Celecoxib Compound M4 Ursodeoxycholi Colon c acid Celecoxib Compound M4 calcium Colon carbonate Celecoxib Compound M4 selenium Colon Celecoxib Compound M4 sulindac Colon sulfone Celecoxib Compound M4 Carboplatin Brain Celecoxib Compound M4 Goserelin Prostate Acetate Celecoxib Compound M4 Ketoconazole Prostate Celecoxib Compound M4 Cisplatin Celecoxib Compound M5 Anastrozole Breast -243- Celecoxib compound M5 Capecitabine Breast Celecoxib Compound M5 Topotaea Lunast Celecoxib Compound M5 GEmtoie Colont Celecoxib Compound M5 lurouraci Colon, Celecoxib Compound M5 Iinstoea Colont Celecoxib Compound MS etaoifnd Colont Celecoxib Compound M5 DFrmOfn Colont Celecoxib Compound MS Vinrod eoxc l Ln Celecoib Comound c aotcd un Celecoxib Compound M5 calcoim Colon Celeco2ib Compound M Caroplatin Bran Celecoxib Compound M5 Grioeeln Cotat ce tate Celecoxib Compound MS etioonzol Coont Celecoxib Compound MS CisplCoton I -244- Celecoxib Compound M7 Anastrozole Breast Celecoxib Compound M7 Capecitabine Breast Celecoxib Compound M7 Docetaxel Breast, Pancreas Celecoxib Compound M7 Gemcitabine Breast Celecoxib Compound M7 Letrozole Breast Celecoxib Compound M7 Megestrol Breast Celecoxib Compound M7 Paclitaxel Breast Celecoxib Compound M7 Tamoxifen Breast Celecoxib Compound M7 Toremifene Breast, Lung.

Celecoxib Compound M7 Vinorelbine Lung Celecoxib Compound M7 Topotecan Lung Celecoxib Compound M7 Etoposide Colon Celecoxib Compound M7 Fluorouracil Colon, Bladder Celecoxib Compound M7 Irinotecan Colon (CPT-11) Celecoxib Compound M7 Retinoids Colon Celecoxib Compound M7 DFMO Colon Celecoxib Compound M7 Ursodeoxycholi Colon c acid Celecoxib Compound M7 calcium Colon carbonate Celecoxib Compound M7 selenium Colon Celecoxib Compound M7 sulindac Colon sulfone Celecoxib Compound M7 Carboplatin Brain Celecoxib Compound M7 Goserelin Prostate Acetate Celecoxib Compound M7 Ketoconazole Prostate -245- Celecoxib compound 147 Cisplatin Rofecxib Bay-12-9 566 Anastrozole Colon Rofecoxib Bay-12-9 566 Capecitabine Brai-n Rot ecoxib Bay-l2- 9566 Docetaxel Prostate RofecoXib Bay-12-9 566 Gemcitabifle Prostate Rofecoxib Bay-12-9 566 Letrozole Breast RofeCoXib Bay-1 2 -_9 566 Megestrol Breast Rofecoxib -Bay-12- 9566 Paclitaxel Breast Rofecoxib Bay-12-9 566 Tamoxif en Breast Rofecoxib Bay-12-- 9566 Toremifele Breast Rofecoxib Bay-12-9 566 XVinorelbirle Breast, Lung Rot ecoxib Bay-12-9 566 Topotecai Lung Rot ecoxib Bay-12-95 66 Etoposide Lung Rofecoxib Bay-12-9 566 Fluorouracil Colon Rofecoxib Bay-12- 9566 Irinotecai Colon, (CPT-l1) Bladder Rofecoxib Bay-1 2 -9566 Retifloids Colon Rofecoxib; Bay-12-9 566 DFMO Colon Rtcoxib Bay-12-95 66 Ursodeoxycholi Colon c acid Rofecoxib Bay-12- 9566 calcium Colon carbonate Rofecoxib Bay-12-95 66 selenium Colon Rofecoxib Bay-12-9 566 sulindac Colon suit one Rofecoxib Bay-12-9566 Ketocoflazole Prostate -246- Rofecoxib Metas tat Docetaxe Breast Rofecoxib IMetastat Gaecitabie Breast, Rofecoxib Metastat Loetozole Breast Rofecoxib Metastat Gegestro].e Breast, RofecoXib Metastat Maclitaxl Breast Rofecoxib Metastat Tamoxif e Breast Rofecoxib Metastat Taoeiifenl Breast Rofecoxib Metastat Vinorelbine Breast, Lung Rofecoxib Metastat Topotecan, Lung Rofecoxib Metastat Etoposide Lung Rofecoxib Metastat Fluorouracil Colon Rot ecoxib Metastat Irinotecan Colon, (CPT-11) Bladder Rofecoxib Metastat Retinoids 'Colon Rot ecoxib Metastat DFMO Colon Rot ecoxib Metastat Ursocleoxycholi Colon c acid Rofecoxib Metastat -calcium Colon carbonate- Rofecoxib Metastat selenium Colon Rofecoxib Metastat sulindac Colon sult one Rofecoxib Metastat Carboplatii Brain Rofecoxib Metastat Goserelin Prostate Acetate Rofecoxib Metastat Ketoconazole Prostate -247- Rof ecoxib Metastat Cisplatin Rofecoxib D-2163 ?Anastrozole Breast Ref ecoxib D-2163 Capecitabile Breast Ref ecoxib D-2163 Docetaxe- Breast Rof ecoxib D-2163 Gemcitabile Breast, Pancreas Rof ecoxib D-2163 LTamoxfen Breast Rot ecoxib D-2163 Toemefle Breast Rof!ecoxib D-2163 Vacinorell Breast, Rot ecoxib D-2163 Taootear Lrens Rofecoxib D-2163 Etopoidee Lungs Rofecoxib D-2163 Vluorourail Colont Rof ecoxib D-2163 Irinotecan Colon, (CPT-1l) Bladder Rofecoxib D-2163 Retinoids Colon Rofecoxib D-2163 DFMO Colon Rofecoxib D-2163 Ursodeoxycholi Colon c acid Ref ecexib D-2163 calcium Colon carbonate Ref ecoxib D-2163 selenium Colon Rot ecoxib D-2163 sulindac Colon sulfone Rof ecoxib D-2163 Carboplatin Brain Rofecoxib D-2163 Goserelin Prostate Acetate Rofecoxib D-2163 Ketoconazole Prostate -248- Rofecoxib D-2163 Cisplatin Rofecoxib D-1927 Anastrozole Breast Rofecoxib D-1927 Capecitabine Breast Rofecoxib D-1927 Docetaxe. Breast Rofecoxib D-1927 Gemcitabifle Breast, Pancreas RofeCoxib D-1927 Letrozole Breast Rofecoxib D-1927 Megestrol Breast Rofecoxib D-1.927 Paclitaxel. Breast Rofecoxib D-1927 Taxnoxif en Breast Rofecoxib D-1927. Toremifene Breast Rofecoxib D-1927 Vinorelbine Breast, Lung Rofecoxib D-1927 Topotecan Lung Rofecoxib D-1927 Etoposide Lung Rofecoxib D-1927 Fluorou~rac2-l colon Rofecoxib D-1927 rntc ol, Rofecoxib D-1927 Ursodeoxycholi Colon c acid Rofecoxib D-1927 calcium Colon carbonate Rofecoxib D-1927. selenium Colon Rofecoxib D-1927 sulindac Colon suif one Rofecoxib D-1927 Carboplatin Brain Rofecoxib D-1927 Goserelin Prostate Acetate Rofecoxib D-1927 Ketoconazole Prostate -249- RofeCOxib D-19'27 Cisplatin.

JTE-522 Compound 141 AnastrozoJ-e Breast JTE-522 Compound M41 Capecitabine Breast JTE-522 Compound M1 Docetaxel Breast JTE-522 Compound M41 Gemcitabine Breast, Pancreas JTE-522 Compound 141 Letrozole Breast JTE-522 Compound M1 Megestrol Breast JTE-522 Compound MI1 Paclitaxel Breast JTE-522 Compound M1 Tainoxif en Bi east JTE-522 Compound M1 Toremifene Breast JTE-522 Compound Ml Etoposide Lung JTE-522 Compound M1 Fluorouracil Colon JTE-522 Compound Ml1 Irinotecan Colon, (CPT-11) Bladder JTE-522 Compound Ml Retinoids Colon JTE-522 Compound M41 DFMO Colon JTE-522 Compound M41 Ursodeoxycholi Colon c acid sulf one JTE-522 Compound M41 Carboplatin Brain J-TE-522 Compound M1 serelin Prostate Acetate -2 JTE-522 Compound Xl Ketoconazole Prostate JTE-522 Compound X41 Cisplatin JTE-522 Compound X42 Anastrozole Breast JTE-522 Compound X42 Capecitabile Breast JTE-522 Compound 142 Docetaxel Breast JTE-522 Compound 142 Gemcitabile Breast, Pancreas JTE-522 Compound 142 LetroZole Breast JTE-522 Compound M42 Megestrol. Breast JTE-522 Compound 142 Paclitaxel Breast JTE-522 Compound 142 Taxnoxif en Breast JTE-522 Compound M42 Toremifene Breast JTE-522 Compound M42 Vinorelbine Breast, Lung JE522 Compound 142 Topotecan Lung JTE-522 Compound 142 Etoposide Lung JTE-522 Compound M42 Fluorouracil Colon JTE-522 Compound M42 Irinotecan Colon, (CPT-11) Bladder JTE-522 Compound 142 Retinoids Colon JTE-522 Compound X42 DFMQ Colon JTE-522 Compound 142 Ursodeoxycholi Colon c acid JTE-522 Compound 142 calcium Colon carbonate JTE-522 Compound 142 selenium Colon JTE-522 Compound 142 sulindac Colon sulf one JTE-522 Compound 142 Carboplatin Brain JTE-522 Compound X42 Goeein Prostate Acetate

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-251- JTE-522 Compound M2 Ketoconazole Prostate JTE-522 Compound M2 Cisplatin JTE-522 Compound M3 Anastrozole Breast JTE-522 Compound M3 Capecitabine Breast JTE-522 Compound M3 Docetaxel Breast JTE-522 Compound M3 Gemcitabine Breast, Pancreas JTE-522 Compound M3 Letrozole Breast JTE-522 Compound M3 Megestrol Breast JTE-522 Compound M3 Paclitaxel Breast JTE-522 Compound M3 Tamoxifen Breast JTE-522 Compound M3 Toremifene Breast JTE-522 Compound M3 Vinorelbine Breast, Lung JTE-522 Compound M3 Topotecan Lung JTE-522 Compound M3 Etoposide Lung JTE-522 Compound M3 Fluorouracil Colon JTE-522 Compound M3 Irinotecan Colon, (CPT-11) Bladder JTE-522 Compound M3 Retinoids Colon JTE-522 Compound M3 DFMO Colon JTE-522 Compound M3 Ursodeoxycholi Colon c acid JTE-522 Compound M3 calcium Colon carbonate JTE-522 Compound M3 selenium Colon JTE-522 Compound M3 sulindac Colon sulfone JTE-522 Compound M3 Carboplatin Brain JTE-522 Compound M3 Goserelin Prostate Acetate

I

-252- JTE-522 Compound M3 Ketoconazole Prostate JTE-522 Compound M3 Cisplatin JTE-522 Compound M4 Anastrozole Breast JTE-522 Compound M4 Capecitabine Breast JTE-522 Compound M4 Docetaxel Breast, Pancreas JTE-522 Compound M4 Gemcitabine Breast JTE-522 Compound M4 Letrozole Breast JTE-522 Compound M4 Megestrol Breast JTE-522 Compound M4 Paclitaxel Breast JTE-522 Compound M4 Tamoxifen Breast JTE-522 Compound M4 Toremifene Breast, Lung JTE-522 Compound M4 Vinorelbine Lung JTE-522 Compound M4 Topotecan Lung JTE-522 Compound M4 Etoposide Colon JTE-522 Compound M4 Fluorouracil Colon, Bladder JTE-522 Compound M4 Irinotecan Colon (CPT-11) JTE-522 Compound M4 Retinoids Colon JTE-522 Compound M4 DFMO Colon JTE-522 Compound M4 Ursodeoxycholi Colon c acid JTE-522 Compound M4 calcium Colon carbonate JTE-522 Compound M4 selenium Colon JTE-522 Compound M4 sulindac Colon sulfone JTE-522 Compound M4 Carboplatin Brain JTE-522 Compound M4 Goserelin Prostate -253- Acetate JTE-522 Compound M4 Ketoconazole Prostate JTE-522 Compound M4 Cisplatin JTE-522 Compound M5 Anastrozole Breast JTE-522 Compound MS Capecitabine Breast JTE-522 Compound M5 Docetaxel Breast, Pancreas JTE-522 Compound M5 Gemcitabine Breast JTE-522 Compound M5 Letrozole Breast JTE-522 Compound M5 Megestrol Breast JTE-522 Compound M5 Paclitaxel Breast JTE-522 Compound M5 Tamoxifen Breast JTE-522 Compound M5 Toremifene Breast, Lung JTE-522 Compound M5 Vinorelbine Lung JTE-522 Compound M5 Topotecan Lung JTE-522 Compound M5 Etoposide Colon JTE-522 Compound M5 Fluorouracil Colon, Bladder JTE-522 Compound M5 Irinotecan Colon (CPT-11) JTE-522 Compound M5 Retinoids Colon JTE-522 Compound M5 DFMO Colon JTE-522 Compound M5 Ursodeoxycholi Colon c acid JTE-522 Compound M5 calcium Colon carbonate JTE-522 Compound M5 selenium Colon JTE-522 Compound M5 sulindac Colon sulfone JTE-522 Compound M5 Carboplatin Brain

I

-254- JTE-522 Compound M5 Goserelin Prostate Acetate JTE-522 Compound M5 .Ketoconazole Prostate JTE-522 Compound M5 Cisplatin JTE-522 Compound M7 Anastrozole Breast JTE-522 Compound M7 Capecitabine Breast JTE-522 Compound M7 Docetaxel Breast, Pancreas JTE-522 Compound M7 Gemcitabine Breast JTE-522 Compound M7 Letrozole Breast JTE-522 Compound M7 Megestrol Breast JTE-522 Compound M7 Paclitaxel Breast JTE-522 Compound M7 Tamoxifen Breast JTE-522 Compound M7 Toremifene Breast, Lung JTE-522 Compound M7 Vinorelbine Lung JTE-522 Compound M7 Topotecan Lung JTE-522 Compound M7 Etoposide Colon JTE-522 Compound M7 Fluorouracil Colon, Bladder JTE-522 Compound M7 Irinotecan Colon (CPT-11) JTE-522 Compound M7 Retinoids Colon JTE-522 Compound M7 DFMO Colon JTE-522 Compound M7 Ursodeoxycholi Colon c acid JTE-522 Compound M7 calcium Colon carbonate JTE-522 Compound M7 selenium Colon JTE-522 Compound M7 sulindac Colon sulfone -255- JTE-522 Compound M7 Carboplatin Brain JTE-522 Compound M~7 Goserelin Prostate Acetate JTE-522 Compound M7 Ketoconazole Prostate JTrE-522 Compound M7 Cisplatin JTE-522 Bay-12-956 6 Anastrozole Colon JTE-522 Bay-l2-95 66 Capecitabine Brain JTE-522 Bay-12-9566 Docetaxel Prostate JTE-522 Bay-12-9566 Gemcitabine Prostate JTE-522 Bay-12-9566 Letrozole Breast 22 Bay-12-9566 Megestrol Breast JTE-522 Bay-12-9566 Paclitaxe. Breast JTE-522 Bay-12-9566 Tamoxif en Breast J'E-22Bay-12-9566 Toreinifene Breast JTE-522 Bay-12-9566 Vinorelbine Breast, Lung JTE-522 Bay-12-9566 Topotecan Lung JTE-522 Bay-12-9566 Etoposide Lung JTE-522 Bay-12-9566 Fluorouracil Colon JTE-522 Bay-12-9566 Irinotecan Colon, (CPT-11) Bladder JTE-522 Bay-12-9566 Retinoids Colon JTE-522 Bay-12-9566 DFXO Colon JTE-522 Bay-12-9566 Ursodeoxycholi Colon c acid JTE-522 Bay-12-9566 calcium Colon carbonate LJTE-522 Bay-12-9566 selenium Colon LJTE-522 Bay-12-9566 sulindac Colon sul fone -256jE-522 Bay-12-9566 Carboplatin Brain JTE-522 Bay-12-9566 Goserelin Prostate Acetate JTE-522 Bay-12-9566 Ketoconazole Prostate JTE-522 Bay-12-9566 Cisplatin jTE-522 Metastat Anastrozole Breast JTE-522 IMetastat Capecitabine Breast JTE-522 Netastat Docetaxel. Breast JTE-522 IMetastat Gemcitabine Breast, Pancreas JTE-522 Metastat Letrozole Breast JTE-522 Metastat Megestro. Breast JTE-522 Metastat Paclitaxel Breast JTE-522 Metastat Tamoxif en Breast JTE-522 IMetastat Toremifene Breast JTE-522 Metastat Vinorelbine Breast, Lung JTE-522 Metastat Topotecan Lung JTE-522 Metastat Etoposide Lung JTE-522 Metastat Fluorouracil Colon JTE-522 Metastat Irinotecan Colon, (CPT-11) Bladder JTE-522 Metastat Retinoids Colon JTE-522 Metastat DFMO Colon JTE-522 Metastat Trsodeoxycholi Colon c acid JTE-522 Metastat calcium Colon c arbonate JTE-522 Metastat selenium Colon JTE-522 Metastat sulindac Colon suif one -257- JTE-522 Metastat Carboplatin Brain JTE-522 Metastat Goserelin Prostate Ace tate JTE-522 Metastat Ketoconazole Prostate JTE-522 Metastat Cisplatin JTE -522 D-2163 Anastrozole Breast JTE-522 D-2163 Capecitabine Breast JTE-522 D-2163 Docetaxe- Breast JTE-522 D-2163 Gemcitabine 'Breast, Pancreas JTE-522 D-2163 Letrozole Breast LJTE-522 D-2163 Megestrol Breast JTE-522 D-2163 Paclitaxel Breast JTE-522 D-2163 Tamoxif en Breast JTE-522 D-2163 Toremifene Breast JTE-522 D-2163 Vinorelbine Breast, Lung JTE-522 D-2163 Topotecan Lung JTE-522 D-2163 Etoposide Lung JTE-522 D-2163 Fluorouracil Colon JTE-522 D-2163 Irinotecan Colon, (CPT-l1) Bladder JTE-522 D-2163 Retinoids Colon LTTE-522 D-2163 DFMO Colon JTE-522 D-2163 Ursodeoxycholi. Colon c acid JTE-522 D-2163 calcium Colon carbonate JTE-522 D-2163 seleniumn Colon JTE-522 D-2163 sulindac Colon sul fone JTE-522 D-2163 Carboplatin Brain JTE-522 D-2163 Goserelin Prostate Acetate JTE-522 D-2163 Ketoconazole Prostate JTE-522 D-2163 Cisplatin JTE-522 D-1927 Anastrozole Breast JTE-522 D-1927 Capecitabine Breast JTE-522 D-1927 Docetaxel Breast JTE-522 D-1927 Gemiorebine Breast, JTE-522 D-1927 LTooea Lungs JTE-522 D-1927 Egtopoid Lungs JTE-522 D-1927 Paloouacl Colont JTE-522 D-1927 Taroifecn Colon, JTE-522 D-1927 Reinolis Colont JTE-522 D-1927 DFopo a CLn JTE-522 D-1927 Etopsdeyhl CLn JTE-522~ acid lorual Coo JTE-522 D-1927 calocim Colon, JTE-522 D-1927 selniu Colon JTE-522 D-1927 sulciuma Colon suif one -259- JTE-522 D-1927 Carboplatin Brain JTE-522 .D-1927 Goserelin Prostate Acetate JTE-522 D-1927 Ketoconazole Prostate JTE-522 D-1927 Cisplatin Further examiples of combinations are listed in Table No 24, below.

Table No. 24.. Pluxther examples of combination therapies COX-2 M Antineoplastic Indication Iihibitor~ inhibitor Agent Celecoxib Compound MI Doxorubicin and Breast Cyclophasphamide Celecoxib Compound MI Cyclophosphamide, Breast Doxorubicin, and Fluorouraci 1 Celecoxib, Compound M1 Cyclophosphamide, Breast Fluorouracil and Mi toxantrone Celecoxib, Compound Ml JMitoxantrone, Flou Breast rouracil and Leucovorin Celecoxib Compound M1 Vinblastine, Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Celecoxib Compound M1 Cyclophosphamide, Breast Methotrexate, -260- Fluorouraci 1 Celecoxib Compound M1 Doxorubicin, Breast Cyclophosphanide, Methotrexate, Fluorouracii Celecoxib Compound M1 Vinbiastine, Breast Doxorubic in, Thiotepa, Fluoxymes terone Celecoxib Compound Ml Fluorouracil, Colon Levamisole Celecoxib Compound Ml Leucovorin, Colon FJluorourac ii Celecoxib Compound M1 Cyclophosphainide, Lung Doxorubicin, Etoposide Celecoxib Compound Ml Cyclophosphaiide, Lung Doxorubic in, Vincr is tine Celecoxib Compound Ml Etoposide, Lung Carboplat in Celecoxib Compound.M1 Etoposide, Lung Cisplatin Celecoxib Compound Ml Paclitaxel, Lung Carboplatin Celecoxib Compound M1 Gemcitabine, Lung Cisplatin Celecoxib Compound M1 Paclitaxel, Lung Cisplatin Celecoxib Compound M2 Doxorubicin arnd Breast Cyclophasphamide -261- Ce2.ecoxib Compound M42 Cyclophosphamide, Breast Doxorubic in, and Fluorourac il Celecoxib Compound M2 Cyclophosphamide, Breast Fluorouracil. and I'itoxantrone Celecoxib Compound M42 Mitoxantrone,Flou Breast rouracil. and Leucovorin Celecoxib Compound 142 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Celecoxib Compound M42 Cyclophosphamide, Breast Methotrexate, Fluorouracil Celecoxib Compound M42 Doxorubicin, Breast Cyclophosphanide, Methotrexate, Fluorouracil Celecoxib Compound 142 Vinbiastine, Breast Doxorubicin, Thiotepa,, Fluoxymesterone Celecoxib Compound M42 Fluorouracil, Colon Levainisole Celecoxib Compound M42 Leucovorin, Colon Fluorouracil Celecoxib Compound 142 Cyclophosphamide, Lung Doxorubic in, Etoposide -262- Celecoxib Compound M2 Cyclophosphamide, Lung Doxorubic in, Vincristine Celecoxib Compound M2 Etoposide, Lung Carbop latin Celecoxib Compound M2 Etoposide, Lung Ci spJatin Celecoxib Compound M2 Paclitaxel, Lung Carboplatin Celecoxib Compound M2 Gencitabine, Lung Cisplatin Celecoxib Compound M2 Paclitaxel, Lung Cisplatin Celecoxib Compound M3 Doxorubicin and Breast Cyc lophasphaxnide Celecoxib Compound M3 Cyclophosphamide, Breast Doxorubicin, and Fluorouracil Celecoxib Compound M3 Cyclophosphamide, Breast Fluorouracil and Mit oxantrone Celecoxib Compound M3 Mitoxantrone ,Flou Breast rouracil and Leucovorin Celecoxib Compound M3 vinbl as tine, Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Celecoxib Compound M3 Cyclophosphamide, Breast Methotrexate, Fluorouracil -263- Celecoxib Compound M3 Doxorubicin, Breast Cyclophosphamide, Metbotrexate, Fluorouracil' Celecoxib Compound M3 Vinbiastine, Breast Doxorubicii, Thiotepa, Fluoxymesterole Celecoxib Compound M3 Fluorouracil, Colon Levamisole Celecoxib Compound M3 Leucovorin, Colon Fluorouracil Celecoxib Compound M3 Cyclophosphamide, Lung Doxorubicin, Etopos ide Celecoxib Compound M3 cyclophosphamide, Lung Doxorubic in, Vinc ri stime Celecoxib Compound M3 Etoposide, Lung Carboplatin Celecoxib Compound M3 Etoposide, Lung Cisplatin Celecoxib Compound M3 Paclitaxel, Lung Carboplatin Celecoxib Compound M3 Gemcitabine, Lung Cisplatin Celecoxib Compound M,3 Paclitaxel, Lung Cisplat in Celecoxib Compound M4 Doxorubicin and Breast Cyclophasphamide Celecoxib Compound M44 Cyclophosphamide, Breast -264- Doxorubicin, and Fluorouracil Celecoxib Compound M4 Cyclophosphanide, Breast Fluorouracil, and Mi toxantrone Celecoxib Compound M4 Mitoxantrofle,Flou Breast rouracil and Leucovorin Celecoxib Compound M4 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Celecoxib Compound M4 Cyclophosphamide, Breast Methotrexate, Fluorouracil.

Celecoxib Compound M4 Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorouraci 1 Celecoxib Compound M4 Viriblastine, Breast Doxorubic in, Thiotepa, Fluoxymesterole Celecoxib Compound M4 Fluorouracil, Colon Levamisole Celecoxib Compound M4 Leucovorin, Colon Fluorouracil Celecoxib Compound M4 Cyclophosphamide, Lung Doxorubic in, Etoposide Celecoxib Compound M4 Cyclophosphamide, Lung -265- Doxorubicin, vincri stine Celecoxib Compound M4 Etoposide, Lung C arbop latin Celecoxib Compound M4 Etoposide, Lung Cisplatin Celecoxib Compound M4 Paclitaxel, Lung Carboplat in Celecoxib Compound M4 Gemcitabine, Lung Cisplatin Celecoxib Compound M4 Paclitaxel, Lung Cisplatin Celecoxib Compound M5 Doxorubicin and Breast' Cyci ophasphamide Celecoxib Compound MS Cyclophosphamide, Breast Doxorubicin, and Fluorouracil Celecoxib Compound M5 Cyclophosphamide, Breast Fluorouracil and Mitoxantrone Celecoxib Compound MS Mitoxantrone,Flou Breast rouraci. and Leucovorin Celecoxib Compound M5 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrofle Celecoxib Compound M5 Cyclophosphanide, Breast Methotrexate, Fluorouracil Celecoxib Compound M5 Doxorubicin, Breast -256- Cyclophosphamfide, Methotrexate, Fluorouracil Celecoxib compound MS Vinbilastine, Breast Doxorubicin, Thiotepa, Fluoxymesterofle Celecoxib Compound M5 Fluorouracil, colon Levani sole Celecoxib Compound MS Leucovorin, Colon Fluorouracil Celecoxib Compound M45 Cyclophosphamide, Lung Doxorubicin, Etoposide celecoxib Compound M5 Cyclophosphamnide, Lung Doxorubic in, Celecoxib Compound M5 Etoposide, Lung Carboplatin Celecoxib Compound MS5 Emcpiaie, Lung Cisplatin Celecoxib Compound M5 Paclitaxel, Lung Cisbp at in Celecoxib compound M7 Doxorubicin and Breast Cyc lophaspharnide Celecoxib Compound M7 Cyclophosphamide, Breast Doxorubicin, anid -267- Fluorouracil Celecoxib Compound M7 Cyclophosphamide, Breast Fluorouracil and Mitoxantrone Celecoxib Compound M47 Mitoxantrone,Flou Breast rouracil and Leucovorin Celecoxib Compound M47 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Celecoxib Compound M47 Cyclophosphamide, Breast Methotrexate, Fluorouracil Celecoxib Compound M7 Doxorubicin, Breast Cyc lophosphamide, Methotrexate, FluorouraC ii Celecoxib Compound 147 Vinbiastine, Breast Doxorubic in, Thiotepa, Fluoxymesterone Celecoxib Compound M47 Fluorouracil, Colon Levami sole Celecoxib Compound M47 Leucovorin, Colon Fluorourac ii Celecoxib Compound M47 Cyclophosphamide, Lung Doxorubicin, Etopos ide Celecoxib Compound M47 Cyclophosphamide, Lung Doxorubicin, -268- Vincristine Celecoxib Compound M7 Etoposide, Lung Carboplatin celecoxib Compound M7 Etoposide, Lung Cisplatin Celecoxib Compound M7 Paclitaxel, Lung Carboplat in Celecoxib Compound M7 Gemcitabine, Lung Cisplatin Celecoxib Compound M7 Paclitaxel, Lung Cisplatin Celecoxib Bay-12-95 66 Doxorubicin and Breast Cyclophasphamide Celecoxib Bay-12-9566 Cyclophosphanide, Breast Doxorubicin, and Fluorouracil Celecoxib Bay-12-9566 Cyclophosphamide, Breast Fluorouracil and Mitoxantrone Celecoxib Bay-12-956 6 Mitoxantrone,F1ou Breast rouracil and Leucovorii Celecoxib Bay-12-95 66 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Celecoxib Bay-12-95 66 Cyclophosphamide, Breast Methotrexate, Fluorouraci- Celecoxib Bay-12-9566 Doxorubicin, Breast Cycl1opho sphamile, -269- Methotrexate, Fluorouracil Celecoxib Bay-l2--95 66 Viriblastine, Breast DoxorUbicin, Thiotepa, Fluoxymesterole Celecoxib Bay-12-9566 Fluorouracil, Colon Levamisole Celecoxib Bay-12-9566 Leucovorin, Colon Fluorourac il Celecoxib Bay-12-95 66 Cyclophosphanide, Lung* Doxorubicii, Etoposide Celecoxib Bay-12-9566 Cyclophosphamide, Lung Doxorubic in, Vincristine Celecoxib Bay-12-9566 Etoposide, Lung Carboplatin Celecoxib Bay-12-9566 Etoposide, Lung Cisplatin Celecoxib Bay-12-9566 Paclitaxel, Lung Carboplat in Celecoxib Bay-12-9566 Gemcitabine, Lung Cisplatin Celecoxib Bay-12-9566 Paclitaxel, Lung Cisplatin Celecoxib Metastat Doxorubicin and -Breast Cyc lophasphanhide Celecoxib Metastat Cyclophosphanide, Breast Doxorubic in, arnd Fluorouracil -270- Celecoxib Metastat Cyclophosphamide, Breast Fluorouracil and Mi toxantrole Celecoxib Metastat Mitoxantrone,Flou Breast rouracil and Leucovorin Celecoxib Metastat Vinblastine,Doxor Breast ubicin, Thiotepa, ard Fluoxymestrole Celecoxib Metastat Cyclophosphamide, Breast Methotrexate, Fluorouracil Celecoxib Metastat Doxorubicii, Breast Cyclophosphamide, Methotrexate, Fluorourac ii Celecoxib Metastat Vinbiastine, Breast Doxorubicin, Thiotepa, Fluoxynes terone Celecoxib Metastat. Fluorouracil, colon Levamisole Celecoxib Metastat Leucovorin, Colon Fluorouracil Celecoxib Metastat Cyclophosphamide, Lung Doxorubic in, Etopos ide Celecoxib Metastat Cyclophosphamide, Lung Doxorubic in, Vincristine -27 1celecoxib Met as tat Etoposide, un Carboplatin Celecoxib Metastat Etoposide, Lung Cisplatin Celecoxib Metastat PacJlitaxe-, Lung Carboplatin Celecoxib Metastat Gemcitabile, Lung Cisplatin Celecoxib; Metastat Paclitaxel, Lung Cisplatin celecoxib D-2163 Doxorubicin and Breast Cyc lophasphamide Celecoxib D-2163 Cyclophosphamride, Breast DoxorubiCin, and Fluorourac il Celecoxib D-2163 cyclophosphatide, Breast FluorouraCil and Mitoxantrole Celecoxib D-2163 Mitoxantrone,Flou Breast rouracil and Leucovorin Celecoxib D-2163 vinblastile Doxor Breast ubicin, Thiotepa, and Fluoxylnestrone Celecoxib D-2163 Cyclophosphamfide, Breast Methotrexate, FluorouraCi 1 Celecoxib D-2163 Doxorubicin, Breast Cyclophosphamfide, Methotrexate, -272- Fluorouracil Celecoxib D-2163 Viriblastine, Breast Doxorubicin, Thiotepa, Fluoxymesterone Celecoxib D-2163 Fluorouracil, Colon Levani sole Celecoxib D-2163 Leucovorin, Colon Fluorourac ii Celecoxib D-2163 Cyclophosphamtide, Lung floxorubic in, Etoposide Celecoxib D-2163 Cyclophosphamide, Lung Doxorubicin, Vincristifle Celecoxib D-2163 Etoposide, Lung Carboplatin Celecoxib D-2163 Etoposide, Lung Cisplatin Celecoxib D-2163 Paclitaxel, Lung Carboplatin Celecoxib D-2163 Gemcitabine, Lung Cisplatin Celecoxib D-2163 Paclitaxe., Lung Cisplatin Celecoxib D-1927 Doxorubicin and Breast Cyclophasphainide Celecoxib D-1927 Cyclophosphamide, Breast Doxorubicin, and Fluorouracil Celecoxib D-1927 Cyclophosphamride, Breast -273- Fluorouracil and Mi toxantrone Celecoxib D-1927 Mitoxantrone,Flou Breast rouracil and Leucovorin Celecoxib D-1927 Vinblas tine, Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Celecoxib D-1927 Cyclophosphanide, Breast Methotrexate, Fluorouracil Celecoxib D-1927 Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorourac il Celecoxib D-1927 vinbiastine, Breast Doxorubic in, Thi o tepa, Fluoxymnes terone Celecoxib D-1927 Fluorouracil, Colon Levamisole Celecoxib D-1927 Leucovorin, Colon Fluorouracil Celecoxib D-1927 Cyclophosphanide, Lung Doxorubicin, Etopos ide Celecoxib D-1927 Cyclophosphamide, Lung Doxorubicin, Vincristine Celecoxib D-1927 Etoposide, Lung -274-- Carboplatin Celecoxib D-1L927 Etoposide, Lung Cisplatin Celecoxib D-1927 Paclitaxel, 'Lung Carboplatin Celecoxib D-1927 Gemcitabine, Lung Cisplatin Celecoxib D-1927 Paclitaxel, Lung Cisplatin.

Rofecoxib Compound Ml Doxorubicin and Breast Cyclophasphanide Rofecoxib Compound Ml Cyclo-phosphamide, Breast Doxorubicin, and Fluorouracil Rofecoxib compound Ml Cyclophosphanide, Breast Fluorouracil and Mitoxantrone Rofecoxib Compound Ml Mitoxantrone,Flou Breast rouracil and Leucovorin Rofecoxib Compound ml Vinblastine, Doxor Breast ubicin, Thiotepa, and F luoxymes trone Rofecoxib Compound ml Cyclophosphanide, Breast Methotrexate, Fluorourac ii Rofecoxib Compound Ml Doxorubicin, Breast Cyclophosphanide, Methotrexate, -27 Fluorouracil Rofecoxib Compound 141 Vinbiastine, Breast' Doxorubic in, Thiotepa, Fluoxymesterone Rofecoxib Compound 141 Fluorouracil, Colon Levainisole Rofecoxib Compound 141 Leucovorin, Colon Fluorouraci 1 Rofecoxib Compound M41 Cyclophosphamfide, Lung Doxorubic in, Etopo side, Rofecoxib Compound 141 Etcopose, de Lung ViCistine Rof ecoxib Compound M1 tPacliael, Lung Carboplatin Rof ecoxib Compound 141 GEmtaie, Lung Cisplatizi Rofecoxib Compound 141 Paclitaxel, Lung Cisbplatin Rofecoxib CompoundM 142 Doxorbin LuBrag Cyplpasph id Rofecoxib Compound 1 Cyclophophaide Breas Doxorubicin, and Fluorouracil.

Rofecoxib Compound M42 Cyclophosphamide, Breast -276- Fluorouracil and Mi toxantrole, Rofecoxib Compound 1M2 Mitoxantrole, Flou Breast rouracil and Leucovorin Rofecoxib Compound M2 Vinblastifle, Doxor Breast ubicin, Thiotepa, and Fluoxymestrofle RofeCoxib Compound M2 Cyclophosphanide, Breast Methotrexate, F 1uorourac il Rofecoxib Compound M2 Doxorubicin, Breast Cyclophosphamide, Methotrexate, F luorourac il Rofecoxib Compound M2 Vinblastl-fe, Breast Doxorubic in, Thiotepa, FluoXymfeS terofle Fluorouracil Rofecoxib Compound M,2 Cyclophosphamfide, Lung Doxorubicin, Etopos2-de Rofecoxib Compound M2 Cyclophosphamfide, Lung Doxorubicil, Vincristine Rofecoxib Compound M2 Etoposide, Lung -277- Carbopi at in Rofecoxib Compound M2 Etoposide, Lung Cisplatin Rofecoxib Compound M2 Paclitaxel, Lung Car:Ooplatil Rofecoxib Compound M2 Gemcitabine, Lung Ci splat in Rofecoxib Compound M2 Paclitaxel, Lung Cisplatin Rofecoxib Compound M3 Doxorubicin and Breast Cyc lophasphanide Rofecoxib Compound M3 Cyclophosphamide, Breast Doxorubicin, and Fluorouracil Rofecoxib Compound M3 Cyclophosphamride, Breast Fluorouracil and Mi toxantrone, Rofecoxib Compound M3 Mitoxantrone,Flou Breast rouracil and Leucovorin Rofecoxib Compound M3 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrone Rofecoxib Compound M3 Cyclophosphamide, Breast Methotrexate, FluorouraCi 1 Rofecoxib Compound M3 Doxorubicin, Breast Cycl1ophosphamide, Methotrexate, Fluorouraci 1 -278- Breast Rofecoxib Compound 143i Vinbiastine, DoxorubiC in, Thiotepa, FluoxymeSterofle Breast Rofecoxib CompounldM3Fluorouracil, Colon Levamisole Rofecoxib Compound M3 Leucovorinf, Colon Fluorouraci.

Rofecoxib Compound M3 Cyclophosphamfide, Doxorubic in, Etopos ide Lung Rofecoxib Compound M3 Cyclophosphamfide, Lung Doxorubyic in, Vincristine Rofecoxib Compound M3 Etoposide, Lung Carboplatin Rofecoxib Compound M3 Etoposide, Lung Cisplatin Rofecoxib Compound M3 Paclitaxel, Lung carboplatin Rofecoxib compound M3 Gemcitabine, Lung Cisplatin Rofecoxib Compound M3 Paclitaxel, Lung Cisplatin Rofecoxib Compound M4 Doxorubicii and Breast Cyclophasphamide Rofecoxib compound M4 Cyclophosphanide, Breast Doxorubic in, and FluorouraCil Rofecoxib Compound M4 Cyclophosphamtide, Breast Fluorouracil and -279- Mitoxantrone Rof ecoxib Compound M4 Mi toxantrone, F1ou Breast rouracil and Leucovorin Rofecoxib Compound M4 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrole Rofecoxib Compound M4 Cyclophosphamide, Breast Methotrexate, Fluorouraci 1 Rofecoxib Compound M4 Doxor'jbicin, Breast Cyclophosphamide, Methotrexate, Fluorouracil Rofecoxib Compound M4 Vinbiastile, Breast Doxorubic in, Thi otepa, Fluoxymesterole Rofecoxib Compound M44 Fluorouracil, colon Levamisole Rofecoxib Compound.M4 Leucovorin, Colon Fluorourac ii Rofecoxib Compound M44 Cyclophosphamide, Lung Doxorubic in, Etopos ide Rofecoxib Compound M44 Cyclophosphamide, Lung Doxorubic in, Vincristine Rofecoxib Compound M44 Etoposide, Lung Carboplatin -280- Rofecoxib Compound M4 Etoposide, Lung Ci splat in Paclitaxel, Lung Rofecoxib Compound M4 Carbopi at in Lung Rofecoxib Compound M4 Gemcitabile, Cisplatil Lung Rofecoxib Compound M4 Paclitaxel, Cisplatin Rofecoxib Compound MS Doxorubicin and Breast Cycl1ophasphamide Rofecoxib Compound M5 Cyclophosphamide, Breast Doxorubicin, and Fluorour acii Rofecoxib Compound M5 cyciophosphamide, Breast Fluorouracil and Mi toxantrofle Rofecoxib Compound M5 mitoxantrorle,Flou Breast rouracil and Leucovorii Rofecoxib compound M5 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrole Rofecoxib Compound M5 Cyclophosphamide, Breast Methotrexate, Fluorouraci 1 Rofecoxib Compound MS Doxorubicii, Breast Cyclophosphanide, Methotrexate, Fluorouracil R~ofecoxib Compound M5 Vinbiastile, Breast -281- DoxorubiCin, Thiotepa, Fluoxymesterole Rofecoxib compound M5 FluorouraCil, Colon Levamisole Rofecoxib Compound M5 Leucovcsriri, colon FluorouraCil Rot coi Compound M5 Cyclophosphamfide, Lung DoxorubiC in, Etoposide Rot ecoxib Compound M5 Cyclophosphamfide, Lung Doxorubic in, Rofecoxib Compound M5 Emcpidife, Lung Cisbplatin Rofecoxib Compound m5 Etpaciae, Lung Ci splat in Rofecoxib Compound MS Doxorub2-Cin and unag Cyclophasphltid Rofecoxib Compound M5 Gmclophsphaaide Breas Rofecxib ompoud M7Doxorubicin, and Bes Fyloourspaie Rot ecoxib Compound M7 CyclophosPhamidle, Breast Fluorouracil and mitoxantrone

I

-282- Rofecoxib Compound M7 Mitoxafltrofle,Flou Breast rouracil and Leucovorin R ofeco2Cib Compound M7 Vinblastifle,Doxor Breast ubicin, Thiotepa, and F luoxymes trone Rofecoxib Compound M7 Cyclophosphamfide, Breast Methotrexate, Fluorouraci- Rofecoxib Compound M*7 Doxorubicin, Breast Cyclophosphamide, Methotrexate,, Fluorouraci- Rofecoxib Compound M7 Vinbiastile, Breast Doxorubic in, Thiotepa, Fluoxymnesterone Rofecoxib Compound M7 Fluorouraci., Colon Levalnisole Doxorubicin,- Etopos ide Rofecoxib Compound M7 Cyclophosphaiflide, Lung Doxorubi cin, Vincristine Rofecoxib Compound M7 Etoposide, Lung Carbopi at in Rofecoxib compound M-7 Etoposide, Lung -283- Ci splatin Rofecoxib Compound M7 Paclitaxel, Ljung Carboplatin Rofecoxib. Compound M7 Gemcitabile, Lung Ci splat in Rofecoxib Compound M7 Paclitaxel, Lung Cisplatin Rofecoxib Bay-12-9566 Doxorubicin and Breast Cyclophasphamide Rofecoxib Bay-12-9566 Cyclophosphamide, Breast Doxorubicin, and Fluorouraci 1 ROfecoxib Bay-12-9566 Cyclophosphamride, Breast Fluorouracil and Mitoxantrone Rofecoxib Bay-12-9566 Mitoxantrone,Flou Breast rouracil and Leucovorin.

Rofecoxib Bay-12-9 566 Vinbiastine, Doxor Breast ubicin, Thiotepa, and Fluoxymestrole Rofecoxib Bay-12-9566 Cyclophosphanide, Breast Methotrexate, Fluorouracil Rofecoxib Bay-12-9566 Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorouraci 1 Rofecoxib Bay-12-9S66 Vinbiastine, Breast Doxorubicin, -284- Thi ot epa, Fluoxyrnesterone Rofecoxib Bay-12-9566 Fluorouracil, Colon Levamnis ole Rofecoxib Bay-12-9566 Leucovorin, Colon Fluorouracil Rofecoxib Bay-12-9566 Cyclophosphamide, Lung Doxorubicin, Etopos ide Rofecoxib Bay-12-9566 Cyclophosphamide, Lung Doxorubicin, Vincristine Rofecoxib Bay-12-9566 Etoposide, Lung Carboplatin Rotecoxib Bay-12-9566 Etoposide, Lung Cisplatin Rofecoxib Bay-12-9566 Paclitaxel, Lung Carboplatin Rofecoxib Bay-12-9566 Geincitabine, Lung Cisplatin Rofecoxib ,Bay-12-9566 Paclitaxel, Lung Cisplatin Rofecoxib Metastat Doxorubicin and Breast Cyclophasphamide Rofecoxib Metastat Cyclophosphamide, Breast Doxorubicin, and Fluorouracil Rofecoxib Metastat Cyclophosphamide, Breast Fluorouracil and Mi toxantrone Rofecoxib Metastat Mitoxantrone,Flou Breast -285rouraci. and Leucovorin Rofecoxib Metastat Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxynestrofle Rofecoxib. Metastat cyclophosphamide, Breast Methotrexate, Fluorouracil Rofecoxib Metastat Doxorubicin, Breast Cyclophosphanide, Methotrexate, Fluorouracil Rofecoxib Metastat Vinbiastine, Breast DoxorubiC in, Thiotepa, Fluoxymesterole Rofecoxib Metastat Fluorouracil, Colon Levalnis ole Rofecoxib Metastat Leucovorin, Colon Fluotouracil Rofecoxib Metastat. Cyclophosphanide, Lung Doxorubic in, Etoposide Rofecoxib Metastat Cyclophosphmnide, Lung Doxorubic in, Vincristine Rofecoxib Netastat Etoposide, Lung Carboplat in Rofecoxib Metastat Etoposide, Lung Cisplatin -2 86- Rofecoxib Metastat Paclitaxel, Lung Carboplat in Rofecoxib Metas tat. Gemcitabine, Lung Cisplatin Rofecoxib Metastat Paclitaxel, Lung Cisplatin Rofecoxib D-2163 Doxorubicin and Breast Cyc lophasphani de Rofecoxib D-2163 Cyclophosphartide, Breast Doxorubicin, and Fluorourac il Rofecoxib D-2163 Cyclophosphamide, Breast Fluorouracil and Mitoxantrone, Rofecoxib D-2163 Myitoxantrone, Flou Breast rouracil and Leucovorin Rofecoxib D-2163 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluox-ymestrone Rofecoxib D-2163 Cyclophosphamide, Breast Methotrexate, Fluorouraci.

Rofecoxib D-2163 Doxorubicin, Breast Cyclophosphamide, lMethotrexate, Fluorouracil Rofecoxib D-2163 Vinblastine, Breast Doxorubicin, Thiotepa, -287- Fluoxyines terone Rofecoxib D-2163 Fluorouracil, Colon Levamiso.e Rofecoxib D-2163 Leucovorin, Colon Fluorourac.

Rofecoxib D-2163 Cyclophosphamide, Lung Doxorubic in, Et opos ide Rofecoxib D-2163 Cyclophosphamide, Lung.

'Doxorubic in, vincristine Rofecoxib D-2163 Etoposide, Lung Carboplatin Rofecoxib D-2163 Etoposide, Lung Cisplatin Rofecoxib D-2163 Paclitaxel, Lung Carboplatin.

Rofecoxib D-2163 Gemcitabine, Lung Cisplatin Rofecoxib D-2163 Paclitaxel, Lung Cisplatin Rofecoxib D-1927 Doxorubicin and Breast Cyclophasphanide Rofecoxib D-1927 Cyclophosphamide, Breast Doxorubicin, and Fluorourac il Rofecoxib D-1927 Cyclophosphanide, Breast Fluorouracil and Mi toxantrofle Rofecoxib D-1927 Mitoxantrone, Flou Breast rouracil and -288- Leucovorin Rofecoxib D-1927 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrole Rofecoxib D-1927 Cyclophosphamnide, Breast Methotrexate, Fluorourac il Rofecoxib D-1927 Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorourac il Rofecoxib D-1927 Vijiblastine, Breast Doxorubicii, Thiotepa, Fluoxymes terone Rofecoxi D-i927Fluorouracil, oo Rofecoxib D-1927 Cyclophosphamide, Lung Doxorubicin, Et opo side Rofecoxib D-1927 Cyclophosphamide, Lung Doxorubic in, Vincristine Rofecoxib D-1927 Etoposide, Lung Carboplat in Rofecoxib D-1927 Etoposide, Lung Cisplatin Rofecoxib D-1927 Paclitaxel, Lung -2.89- Carboplatin Rofecoxib D-1927 Gemcitabi- ne, Lung Cisplatifl Rofecoxib D-1927 Paclitaxel, Lung Cisplatin JTE-522 Compound M41 Doxorubicifl and Breast Cyclophasphainide JTE-522 Compound Ml Cyclophosphamide, Breast Doxorubicin, and Fluorouracil JTE-522 Compound Ml Cyclophosphamide, Breast Fluorouracil and Mi toxantrone JTE- 522 Compound Ml Mitoxantrone,F1ou Breast rouracil and Leucovorin JTE-522 Compound Ml Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrole JTE-522 Compound MI Cyclophosphanide, Breast Methotrexate, Fluorouraci 1 JTE-522 Compound Ml Doxorubicii, Breast Cyclophosphamfide, Methotrexate, Fluorouraci 1 JTE-522 Compound Ml vinblastine, Breast Doxorubici', Thiotepa, -290- F luoxymes terone UTE-522 Compound M41 Fluorouracil, Colon Levamisole, JTE-522 Compound Ml1 Leucovorinf, Colon Fluorourac il2 JTE-522 Compound M41 Cyclophosphamide, Lung Doxorubic in, Etopo side JTE-522 Compound M41 Cyclophosphamtide, Lung Doxorubic in, Vincristile JTE-522 Compound M1 Etoposide, Lung Carbopi at in JTE-522 Compound Ml Etoposide, Lung Cisplatin JTE-522 Compound M1 Paclitaxel, Lung.

Carboplat in JTE-522 Compound M1 Gemcitabine, Lung Cisplatin JTE-522 Compound Ml Paclitaxel, Lung Cisplatin.

JTE-522 Compound 142 Doxorubicin and Breast Cyc lophasphamide JTE-522 Compound M42 Cyclophosphamide, Breast Doxorubicin, and F luorourac ii JTE-522 Compound M42 Cyclophosphamide, Breast Fluorouracil and Mi toxantrone JTE-522 Compound 142 Mitoxantrone ,Flou Breast rouracil and -2 91- Leuc ovorin JTE-522 Compound M42 Vinblastine,Doxor Breast ubicin, Thiotepa, and F luoxyinestrofle JTE-522 Compound 142 Cyclophosphamide, Breast Methotrexate, Fluorouracil JTE-522 Compound 142 Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorouracil JTE-522 Compound M42 Vinbiastine, Breast Doxorubic in, Thiotepa, F luoxymes terone JTE-522 Compound 142 Fluorouracil, Colon Levamisole JTE-522 Compound 142 Leucovorin, Colon Fluorouracil JTE-522 Compound M42 Cyclophosphamide, Lung Doxorubicin, Etoposide JTE-522 Compound M42 Cyclophosphamide, Lung Doxorubi cin, Vincristine JTE-522 Compound M42 Etoposide, Lung Carboplat in JTE-522 Compound M42 Etoposide, Lung Cisplatin JTE-522 Compound M2 Paclitaxel, Lung -292- Carboplatin JTE-522 Compound M2 Gemcitabine, Lung Cisplatin JTE-522 Compound M2 Paclitaxel, Lung Cisplatin LJTE-522 Compound M3 Doxorubicin and Breast Cycl1ophasphamide JTE-522 Compound M3 Cyclophosphanide, Breast Doxorubic in, and Fluorourac il JTE-522 Compound M3 Cyclophosphamide, Breast Fluorouracil and Mit oxantrone JTE-522 Compound M3 Mitoxantrone,Flou Breast rouracil arnd Leucovorii JTE-522 Compound M43 VinblastineDoxor Breast ubicin, Thiotepa, and Fluoxymestrone JTE-522 Compound M3 Cyclop~hosphamide, Breast Methotrexate, Fluorouracil JTE-522 Compound M3 Doxorubicin, Breast- Cyclophosphamfide, Methotrexate, Fluorouracil JTE-522 Compound M3 Vinbiastine, Breast Doxorubicin, Thiotepa, Fluoxymesterone -293- JTE-522 Compound 43 Fluorouracil, Colon Levamisole JTE-522 Compound M3 Leucovorin, Colon Fluorouracil JTE-522 Compound M3 Cyclophosphamide, Lung Doxorubicin, Etoposide JTE-522 Compound M3 Cyclophosphamide, Lung Doxorubicin, Vincristine JTE-522 Compound M3 Etoposide, Lung Carboplatin JTE-522 Compound M3 Etoposide, Lung Cisplatin JTE-522 Compound M3 Paclitaxel, Lung Carboplatin JTE-522 Compound M3 Gemcitabine, Lung Cisplatin JTE-522 Compound M3 Paclitaxel, Lung Cispilatin JTE-522 Compound M4 Doxorubicin and Breast Cyclophasphamide JTE-522 Compound M4 Cyclophosphamide, Breast Doxorubicin, and Fluorouracil JTE-522 Compound M4 Cyclophosphamide, Breast Fluorouracil and Mitoxantrone JTE-522 Compound M4 Mitoxantrone,Flou Breast rouracil and Leucovorin -294- JTE-522 Compound 144 Vinblastine, Doxor Breast ubicin, Thiotepa, and Fluoxymestrone JTE-522 Compound M44 Cyclophosphanide, Breast Methotrexate, Fluorouracil JTE-522 Compound M44 Doxorubicin, Breast Cyclophosphamide, Methotrexate, F luorourac ii jTE- 522 Compound 144 Vinbiastine, Breast Doxorubic in, Thiotepa, Fluoxymes terone JTE-522 Compound M44 Fluorouracil, Colon Levainisole JTE-522 Compound M44 Leucovorin, Colon Fluorouracil JTE-522 Compound M44 Cyclophosphamide, Lung Doxorubic in, Etoposide JTE-522 Compound M4 Cyclophosphamide, Lung Doxorubi cin, Vincristine, JTE-522 Compound M44 Etoposide, Lung Carboplatin JTE-522 Compound M44 Etoposide, Lung Cisplatin JTE-522 Compound M44 Paclitaxel, Lung Carboplatin -295- JTE-522 Compound M4 Gemcitabine, Lung Cisplatin JTE-522 Compound M44 Paclitaxel, Lung Cisplatin JTE-522 Compound M5 Doxorubicin and Breast Cyc lophasphamide JTE-522 Compound MS Cyclophosphanide, Breast Doxorubicin, and Fluorouracil JTE-522 Compound M5 Cyclophosphamide, Breast Fluorouracil and Mi toxantrone JTE-522 Compound MS Mitoxantrone,Flou Breast rouracil and Leucovorin JTE-522 Compound M5 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxymestrone JTE-522 Compound MS Cyclophosphamide, Breast Methotrexate, Fluorouracil JTE-522 Compound MS Doxorubicin, Breast Cyclophosphanide, Methotrexate, Fluorouracil JTE-522 Compound MS Vinbiastine, Breast Doxorubicin, Thiotepa, Fluoxymesterone JTE-522 Compound MS Fluorouracil, Colon -296- Levamnisole JTE-522 Compound M5 Leucovorin, Colon Fluorouracil JTE-522 Compound 145 Cyclophosphamide, Lung Doxorubi cin, E topos ide JTE-522 Compound MS Cyclophosphanide, Lung Doxorubicin, Vincristine JTE-522 Compound MS Etoposide, Lung Carboplatin JTE-522 Compound M45 Etoposide, Lung Cisplatin JTE-522 Compound MS Paclitaxel, Lung Carbop latin JTE-522 Compound MS Gemcitabine, Lung Cisplatin JTE-522 Compound MS Paclitaxel, Lung Cisplatin JTE-522 Compound 147 Doxorubicin and Breast Cyclophasphanide JTE-522 Compound M47 Cyclophosphamide, Breast Doxorubicin, and Fluorouracil JTE-522 Compound M47 Cyclophosphanide, Breast Fluorouracil and Mitoxantrone JTE-522 Compound M47 Mitoxantrone,Flou Breast rouracil and Leuc ovorin JTE-522 Compound 147 Vinblastine,Doxor Breast -297ubicin, Thiotepa, and Fluoxymestrole JTE-522 Compound M7 Cyclophosphamide, Breast IMethotrexate, Fluorouracil JTE-522 Compound M7 Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorourac ii JTE-522 Compound M7 Vinblastine, Breast Doxorubic in, Thiotepa, F luoxymes terone JTE-522 Compound M7 Fluorouraci-, Colon Levamisole JTE-522 Compound M7 Leucovorin, Colon Fluorouracil JTE-522 Compound M7 Cyclophosphamide, Lung Doxorubic in, Etoposide JTE-522 Compound M7 Cyclophosphamfide, Lung Doxorubi cin, Vincristine JTE-522 Compound M7 Etoposide, Lung Carbopi atin JTE-522 Compound M7 Etoposide, Lung Cisplatin LTTE-522 Compound M7 Paclitaxel, Lung Carboplatin JTE-522 Compound M7 Gemcitabine, Lung -29 8- Cisplatin JTE- 522 compound m7 Paclitaxel, Lung Cisplatin JTE -522 Bay-12-9 5 6 6 Doxorubicin and Breast Cyc lophasphamide JTE-522 Bay-12-95 6 6 Cyclophosphamide, Breast Doxorubicin, and Fluorouracil JTE-522 Bay-12-95 66 Cyclophosphamide, Breast Fluorouracil and Mitoxaitrofle JTE-522 Bay-12-95 66 Vinblastifle,Doxor Breast ubicin, 'rhiotepa, and F luoxymes trone JTE-522 Bay-12-956 6 Cyclophosphamide, Breast Methotrexate, Fluorouracil JTE-522 Bay-12-9 566 Doxorubicin, Breast Cyclophosphamtide, Methotrexate, Fluorouraci- JTE-522 Bay-12-95 66 Vinbiastile, Breast Doxorubic in, Thiotepa, Fluoxymesterole JTE-522 Bay-12-95 66 Fluorouracil, Colon Levami sole Doxorubic in, Etoposide JTE-522 Bay-1 2 -9 566 CyclophoSPhamfide, Lung Doxorubic in, Vincristile JTE-522 Bay-12-9 566 EtopoSide, Lung Carboplatin JTE-522 Bay-12-9 566 Etoposide, Lung Cisplatinf JTE-522 Bay-12- 9566 Paclitaxel, Lung Carbopi-atin JTE-522 Bay-12-9 566 Gemcitabile, Lung Cisplatin JTE-522 Bay-12- 9

S

66 Paclitaxel, Lung Cisplatin JTE-522 metastat Doxorubicin and Breast Cyc lophasphamide JTE-522 Metastat Cyclophosphamide, Breast Doxorubicin, and Fluorourac ii JTE-522 Metastat Cyclophosphamide, Breast Fluorouracil and 14i toxantrole JTE-522 Metastat Mitoxantrone,Flou Breast rouracil and Leucovor in JTE-522 metastat VinblastinerDoxor Breast ubicin, Thiotepa, -300and F luoxymes trone JTE-522 Metastat Cyclophosphainide, Breast Methotrexate, Fluorouracil JTE-522 ?Aetastat Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorouracil JTrE-522 Metastat Vinbiastine, Breast Doxorubicin, Thi otepa, JTE-522 Metastat Leucovorin, Colon Fluorourac il JTE-522 Metastat Cyclophosphamtide, Lung Doxorubic in, Etopos ide JTE-522 Metastat Cyclophospbamfide, Lung Doxorubicin, Vincrist ine Cisplatin -3 01- JTE-522 Metastat Paclitaxel, Lung Cisplat in JTE-522 D-2163 Doxorubicin and Breast Cyclophasphamide JTE-522 D-2163 Cyclophosphamide, Breast Doxorubic in, and Fluorouracil, JTE-522 D-2163 Cyclophosphamide, Breast Fluorouracil. and Mi toxantrone JTE-522 D.-2163 Mitoxantrone,Flou Breast rouracil and Leuc ovor in JTE-522 D-2163 Vinblastine,Doxor Breast ubicin, Thiotepa, and Fluoxynes trone JTE-522 D-2163 cyclophosphamnide, Breast Methotrexate, Fluorouracil JTE-522 D-2163 Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorou'rac ii JTE-522 D-2163 Vinbiastine, Breast Doxorubic ir, Thiotepa, Fluoxymes terone JTE-522 D-2163 Fluorouracil, Colon Levami sole JTE-522 D-2163 Leucovorin, Colon -3 02- Fluorouracil JTE-522 D-2163 Cyclophosphamide, Lung Doxorubic in, Etoposide JTE-522 D-2163 Cycilophosphamide, Lung Doxorubicin, Vincristine JTE-522 D-2163 Etoposide, Lung Carbopl1at in JTE-522 D-2163 Etoposide, Lung Cisplatin JTE-522 D-2163 Pacilitaxel, Lung I Carboplatin JTE-522 D-2163 Gemcitabine, Lung Cisplatin JTE-522 D-2163 Paclitaxel, Lung Cisplat in JTE-522 D-1927 Doxorubicin and Breast Cycl1ophasphamide JTE-522 D-1927 Cyclophosphamide, Breast Doxorubicin, and Fluorouracil JTE-522 D-1927 Cyclophosphamide, Breast Fluorouracil and mi toxantrole JTE-522 D-1927 Mitoxantrone, F1ou Breast rouracil and Leucovorii JTE-522 D-1927 Vinblastine,Doxor Breast ubicin, Thiotepa, and -3 03- Fluoxymestrofle JTE-522 D-1927 Cyclophosphafide, Breast Methotrexate, FluoroUraCil JTE-522 D-1927 DoxorUbicin, Breast Cyclophosphamfide, Methotrexate, FluoroUracil JTE-522 D-1927 Vinbiastile, Breast DoxorubiC in, Thiotepa, Fluoxylesterofle JTE-522 D-1927 Fluorouracil, Colon JTE-522 D-1927 Cyclophosphamide, Lung Doxorubic in, Etopos ide JTE-522 D-1927 Cyclophosphamfide, Lung Doxorubicin, Vincristinfe J'rE-522 D-1927 Etoposide, Lung Carbopi at in JTE-522 D-1927 Etoposide, Lung Cisplatin JTE-522 D-1927 Paclitaxel, Lung Carboplatin JTE-522 D-1927 Geincitabile, Lung Cisplatin JTE-5222 D- 192 7 Paclitaxel, Lung

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-304- Cisplatin Biological Evaluation COX-2 Inhibitors 1. Lewis Lung Model: Mice were injected subcutaneously in the left paw 1 x 10' tumor cells suspended in 30 Matrigel) and tumor volume was evaluated using a phlethysmometer twice a week for 30-60 days. Blood was drawn twice during the experiment in a 24 h protocol to assess plasma concentration and total exposure by AUC analysis. The data are expressed as the mean SEM. Student's and Mann-Whitney tests were used to assess differences between means using the InStat software package.

Celecoxib given in the diet at doses between 160-3200 ppm retarded the growth of these tumors. The inhibitory effect of celecoxib was dose-dependent and ranged from 48 to 85 as compared with the control tumors.

Analysis of lung metastasis was done in all the animals by counting metastasis in a stereomicroscope and by histochemical analysis of consecutive lung sections.

Celecoxib did not affect lung metastasis at the lower dose of 160 ppm, however surface metastasis was reduced by more than 50 when given at doses between 480-3200 ppm. In addition, histopathological analysis revealed that celecoxib dose-dependently reduced the size of the metastasic lesions in the lung.

-305- 2. HT-29 Model: Mice were injected subcutaneously in the left paw (1 x 106 tumor cells suspended in 30 Matrigel) and tumor volume was evaluated using a phlethysmometer twice a week for 30-60 days. Implantation of human colon cancer cells (HT-29) into nude mice produces tumors that will reach 0.6-2 ml between 30-50 days. Blood was drawn twice during the experiment in a 24 h protocol to assess plasma concentration and total exposure by AUC analysis. The data are expressed as the mean

SEM.

Student's and Mann-Whitney tests were used to assess differences between means using the InStat software package.

A. Mice injected with HT-29 cancer cells were treated with cytoxin i.p at doses of 50 mg/kg on days 5,7 and 9 in the presence or absence of celecoxib in the diet. The efficacy of both agents were determined by measuring tumor volume. Treatment using a celecoxib related COX-2 inhibitor (SC-58236) reduced tumor volume by 89 In the same assay, indomethacin given at near the maximum tolerated dose of 2 mg/kg/day in the drinking water inhibited tumor formation by 77%.

Moreover, the COX-2 selective inhibitor completely inhibited the formation of lung metastasis while the non-selective NSAID indomethacin was ineffective. The results from these studies demonstrate that celecoxib administered in the diet to tumor bearing mice can delay the growth of tumors and metastasis when administered as sole therapy. Moreover, a positive benefit is observed when celecoxib is administered in combination with a cytotoxic agent such as cyclophosphamide.

-306- B. In a second assay, mice injected with HT-29 cancer cells were treated with 5-FU on days 12 through Mice injected with HT-29 cancer cells were treated with 5-FU i.p at doses of 50 mg/kg on days 12, 13, 14, and 15 in the presence or absence of celecoxib in the diet. The efficacy of both agents were determined by measuring tumor volume. Treatment using a celecoxib reduced tumor volume by 68 In the same assay, decreased tumor volume by 61%. Further, the combination of celecoxib and 5-FU decreased tumor volume by 83%.

C. In a third assay, mice injected with HT-29 colon cancer cells were treated with 5-FU i.p 50 mg/kg on days 14 through 17 in the presence or absence of celecoxib (1600ppm) and valdecoxib (160 ppm) in the diet. The efficacy of both agents were determined by measuring tumor volume. Treatment with 5-FU resulted in a reduction in tumor voloume. Treatment with celecoxib and valdecoxib reduced tumor volume by 52 and 69 respectively. In the same assay, the combination of FU and celecoxib decreased tumor volume by 72 while the combination of 5-FU and valdecoxib decreased tumor volume by 74b (Table Table 25. Tumor Volume Effect of Celecoxib and Valdecoxib alone and in combination with Fluorouracil.

Days Vehicle 5FU celec- celec- valdec- valdecoxib oxib oxib oxib 160ppm 160ppm 160ppm 160ppm/

L

L

-307- L1 0.04 0.05 0.05 0.05 0.06 0.06 L4 0.13 0.12 0.13 0.13 0.13 0.13 18 0.19 0.16 0.17 0.14 0.17 0.16 21 0.23 0.21 0.2 0.17 0.2 0.19 28 0.38 0.3 0.25 0.22 0.25 0.21 0.62 0.46 0.35 0.28 0.32 0.29 42 1.01 0.68 0.52 0.32 0.36 0.31 Volume (ml) D. In a fourth assay, mice injected with HT-29 colon cancer cells were treated with celecoxib (10, or 160 ppm) in the diet beginning at day 10. An approximate dose dependent effect was observed. (Table 26).

Table 26. Celecoxib Inhibitis HT-29 Human Colon Carcinoma

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Days 14 22 28 42 vehicle 0.114 0.25 0.45 0.79 1.38 1.9 10 ppm 40 ppm 160 ppm 0.124 0.125 0.120 0.25 0.19 0.14 0.36 0.27 0.21 0.57 0.4 0.3 0.89 0.68 0.49 1.49 1.04 0.8 Volume (ml) MMP Inhibitors 1. Pancreatic Cell (PC-3) Model: In this study, the test groups were a vehicle control, Compound M14, Compound M14 with cisplatin and cisplatin alone with n=10 for each group. The tumors

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-308were measured with a caliper and the volume calculated using the formula for the volume of an elipsoid. The cisplatin dose was 10 mpk administered by the intraperitonal route on day 8 post injecion of tumor cells Compound M14, 50 mpk, was first-administered about 6:00 pm the evening of the same day that the tumor cells were injected in the morning. The same dose of Compound M14 was administered bid for each following day. Tumor volume (mm 3 was measured on day 25. The data below clearly show an improved response with the combination of the MMP inhibitor and cisplatin.

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-309- 2. Breast Tumor Model: This study was carried out essentially as PC-3 model. MX-1 breast tumor pieces were implanted (with a trocar) into nude mice with n=10 per group. Dosing with Compound M14(10 mpk or 50 mpk, PO bid) was initiated when the tumors reached a size of 60-120 mg. Dosing was continued for 26 days. Taxol was administered at a dose of 9 mpk for the first five days following the start of dosing by the interperitonal route. The tumors were measured using a caliper and the volume calculated using the formula for the volume of an elipsoid. The results tabulated below clearly show an improved response with combination therapy. An improved response is obtained with lower doses Compound M14.

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-310- Compound M14 1260 50 mpk Compound M14 50 mpk taxol 9 mpk Compound M14 10 mpk taxol 9 mpk 3. MX-1 Adjuvant Model: 480 240 Mice were implanted with MX-1 tumors and allowed to grow to 50 100 mm3. The animals were dosed with cyclophosphamide 100 or 80 mpk). This was considered Day 1. Two weeks later the animals were pair matched after tumor regression and dosing BID with the MMPI was begun until the end of the experiment. Tumors were measured weekly. The endpoint for the study was a final tumor size of 1.5 g.

Cycloph- MMPI MMPI MDS sem osfamide Dose Dose (mpk) (mpk) saline 23.9 1.3 cyclophosphamide 100 39.5 1.2 cyclophosphamide 80 37.2 cyclophosphamide 100 Compound M14 200 52.7 2.9 cyclophosphamide 100 Compound M14 50 43.7 1.6 cyclophosphamide 80 Compound M14 200 53.9 2.9 cvclophosphamide 80 Compound M14 50 44.2 1.8 MDS mean days to tumor weight of 1.5 g

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-311- 4. MX-1 breast tumor with taxol: Mice were implanted with MX-1 tumors and allowed to grow to 50 100 mg. The animals were pair matched and this was considered Day 1. Treatment with MMPI was begun BID on Day 1 until the end of the experiment. Taxol was injected IP (15 or 9 mpk) QD for 5 days (days 1 Tumors were measured weekly until an endpoint of 1.5 g was reached.

Taxol MMPI MMPI MDS sem Dose 'Dose (mpk) (mpk) vehicle 25.3 0.8 mmpi Compound 100 32.2 2.8 M14 mmpi Compound 20 34.7 3 M14 taxol mmpi 18 Compound 56 11 M14 taxol mmpi 9 Compound 30.1 1.8 M14 taxol mmpi 18 Compound 100 61 M14 taxol mmpi 9 Compound 100 46.7 3.7 M14 taxol mmpi 18 Compound 20 59.3 7 M14 taxol mmpi 9 Compound 20 39.3 1.9 0M14 MDS 1.5 g 5. SK-mes tumor with Taxol Mice were implanted with SK-mes tumors and allowed to grow to 50 100 mg. The animals were pair matched and this was considered Day 1. Treatment with MMPI was begun BID on Day 1 until the end of the experiment.

Taxol was injected IP (18 or 9 mpk) QD for 5 days (days

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-312- 1 Tumors were measured weekly until an endpoint of g was reached.

MDS 1.0 g 6. HT-29 tumor with Irinotecan Mice were implanted with HT-29 tumors and allowed to grow to 50 100 mg. The animals were pair matched and this was considered Day 1. Treatment with MMPI was begun BID on Day 1 until the end of the experiment.

Irinotecan was injected IP (100 or 50 mpk) QD for 5 days (days Tumors were measured weekly until an endpoint of 1.0 g was reached.

Irinotecan MMPI MMPI MDS

SEM

Dose Dose (mpk) _(mpk)

A

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-313- MDS 1.0 g In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express.language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, to specify the presence of the stated features but not to preclude the presence or addition or further features in various embodiments of the invention.

It is to be understood that a reference herein to a prior art publication does not constitute an admission that the publication forms a part of the common general knowledge in the art in Australia, or any other country.

Claims (144)

1. A method for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, which method comprises administerinlg to said mamrmal a therapeutically-effective amount of a combination of a cyclooxygeflaSe- 2 inhibitor, a matrix metalloproteinase inhibitor, and an antineoplastic agent, wherein said antineopjlastic agent is selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461, docetaxel, doxorubicin, etoposide, fluorouraCil (5 fluoxymestrine, gemcitabiie, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retEinoic acid, tarnoxif en, thiotepa, topotecan, torem2.fene, vinorelbine, vinbiastifle, vincristifle, selenium C selenomethiofline), ursodeoxycholiC acid, sulindac sulf one, exemestale and eflornithile (DMO).

2. The method of Claim 1 wherein the combination is administered in a sequential manner. 3, The method of Claim 1 wherein the combination is administered in a substantially simultaneous manner.

4. The method of Claim 1 wherein the antineoplasti~c agent is capecitabiie. I The method antineoplastic agent

6. The method antineoplastic agent

7. The method antineoplastic agent

8. The method antineoplastic agent

9. The method antineoplastic agent The method antineoplastic agent

11. The method antineoplastic agent -315- of Claim 1 wherein the is carboplatin. of Claim 1 wherein the is cisplatin. of Claim 1 wherein the is Cell Pathways CP-461. of Claim 1 wherein the is docetaxel. of Claim 1 wherein the is doxorubicin. of Claim 1 wherein the is etoposide.

12. The method of antineoplastic agent is

13. The method of antineoplastic agent is

14. The method of antineoplastic agent is The method of antineoplastic agent is Claim 1 wherein the fluoxymestrine. Claim 1 wherein the gemcitabine. Claim 1 wherein the goserelin. Claim 1 wherein the irinotecan. Claim 1 wherein the ketoconazole. -316-

16. The method antineoplastic agent

17. The method antineoplastic agent

18. The method antineoplastic agent

19. The method antineoplastic agent The method antineoplastic agent

21. The method antineoplastic agent

22. The method antineoplastic agent

23. The method antineoplastic agent

24. The method antineoplastic agent The method antineoplastic agent Claim 1 wherein the letrozol. Claim 1 wherein the leucovorin. Claim 1 wherein the levamisole. Claim 1 wherein the megestrol. Claim 1 wherein the mitoxantrone. Claim 1 wherein the paclitaxel. Claim 1 wherein the raloxifene. Claim 1 wherein the retinoic acid. Claim 1 wherein the tamoxifen. Claim 1 wherein the thiotepa. -317-

26. The method of Claim 1 wherein the antineoplastic agent is topotecan.

27. The method antineoplastic agent

28. The method antineoplastic agent LO

29. The method antineoplastic agent The method antineoplastic agent

31. The method antineoplastic agent of Claim 1 wherein the is toremifene. of Claim 1 wherein the is vinorelbine. of Claim 1 wherein the is vinblastine. of Claim 1 wherein the is vincristine. of Claim 1 wherein the is selenium (selenomethionine)

32. The method of Claim 1 wherein the antineoplastic agent is sulindac sulfone.

33. The method of Claim 1 wherein the antineoplastic agent is eflornithine (DFMO).

34. The method of Claim 1 wherein the cyclooxygenase- 2 inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: I I 4 Ail- 3 1 8 H 2 N 0 0 4- (4-cyclhexY.12mthyl .oao 2- fJ.uorobenzenesufonami~dey) 2) S-hloro-'3- (mnethyjmuEfoly1)pheflyl) -2- (mTethy -5 pyr dnyl) pyhl dne 4) 2 S NH N CF 3 4- (4 -methyiphenyl) 3- (triflu.omt1) 1 P.'ZOl1Yl. beflzenesulfnaie -3 19- rofecoxib, 4- (methylsulfonyl)phelll-3- phenyl-2 (51) -furanone, 4- (5-xethyl-3-phefylisoxazol- 4 yl) benzenesulfonamide, 7) N-lI[4- (3-methyl-3-phelylisoxazo- 4yl] phenyl] sulfonyl) propanamide, 4- 5- (4-choropheny-) (trifluoromethyl) -lH- pyrazole-1-yl) benzenesulf onaxaide, -320- 9) 0 CI OH 0 CF 3 NHSQ 2 CH 3 01 0 511 0 C N N,. NH 6- 5- (4-chlorobenzoyl) -1,4-dimethyl-1H- pyrrol-2-yllrnethyl] -3 (2i) -pyriaazinone, 12) NHSO 2 CH 3 0 N0 2 N- (4-nitro-2-phenoxyphelyl)metanesloamd, -3 21- 0 cl 0C 2 H W O0 C F 3 CI 3-(3,4-difluorophenoxy) 5-dimethyl-4- [4- (methylsulfonyl)phenyl] -2 (5H) -furanoie, (2,4-difluorophenyl)thio]-2,3-dihylro-1- -yl methanesulf onanide, 322 16) N 0 0 0 3- (4-chiorophenyl) [4- (methylsulfonyl)PheYl] -2 (3H)-oxazolone, 17) F NA H 2 N, 00 4- (4-fluorophelyl) 3-dihydro--2-oxo-4- oxazolyl] benzenesulfonam~ide, 18) H 3 CO 2 S, 10?0 3- (methylsulfonyj-)phel) -2-phenyl-2- cyclopenten--ofle, -323- 19) N. H 2 4- (2-methyl-4-PhenylS5 oxazolyl) benzefeleUfoflmide, FNO 3- (4-fluorophel) (methy1sulfofl)phenyl3 -2 (3H) 21) CH 3 CF 3 F (4-fluorophelYl) 4- (methylSUlfolYl) phenyll Ctrifluoroflethyl) IH-pyrazole, -3 24- 22) NH 2 0 N' F 3 (trifluorOmethYl) -lH-pyrazol-l- 23) 4- [1-pheflyl- 3 (trifluoromethyl) -1H-pyrazoJl-S yl] benzeflesulfonamide, 24) 4-[15- (4-fluoropheflYl) (trifluorolnethYl) -iH- pyrazol--ll Ibenzenesulfonamiide, -325- .NHSO 2 CH 3 0 N0 2 N- (cyclohexyloxY) -4- nitrophelyl Imethanesul~fonaide, 26) NHSO 2 CH 3 F F 0 N- 2 ,4-difluoropheloxy)-2,3dhyro-lOXO- methaflesulfonamide, 27) NHS0 2 CH 3 7 ::CI H 2 N 0 3- (4-chloropheloxy) -4- [i(methyl Sulf OnYl) amino]I benzenesul f ofamide, -326- 28) NHSO 2 CH 3 H 2 Ns 0 3- (4-fluorophenoxy) -4- [(methylsulfoflYl) amino] benzeeleS]~flamide, 29) NHSO 2 CH 3 CH 3 AT 3-1 (l-methy1H-imidazo12-yl) thiol -4 [(methylsulfoflyl) aininolbenzefesulfonamide, CH 3 0 H 3 aC OH 3 5-dimnethyl-- 4 (methylsulfoflyl)phenYl]- 3 phenoxy- 2 (5i) -furanonfe, -327- 31) NHSO 2 CH 3 0 32) NHSO 2 CH 3 CI A=0 H 2 N 0 3- 4-dichiorophelyl) thia] -4- [(methylsulfolyl) amino 3benzenesulfolamide, 33) CH 3 sF 1-fluoro-4-[2 [4- (methylsulfofl) phenyll cyclopentel-l- yl] benzene, -32 8- H 2 NO 2 S0 pc N CH F 2 4 (4 -chiorophelyl) -3 (dif luoromethy2.) -lIH- pyrazol-1-yl lbenzenesulfoflamfide, 3- (methylsulfoflYl)phenyll -4- (tri fluoromethyl) H mdzo 2 y yiie -32 9- .36) CF 3 NN H 2 N/ 0 4- E2- 3-pyridiflyll) (trifluoromethyl) -lH- imidazol-lY)-1 benzenesulfoflmide, 4-[15- (hydroxymethyl) _3-phenylisoxazo- 4 yl ]benzenesulfoflmide, 4- 13- (4-chlorophenl~) 3-dihydro-2-oxo 4 oxazolyl)belzefesulfonamide, -330- 4-tS- (difluoromethYl) -3-phenylyisoxazol- 4 yl) benzenesulfoflmide, NH 2 ,1n7terphenyl)4-sulfonamide, 4-(methylsulffonl1rl,2h1"l-terphelyl, -331- 4- (2-pheny--3 -pyridinyl) benzenesul~flamide, 43) N- (2,3-dihydro-1 1-dioxido-6-phefloxyl, 2- methanesulfoflamfide, and (forinylainino) -4-oxo-6-phefloCy-4H-1 benzopyran-7 -yl) methanesu-folamide, -332- .46) 0 c I 0 N a 0 C F 3 CI 0 ci z NH 2 zz, 0 CF 3 CI 47) Fanid tH 3 The method of Claim 1 wherein the cyclooxygenase- 2 inhibitor is 5-chloro-3-(4- (methylsulf onyl.) phenyl) -2 (methyl -5 -pyridinyl )pyridine. -333-

36. The method of Claim 1 wherein the cycloo7xygenase- 2 inhibitor is 2-C 3, 5-difluorOPhelYl) 4- (methylsulfoflyl) phenyl) -2-cyclopenten-l-Ofle.

37. The method of Claim 1 wherein the cyclooxygenase- 2 inhibitor is pyrazol-1-y). I ben~zenesulfOflaide.

38. The method of Claim 1 wherein the cyclooxygenase- 2 inhibitor is rofecoxib, 4- (methylsulfolyl)Phell-3- phenyl-2 -turanole

39. The method of Claim 1 wherein the cyciooxygeflase- 2 inhibitor is 4- C5-rethyl-3-pheflylisoxazo> 4 yl) benzenesulfOtfllfide. -334- The method of Claim 1 wherein the cyclooxygenase-2 inhibitor is N-[[4-(5-methyl-3- phenylisoxazol-4yl]phenyl]sulfonyl]propanamide.

41. The method of Claim 1 wherein the cyclooxygenase-2 inhibitor is NH 2 0 CF 3 -J CI 4-[5-(4-chorophenyl)-3-(trifluoromethyl) -H- pyrazole-l-yl]benzenesulfonamide.

42. The method of Claim 1 wherein the neoplasia is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.

43. The method of Claim 1 wherein the neoplasia is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, I -335- hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor.

44. -The method of Claim 1 wherein the matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: -336- ECI N-hydroxy-1-(4-methylphenyl) 4-[4- (trifluoromethyl)phefloxy)phenylI sulfolY1-]-4- piperidinecarboxam~ide monohydrochloride, H ,N' H HC1 N ,L 1-cyclopropyl-Nhydroxy- 4 [4- (trifhlorornethoxy) phenoxy] phenyl] sulfonyll -4- piperidiriecarboxamide monohydrochioride, -337- HC1 N I- N-hydroxy-1- (phenylmethyl) [4- (trifluoroinethoxy) phenoxy] -1- piperidinyl I sulf onyl) -4 -piperidinecarboxamfide monohydrochioride, HCl N-hyciroxy-1- (4-pyridinylinethyl) [4- (trifluorome thyl) pheloxy]phenl' sulf onyl) -4- piperidinecarboxamfide dihydrochloride, -33 8- CH 3 N-hydXroxy-2 ,3 -dimethoxy- 6 [4- (trifluoromethyl) pherioxy] -1- piperidinyl] sulfonyllbelzamfide, HCI HCI N-hYdrOXY-l (4-pyridinylmethY))-4-[lil- [4- (trif luoromethYl) phenoxy) phenyll sulfonyl] -4- piper idinecarboxamide dihydrochioride, .CF 3 HOWN HCI HCI N-hydroxy-1- (3-pyridiflmethYl) 14- (trifluoromrethy1)phenoxy]phenYl) sulfonyl] -4- piperidiflecarboxaJmide dihydrochloride, I -339- 8) -ocy HOHN S a CF N N-hydlroxy-l- (2-pyridinylmethyl)-4- t4- (trifluoromethyl) phenoxyl phenyll sujlfonyll -4- piperidinecarboxanide inonohydrochioride,. 9) HOHN N OHH Brit ish Biotech BB-2 516 (Myarimastat) N4- 2,2 dimethyl- 1-1 (iethylaxnino) carbonyl] propyll Ni, 2 -dihydroxy-3 (2-methyipropyl) [2S- -340- 100 Bayer Ag Bay-12-9566, 4-[(4'-chloro[l,1'- iphenyl)- 4-yl)oxy)-2- [(phenylthio)methlylibutaloic acid, HOHNVO0 0 Agouron Pharmaceuticals AG-3340, N-hydroxy-2,2 dimethyl-4-E[4-(4- pyridinyloxy)phenyl] sulfonyl) 3- thiomorpholinecarboxamide, 12) CollaGenex Pharmaceuticals Cb4T-3 (Metastat), 6-demethyl-6-deoxy-4- dedimethylaxninotetracyc line, 13) Chiroscience D-21 63, 2- [iS- ([C2R,S)- acetylxnercapto- 5- phthalimidolpeitaoyl- L- leucyl) amino- 3- methylbutyll]imidazole, -341- iC I N-hydroxy- 4 1 (phenylthio) phenyl] sulfoflyl] 1- (2 -propynyl) -4 -piperidinecarbOXamide monohydrochi oride, HOHN' 16) N-hydroxy-l (2 -methoxyethYl) 4- 14 [4 (trifluoromethoxy) ph enoxy) phenyl] sulfoflyl] -4- piperidinecarboxaflide monohydxochl0ride, HOHN CF 3 0 N N-hydroxy-l- (2-met1hoxyethyl) 14- (trifluoromethYl) phenoxy) phenyl] su3fony 1 -4- piperidinearboxamide, -3 42- AHCI 1-cycopropylNhydroy 4 -14- [4- (trifluoromethYl) phenoxy) phenyl] sulfonyl 11-4- piper idinecarboxamfide monohycirochloride, OH N HCI 4-1 (cyclohexylthio)Phells ulfonyl] -N- hydroxy- 1-(2 -propynyl) -4 -piperidinecarboxamide zonohydrochJlride, 4-1 (4- chlorophenoxy) phenyl] sulfonyl 1tetraydro-N hydroxy-2H-pyran- 4 -carboxamide, -343- 0 0 0 S OCH 3 HOHN 0j N N-hydroxy- 4- [4 (4 methoxypheloxy)phelYl) sulfonyl (2- propynyl) -4-piperidinecarboxamide, 21) HOHN F NzN. N 1-cyclopropyl-4-[ fluorophenyl) thioiphenyl] sulfonyl] -N-hydroxy- 4-piperidilecarboxamfide, 22) 0 HOHN b I- 1-cyclopropy1-N-hydroxy- 4 (phenylthio)pileyl] sulfonyl]l-4- piperidinecarboxanide, -3 44- HOHN' tetrahydro-N-hydroxy- 4 (4- pyridinylthio) phenyl] sulfoflyl) -2H-pyran- 4 carboxamide, and 24) HOHN tetrahydroNhYdroxy- 4 [14- [4- (trifluorOmethYl)phenoxy]phenyl] sulfonyl] -2H- pyran-4-Carboxamfide. The method of Claim 1 wherein the matrix metaj-loproteiflase inhibitor is H ,ON' H CH 3 N-hydroxy-l- (4-methyiphelYl) [4- (trifluoromfethYl}phenoxy] phenyll sulfony1-]-4- piper idinecarboxanfide monohydrochloride. -3

46-. The method of Claim 1 wherein the matrix metalloproteilase inhibitor is o 0 CF 3 S0 H N H 0 HCJ N 1 -CyClopropyl-N-hydroxy- 4 4 4 (trifluoromethoxy)PheloxyiIPhellsulfonyl] -4- piperidinecarboxanide monohydrochloride.

47- The method of Claim 1 wherein the matrix metalloproteinase inhibitor is o 0 CF 3 HI 100 N-hydroxy-1- (phenylmethyl) [14-[14- trif luoromethoxy) phenoxy) -1- piperidinyll sulfonyl] -4-piperidiflecarboXamide ionohydrochloride. -346-

48. The method of Claim 1 wherein the matrix metalloproteiflase inhibitor is He..NN N CF 3 H HCI N H 3 C N-hydroxy-l- (4-pyridinylmethyl) [4- (trif-luoromethyl)phenoxy)phellsulfonyl] -4- piperidinecarboxanide dihydrochioride.

49. The method of Claim 1 wherein the matrix metalloproteiflase inhibitor is 0 ~0 CF 3 HH /0 H 3 C 0 CH 3 N-hydroxy-2, 3-dimethoxy-6- II[4- [4- (trifluoromethyl) phenoxy] -1- pipericlinyl] sulfonyllbenzamide. -347- The method of Claim 1 wherein the matrix metalloproteiflase inhibitor is H-OHN' HI-C HCI 1 (trifluoromethYl) phenoxylphenyl] suif any.]-4- piperidinecarboxamfide dihydrochioride.

51. The method of Claim 1 wherein the matrix retalloproteinase inhibitor is CF 3 HCI HCI (3-pyridinyXlethYl)-4-[[4-114- (trifluorornethYl) phenoxyl phenyl] suif anyl.]-4- piperidinecarboxamfide dihydrochioride. -348-

52. The method of Claim 1 wherein the matrix xnetalloproteiflase inhibitor is 0 0 N N-hydroxy- 1 (2 -pyridinylmethyl) 4- [14- [4- (trifluoromethyl) phenoxy) phenyl] sulfonyl 1-4- piperidinecarboxamfide monohydrochloride.

53. The method of Claim 1 wherein the matrix metalloproteiflase inhibitor is HOH* N W NH3 0HO 4 H British Biotech BB-2516 (IMarimastat), N4-[2,2- dimethyl- 1- 11(methylam~ino) carbonyl) propyl] N1,2 -dihydroxy-3 methylpropyl)-, [2S- -349-

54. The method of claim 1 wherein the matrix metalloproteilaSe inhibitor is Bayer Ag Bay-1 2 9 SG 6 6 4-L(4'-chlorotl,l'- iphenyll 4-yl) oxyl -2- [(phenylthio)methyllbutanoic acid. The method of Claim 1 wherein the matrix metalloproteilase inhibitor is HOHN0 S Agouron Pharmaceuticals AG-33 4 O, N-hydroxy- 2,2-dimethYl-4-[[4-(4- pyridinyloxy) phenyll]sulfonyl] 3- thiomorpho linecarboxamide.

56. The method of Claim 1 wherein the matrix inetalloproteiflase, inhibitor is CollaGeflex Pharmaceuticals Cl4T-3 (lMetastat), 6-demethyl-6-deoxy- 4 dedimethylamtiflotetracycline. -350-

57. The method of Claim 1 wherein the matrix metalloproteiflase inhibitor is Chiroscienice D-2163, 2- illS- S) acetylmercapto- 5- phthalimidolPeltanl- L- leucyl) amino- 3- methylbutyll imidazole.

58. A method for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, which method comprises administering to said mammual a therapeutically-effective amount of a combination of radiation, a cyclooxygeflase- 2 inhibitor, a matrix metalloproteinase inhibitor, and an antineoplastic agent, wherein said antineoplastic agent is selected from,the group consisting of anastrozo.e, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461, docetaxel, doxorubicin, etoposide, fluorouracil (5-FtJ), fluoxymestrine, gemcitabile, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrole, paclitaxel, raloxifene, retinoic acid, tainoxif en, thiotepa, topotecai, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionile), ursodeoxycholic acid, sulindac suif one, exemestane and eflornithine (DFMO).

59. The method of Claim 58 wherein the combination is administered in a sequential manner. The method of Claim 58 wherein the combination is administered in a substantially simultaneous manner. -351-

61. The method of Claim 58 wherein the antineoplastic agent is capecitabine.

62. The method antineoplastic agent

63. The method antineoplastic agent LO

64. The method antineoplastic agent The method antineoplastic agent

66. The method antineoplastic agent of Claim 58 wherein the is carboplatin. of Claim 58 wherein the is cisplatin. of Claim 58 wherein the is Cell Pathways CP-461. of Claim 58 wherein the is docetaxel. of Claim 58 wherein the is doxorubicin.

67. The method antineoplastic agent

68. The method antineoplastic agent

69. The method antineoplastic agent The method antineoplastic agent of Claim 58 wherein the is etoposide. of Claim 58 wherein the is fluoxymestrine. of Claim 58 wherein the is gemcitabine. of Claim 58 wherein the is goserelin.

71. The method of Claim 58 wherein the antineoplastic agent is irinotecan. I -352-

72. The method of antineoplastic agent is

73. The method of antineoplastic agent is

74. The method of antineoplastic agent is The method of antineoplastic agent is Claim 58 wherein the ketoconazole. Claim 58 wherein the letrozol. Claim 58 wherein the leucovorin. Claim 58 wherein the levamisole. Claim 58 wherein the megestrol.

76. The method antineoplastic agent

77. The method antineoplastic agent

78. The method antineoplastic agent of Claim 58 wherein the is mitoxantrone.

79. The method antineoplastic agent The method antineoplastic agent Claim 58 wherein the paclitaxel. Claim 58 wherein the raloxifene. Claim 58 wherein the retinoic acid.

81. The method of antineoplastic agent is Claim 58 wherein the tamoxifen. I -353-

82. The method antineoplastic agent

83. The method antineoplastic agent

84. The method antineoplastic agent .0 85. The method antineoplastic agent

86. The method antineoplastic agent

87. The method antineoplastic agent of Claim 58 wherein the is thiotepa. of Claim 58 wherein the is topotecan. of Claim 58 wherein the is toremifene. of Claim 58 wherein the is vinorelbine. of Claim 58 wherein the is vinblastine. of Claim 58 wherein the is vincristine.

88. The method of antineoplastic agent is

89. The method of antineoplastic agent is

90. The method of antineoplastic agent is Claim 58 wherein the selenium (selenomethionine). Claim 58 wherein the sulindac sulfone. Claim 58 wherein the eflornithine (DFMO). -354-

91. The method of Claim 58 wherein the cyclooxygenase- 2 inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: JTE-522, 4- (4-cyclohexyl-2-methyloxazol5yl) 2-fluorobenzenesulfoam~lide, 5-chloro-3-(4- (methylsulfonyl)phelyl) -2- (methyl-S -pyridinyl )pyridine, 2- 5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2 -cyclopenten--ofle, H 2 NO 2 (4-methyiphenyl) (trifluoromethYl) -li- pyrazol-1-yl] -benzenesulfonamide, -3 0 rofecoxib, 4- (methylsulfoflyl)phelYl] -3- phenyl-2 (5H) -furanone, 6) H 2 NO 2 S /N H 3 C 0o1. 4- {5-methyl-3-phelylisoxazol- 4 yl) benzenesulf onainide, 7) N- [4 (5-methyl -3 -phenlyl isoxazol 4yl)phenyl) sulfonyl~propalamide, 8) NH 2 I- ClF (4 -choropheny-) 3 -(trif luoronethYJ-) 1H- pyrazole-l-yll benzenesulfolamide, -356- 9) 0 N. OH O0 CF 3 NHSO 2 CH 3 0 51) 0 C N N 1/ 0 6- (4-chlorobenzoyl) 4-dimethyl-1H- pyrrol-2-yl]methyl] -3(21) -pyridazinone, 12) NHS0 2 CH 3 0 N0 2 N- (4-nitro-2-pheloxypheyl)methalesulfonam2de, -357- 0 CI 0C 2 H kC1 1 0 CF 3 CI 14) F 1N 3- (3 ,4-difluoropheloxy) 5-dimethyl-4- [4- (mnethylsulfol))phenyl] -2 (5H) -furanole, NHSO 2 CH 3 F S K- F N- 4-difluorophelYl) thio] 3-dihydro-l oxo- 1H- inden- 5-yl] methaiesulfoflamide, 3- (4-chlorophelYl) 4- (methylsulfoflyl)phenll> 2 (3H) -oxazolone, -358- 4-t3- (4-f luorophenyl) 3-dihyclro-2-oxo-4- oxazolyl Ibenzene sulfonamide, 3- (methylsulfonyl)phenyl) -2-phenyl-2- cyclopenten-1-one, 4- (2-methyl-4-phenyl-5- oxazolyl )benzenesulfonanide, 0 3- (4-f luorophenyl) [4- (methylsulfonyl)phenyl) -2 (3H) -oxazolone, -359-w 21) 0 NN 7F F (4-fluorophelyl) (methylsulfonyl) phenyl 1-3- (trifluoromethyl) 1H-pyrazole, 22) NH 2 0/s N N~ CF 3 4- [5-phenyl) (trifluoromethy.) -1H-pyrazOl-l- yl )benzenesulfonaflide, 23) NN H 2 N, 7 0 0 4- [1-phenyl-3-(trifluoromethY)- yl] benzenesulfoflamride, -360- 24) NH 2 F 4- (4-f luoropheflyl) (trifluoromethYl) -1H- pyrazol1-yl]beflzeIesulfonamide, NHSO 2 CH 3 0 N02 N- (cyclohexyloxy) -4- ni trophenyl] methanesu]-f onainide, 26) NHSO 2 CH 3 F 0 7 F 0 N- (2 4difluoropheloxy) -2,3 1H- inden-5 -yl ]methanesul-fonamide, -3 61- 27) NHSO 2 CH 3 H 2 N" 3- (4-chiorophenoxy) -4- [(methylsulfonyl) amino) benzenesulfonamide, 28) NISO 2 CH 3 H 2 N~ 3- (4-f luorophenoxy) -4- [(methylsulfonyl) amino]benzenesulfonamide, 29) NHSO 2 CH 3 H Ks N H 2 N 0 3- (-methyl-1H-imidazol-2-yl) thic] -4 (methylsulfonyl) aminollbenzenesulfonamide, -362- CH3 H 3 COH 5-dimethyl-4- (methylsulfoflYl)phell -3- phenoxy-2 31) NHSO 2 CH 3 CH 3 0 N- [16- (4 ethyl- 2 -thiazolYl) thiol 3-clihydro- methanesu-folamide, 32) NHSO 2 CH 3 Cl S= H 2 N' 0 3-11(2, 4-dichloropheflyl) thiol -4- [(iethylsulf onyl) amino~benzelesufonamide, -363- 33) 1-f luoro-4- [4- (iethylsulfonyl) phenyl] cyc-lopenten-1- y~jbenzene, 34) H 2 NO 2 S IC N CHF 2 4- (4-chiorophenyl) (difluoronethyl) -lii- pyrazol-1-yl Ibenzenesulfonanide, CF 3 N NN H 3 c/f o (methylsulfonYl)phelyl] -4- (trifluoromethyl) -lH-imidazol-2-yl] pyridine, -364- 36) 4- (3-pyridil2) (trifluoromfethyl) -lH- iinidazol--llbenzenesulfonamide, 4- [5-(hydroxymethYl) -3-phenylisoxazol- 4 yl] benzenesulfoflmide, 38) 4- (4-chlorophelyl) -2,3-dihyro-2-oxo 4 oxazolyl benzenesulf ofamfide, -365- 4-[15- (difluoromethYl) -3-pheflisoxazol- 4 yl] benzenesufofla1Tide, ,h1-terphefylY14-sulfonamide, 4-(methyl$uJfoflyl)1,1 ,1"-terphelyl, -366- 42) 4- (2 -phenyl-3 -pyridinyl) benzenesulfonamide, 43) NHSO 2 CH 3 0 N- (2.3-dihydro-1, 1-dioxido-6-phenoxy-1,2- methanesulfonamide, and N- (formylamino) -4-oxo-6-phenoxy-4H-1- benzopyran-7 -yl Imethanesulfonamide, -367- 0 cl 0-ONa+ 0 CF 3 0 CI NH 2 0 CF 3 46) I and 48)

92. The method of Claim 58 wherein the cyclooxygease- 2 inhibitor is 5-chloro-3-( 4 (iethylsu-foflyl) phenyl) -368-

93. The method of Claim 58 wherein the cycloo7xygeflase- 2 inhibitor is 2- (3 ,5-difluoropheflyl)-3- 4- (rethylsulfoflYl)phelYl) -2-cyclopentel-ofle.

94. The method of Claim 58 wherein the cyclooxygenase-2 inhibitor is 4- (4-methyiphenyl) (trifluoromethyl) -H- pyrazol-1.-yl) -benzenesulfonaiide. The method of Claim 58 wherein the cyclooxygenase-2 inhibitor is rofecoxib, 4- (methylsulfonyl)phenYl] -3- phenyl-2 (SH) -furanone.

96. The method of Claim 58 wherein the cyclooxygenase-2 inhibitor is 4- (5-methyl-3-phenylisoxazo-- yl) benzenesulfonaiide. I -369-

97. The method of Claim 58 wherein the cyclooxygenase-2 inhibitor is N-[[4-(5-methyl-3- phenylisoxazol-4yl]phenyl]sulfonyl]propanamide.

98. The method of Claim 58 wherein the cyclooxygenase-2 inhibitor is NH 2 I o=s OSNN CF3 CI 4-[5-(4-chorophenyl)-3-(trifluoromethyl)-1H- pyrazole-1-yl]benzenesulfonamide.

99. The method of Claim 58 wherein the neoplasia is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.

100. The method of Claim 58 wherein the neoplasia is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, I -370- glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor. -371-

101. The method of Claim 58 wherein the matrix metalloproteilase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: N-hydroxy-1- (4-methyiphenyl).-4- 4- t4- (tri fluoromethyl) phenoxy) phenyl Isulfonyl] -4- piperidinecarboxamide monohydrochloride, HCI N 1-cyclopropyl-N-hydroxy-4- 4- t4- (trifluoromethoxy)phenoxy]phenYl] sulfony-)-4- piperidinecarboxamide monohydrochloride, -372- H 11 N N IC HC1 N N-hydroxy-l- (phenylmethyl) [4- (trifluoromethoxy)pheloxy] -1- piperidinyl) sulfonyl] -4-piperidinecarboxamfide mcrnohydrochloride, HCI N HO-C0 N-hydroxy-1- (4-pyridinylnethyl)-4-f [4- (trifluorone.hyl) phenoxylphenyl] suilfonyl] -4- piperidinecarboxamide dihydrochioride, -373- CH 3 N-hydroxy-2, 3-dixnethaxy-G- (trifluoroinethyl )phenoxy) -1- piperidinyl Isu2.fonyl) benzanide, 0 HOHN CF N HG! HCI N-hydroxy-l- (4-pyridinylmethyl) [4- (trifluoromethyl) phenoxy] phenyl] sul-fonyl) -4- piperidinecarboxamide dihydrochioride, CF 3 HCE' HCI N-hydroxy-1- (3-pyridinyirnethyl) [4- (trifluoromethyl) phenoxyphenyl-]sulfonyl] -4- piperidinecarboxanide dihydrochio ride, -374- HOHN Nzz CF 3 I. N-hydroxy-1-(2-pyridinymethyl) trifluoromethyl) phenoxy]phenyl-]sulfonyll -4- piperidinecarboxamide monohydrochloride, HOHN N 'NCH OHO H British Biotech. BB-2516 (Marimastat), N4-[2,2- dimethyl- (rethylamino)carbofll]propyl] N1,2 -dihydroxy-3 (2-methylpropyl)-, [2S- ,2R*,3S*1 -37S- Bayer Ag Bay-12-9 566 4-[(4'-chloro[1,1'- iphenyl]- 4-yl)oxy] -2- t(phenylthio)methYllbutanoic acid, 11) HOHN 0 Agouxol Pharmaceuticals AG-334 0 Ni-hydZoxy-2,2 dimethyl-4- (4- pyridinyloxy)phellsulfor'yl] 3- thiomorphol1inecarboxamide, 12) CollaGenex Pharmaceuticals CMT-3 (Metastat), 6 -demethyl-6 -deoxy-4- dedimethylamilotetracyclile, 13) ChiroscienCe D-2163, 2- [iS- acetylmercaPto- 5- phthalimido]peltanl L- leucyl) amino- 3- methylbutyl-]imidazole, -376- HCI NAC N-hydroxy-4- 4- (phenylthio)phlellsulfonyl- 1- (2 -propynyl) -4 -pipearidinecarboxamide monohydrocbi or ide, HOWN r) HOI N-hydroxy-l- (2-inethoxyethYl) -4-1[4-1[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl) -4- piperidinecarboxamide monohydrochioride, HOHN' 0 N-hydroxy-1- (2-methoxyethyl) [4- (trifluoromethyl)pheloxyphel]suJfonyl]-4- piperidinearboxanide, -37 7- 17) HOH CF 3 N L HCI 1-cyclopropyl-N-hydroxy-4- [4- (trifluoromethyl) phenoxyl phenyl] sulfonyl] -4- piperidinecarboxamide monohydrochloride, 18) S HOHNI N HOI 4- 4- (cyclohexylthio)phenyl]sulfoflyl] -N- hydroxy-l- (2-propynyl) -4 -piper idinecarboxarnide monohydrochioride, 19) H-OHN 0 0 4-[14-(4- chiorophenoxy) phenyl] sulfonyll tetrahydro -N- hydroxy-2H-pyran-4-carboxamide, -3 78- HOHN 0aOH N N-hydroxy-4-E (4- methoxyphenoxy)phelyl) sulfonyl propynyl) -4-piperidinecarboxamide, 21) S F HOHNF N 1-cyclopropyl-4-[[4- fluorophenyl) thioliphenyl) sulfonyll-N-hydroxy- 4-piperidinecarboxamide, 22) S HOHN S N 1-cyclopropyl-N-hydroxy- 4 (phenylthio)phenyl] sulfonyl) -4- piperidinecarboxamide, -379- tetrahydro-N-hydroxy- 4 (4- pyridinylthio) phenyl] sulfonyll -2H-pyran- 4 carboxamide, and 24) HOHI tetrahydro-N-hydroxy 4 [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl 3-2H- pyran- 4- carboxani de.

102. The method of Claim S8 wherein the matrix metalloproteilase inhibitor is OH 3 N-hydroxy-1- (4-methyiphenyl) -4-Il[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4- piperidinecarboxanide monohydroch.oride. -3

103. The method of Claim 58 wherein the matrix metalloproteilase inhibitor is UCI N 1-cycopropy-Nhydroxy- 4 4- [4- (trifluoromethoxy)phenoxy) phenyl) sulfonyl) -4- piperidinecarboxamide monohydrochloride.

104. The method of Claim 58 wherein the matrix metalloproteilase inhibitor is 0 0 0 cIF 3 .J a 0 HON N I- N-hydroxy-l1- (phenylinfethyl) 4 t- [4 (trifluoromethoxy) phenoxyl -1- piperidinyl]sulfonylyI 4 -piperidilecarboxamlide monohydrochioride. *3 81-

105. The method of Claim 58 wherein the matrix ietalloproteiflase inhibitor is CF 3 H .aN N H MCI N N-hydroxy-1- (4-pyridiflylmethyl) [4- ctrifluoromethyl)PhelOXY)Phellsulfonyl] -4- piperidinecarboxahide, dihydrochioride.

106. The method ot Claim 58&wherein the matrix metalloproteilase inhibitor is 0 ,o CF 3 H 0 H 3 C 0 OH 3 N-hydroxy-2, 3-dimethoxy-6-[[4- [4- (trifluoromethyl) phenoxy) -1- piperidinyll suit onyllbenzamide. -3 82-

107. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is HOWN HCII NO, HCI N-hydroxy-l-(4-pyridinylnethyl) -4-f (trif luoromethyl) phenoxy) phenyl]I sulf onyl)1 -4- piperidinecarboxamide dihydrochioride.

108. The m~ethod of Claim 5 8 wherein the matrix metalloproteinase inhibitor is HOWN N-hydroxy-l- (3-pyridinylmethyl) -4-f (trifluoromethyl) phenoxy] phenyll sulfonyl) -4- piperidinecarboxamide dihydrochloride. -3 83-

109. The method of Claim 58 wherein the matrix ietalloproteinase inhibitor is 0OQ HOHN CF 3 N N-hydroxy-l- (2-pyridinylmethyl) [4- (trifluoromethyl)phenoxylphellsulfonyl] -4- piperidinecarboxaaide monohydrochioride.

110. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is 0 H 0 H HOHNN British Biotech BB-2516 (Narirnastat), N4-[2,2- dimethyl- 1-[t(methylamino) carbonyl] propyl] N1 1 2. -dihydroxy-3 methylpropyl)-, [2S- -384- ill. The method of Claim 58 wherein the matrix metalloproteiflaSe inhibitor is I-I Bayer Ag Bay-12- 9566 4-[(1-ch-oroII),1'- iphenyl]- 4-yl)oxy]- 2 [(phenylthio)methyl]btan~oic acid.

112. The method of Claim 58 wherein the matrix inetalloproteiflase inhibitor is HOHN N, 0 NSN Agourofl Pharmaceuticals AG-3340, N-hydroxy- 2,2-dimethyl-4-[[4( 4 pyridinyloxy)phellsulfonyl] 3- thi omorpho line carboxamide.

113. The method of Claim 58 wherein the matrix metalloproteiflase inhibitor is CollaGenex Pharmaceuticals CM'T-3 (Metastat), 6-demethyl-6-deoxy- 4 dedimethyl amino tetracycline.

114. The method of Claim 58 wherein the matrix metalloproteiflase inhibitor is Chiroscience D-2163, 2- -385- [Is- acetylmercaPtO- 5- phthalimidolPeltaloyl- L- leucyl)amriflo- 3- methylbutyllimtidazole-

115. A combination comprising a cyclooxygeflase- 2 inhibitor, a matrix metalJ-oproteiflase inhibitor, and an antineoplastiC agent, wherein said antineopi-astic agent is selected from the group consisting of anastrozole, calcium carbonate, capecitabile, carboplatin, cisplatin, Cell Pathways CP-461, docetaxel, doxorubicii, etoposide, fluorouracil fluoxyrnestrile, gexncitabine, goserelin, irinotecan, ketoconazole, letrozo-, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxe- 1 raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, torexnifefle, vinorelbile, vinblastile, vincristile, selenium (selenomethioline), ursodeoxycholic acid, sulind ac suif one, exemestane and eflornithifle (DFb4O).

116. The combination of Cla im 115 wherein the cyclooxygeflase- 2 inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: 1) N>CH 0 H2,S 0 0 F JTE-522, 4- (4-cyclohexyl 2-methyloxazolS'-Yl) 2- fluorobeflzeflesulfonam~ide, -38 6- 5-chloro-3-(4- (methylsulfoflyl)phenYl) -2- pyridine, 2- 5-difluorophel)-3-4- (methylsulfol) phenyl) -2 -cyclopentel-l-0fle, (4-methyiphelyl) (trifluo~rOmethYl) -W- pyrazol--y.J benzenesufoflam~ide, rofecoxib, 4- (methylsulfoflYl)phenyll- 3 phenyl-2 (5H) -furanole, 4- (5-methyl-3-pheflisoxazo' 4 yl) benzene sulfonamide, -387- 7) N- (5-methyl-3-phenylisoxazol- 4yl] phenyl Jsulfonyl] propanai ie, 8) NH 2 CF 3 4- (4-chorophenyl) (trifluoromethyl) -IH- pyrazole-1-yil benzenesuifonamide, 0 0 CF, 3 NHSO 2 CH. 3 HN-S\-o 0 (4-chlorobenzoyl) 4-dimethyl-i- pyrrol-2-y1lnethyl3 -3 (2H)-pyridazinone, -388- NHSO 2 CH 3 N0 2 N- (4nto2peoyhny~ehnsloaie 0 cN. 0C 2 H 0 CF- 3 CI, 3- (3 ,4-difluoropheloxy) 5-dimethyl-4- [4- (methylsulf oyl) phenyl 1 -2 (5H) -furanone, 2 ,4-difluoropheylY) thio 2,3dihyro-l methanesulf ofaIfide, -389- 16) 3- (4-chiorophenyl) (4- (methylsulfolyl)phell-2 (3i) -oxazolone, 4- (4-fluorophenly) -2,3-dihydro-2-oxo-4- oxazolyl] benzenesulfoflamfide, 18) (methylsulfolyl)phell-2-phehyl-2- cyclopenten--ofle, -3 19) CH, H 2 N, s 4- (2-methyl-4-Phefl1S oxazolyl) benzenesulfolamide, F0 3- (4-fluorophelyl) [4- (methylsulfaflyl)phell-2 (3H)-oxazolole, 21) CH 3 CF 3 F (4-fluorophel)--14- (methylsulfofl)phenyll1-3- (trifluoronethYl) IH-pyrazole, -391- CF3 4- [S-phenyl)-3- (trifluoromethyl)-1H-pyrazol-1- yl) benzenesulfonanide, 23) 4- tl-phenyl-3- (trif luoromethyl) -1H-pyrazol-- yl] benzenesulfonamide, 24) (4-f luoropheriyl) (trifluoromethyl) -1H- pyrazol-1-y1l benzenesulfonamide, -3 92- NHSO 2 CH 3 0 N0 2 (cyclohexy)oxy) -4- nitrophenyl] methanesutofl8X1ide, 26) NHSC CH 3 F 0 1 F 0 N- G- 4-difluoropheloxy) 3-dihyaro-1-oxo- ]methanesulfolamide, 27) NHS0O 2 CH 3 H 2 N 0 3- (4-chioropheloxy) -4- (methylsulfolyl) axino]benzefeleSJf0oamiae, -393- 28) NHSO 2 CH, 0 3- (4-f luorophenoxy) -4- [(methylsulfonyl) amino IIbenzenesulfonamide, 29) NHS0 2 CH 3 OH 3 3- (1-methyl-lH-imidazol-2-yl) thiol -4 (methylsulfonyl) amino]benzenesulfonanide, CH 3 0=s o ~H 3 C H 100 5-dimethyl-4- (methylsulfonyl)phenyl] -3- phenoxy-2 (5H) -furanone, -394- 31) NHSO 2 CH 3 N' CH 3 0 0 N- (4-ethyl-2-thiazolyl) thio] -1,3-dihydlro- 1-oxo-5-isobelzofura.IY1 ]methanesu-f onainide, 32) NHSO 2 CH 3 CI Acl 3 4-dichlorophenyl) thic]1 -4 [(methylsulfolyl) amino] benzelesuffl~fonide, 33) CH- 3 F 1-f luoro-4- [4- (methylsulfoflyl)phel] cyclopeflten-l yl] benzene, -395-. *34) H 2 NO 2 S CI N N CHF 2 4-15- (4-chiorophenyl) (difluoromethyl) -1K- pyrazo.-1 -yl Ibenzenesul fonamide, CF 3 N s-,O H 3 cf 0~ 3- 4- (rethylsulfonyl)phenyl) -4- (trifluoromethyl) -1H-iinidazol--2-yl) pyridine, -396- 4- (3-pyridi1yJl) (trifluOrOmethYl) -1H- imidazol-l-yl benzenesulfoflmide, H 2 N. 4- (hydroxymethyl-3-phenylisoxazOl- 4 yll benzenesufoflam'ide, 38) 4-[3-(4-chlorophel-2,3-diYdo2-oxo- 4 oxazoly1]beflzefesulfonamide, -397- 39) H 2 N. C F 2 H 4- (difluoromethYl) -3-phenyliSoxazoV 4 yl Ibenzenesulfolamfide, [1,1':21,1--terphenyl]-4-sulfonamide, 4-(methylsulfonyl)-1,1',21,1,,-terphenyl, -398- I- o-s IT-1 4- (2-phenyl-3-Pyrdinl) benzenesuflfide, 0 N- (2,3-aihYdro-l, -dioxido-6--phefloxyl, 2 benzisothiazol 5 -yl) methanesulfoflamfide, and N- [3 (f ormylamilo) -4 -oxo-6--phenoxy-4H-- benzopyrafl-7-yl Imethanesul~ffanfide, -399- 0 C1 U0Na 0 CF 3 C1 0 C 1 000 NH 2 k 0 CF 3 C1 47) 0 and 48) tH 3

117. TIhe combination of claim 115 wherein the cyclooxygena~se- 2 inhibitor is 5-chloro-3-( 4 (methylsulfoflyl)phenyl) -400-

118. The combination of Claim 115 wherein the cycloo7xygenase-2 inhibitor is 2- 5-difluorophenyl) -3- 4- (methylsulfonyl) phenyl) -2 -cyclopenten- 1-one.

119. The combination of Claim 115 wherein the cyclooxygenase-2 inhibitor is H 2 NO 2 S OL CH 3 N NN CF 3 4- (4-methyiphenyl) (trifluoromethy-) -111- pyrazol-1-yl] -benzenesulfonamide.

120. The combination of Claim 115 wherein the cyclooxygenase-2 inhibitor is H300 2 S rofecoxib, 4- (methylsulfonyl)phenyl] -3- phenyl-2 -furanone.

121. The combination of Claim 115 wherein the cyclooxygenase-2 inhibitor is H 2 NO 2 S H 3 C 0Or 4- (5-methyl-3-phenylisoxazol- 4 yl )benzenesulfonamide. I -401-

122. The combination of Claim 115 wherein the cyclooxygenase- 2 inhibitor is N-[[4-(5-methyl-3- phenylisoxazol- 4 yl]phenyl]sulfonyl]propanamide.

123. The combination of Claim 115 wherein the cyclooxygenase- 2 inhibitor is NH 2 0 N^--N CF 3 CI 4- 5- (4-chorophenyl) (trifluoromethyl) -1H- pyrazole-1-yl]benzenesulfonamide

124. The combination of Claim 115 wherein the neoplasia is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.

125. The combination of Claim 115 wherein the neoplasia is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, I -402- glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor.

126. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceuticallY acceptable salts thereof, of the group consisting of: -403- HCI N-hydroxy-l1 (4 -methyJlpheflyl) -4 4- [4 (trif luoromfethYl) phenoxy] phenyl] sulfonyl] -4- piperidinecarboxamide monohydroChloride,. HOI N 1-cyclopropyNhydroxy 4 4- (trif luoromtethOxY) phenoxy] phenyl] sulfonyl] -4- piper idinecarbOxam~ide monohydroch:Loride, -404- OO~ CF 3 0 0 0 HCi N N-hydroxy-l (phenylmfethyl) E 4- [4- (trifluoromfethox-y)phenoxY]-1- piperidillsulfonYl-4 4 piperidifecarboxmide monohydrochloride, HCI H3 N-hydroxy-l(4-pyridilIethYl) [4- (trifluoromethyl) phenoxy) phenYl] 5ulfOnflyJ]-4- piperidinecarboxaide dihydrochloride, -405- N-hydroxy-2,3-dimetox-6[[4- [4- (trifluoromethYl )phenoxy]ll- piperidinyl-)sulfonyl) benzaxnide, HCI N-hydrOXY-l (4-pyriaiflmethYl) (trif luorome thYl) phenoxy] PhenYl I sulfoflYl] -4- piperidinecarboxamide dihydrochJloride, HCI li-ydrOXY-l-(3-pyridilmethyl) (trifluoromfethyl )phenoxY) phenyl3ISUlfonyll]-4- piperidinecarboxamidt~e dihydrochioride, -406- CF 3 HOHNI t.0 N N HCI N-hydx'OXY-1- (2-pyridirlylmethYl) [4- (trifluoromethyl) phenoxy) phenyli sulfoll-4- piperidinecarboxamfide monohydrochloride 1 0H 0 HOH-NN H OH0 British Biotech BB-2516 (IMarimastat), N4-[2,2- dimethyl- 1- [(methylaino) carbonyl] propy- NI, 2 -dihydroxy-3 (2-methylpropyl)-, [2S- -4D7- Bayer Ag Bay-l2- 9566 4-E(4'-chloro[lal'- iphenyll- 4-yl)oxY]- 2 [(phenylthio)methYJl3butaIoic acid, HOHNVOO 0 Agouron Pharmaceuticals AG-33 4 0, N-hyaroxy- 2 2 dizethyl-4[E 4 i 4 pyridinyloxY)phellsulfonyl) 3- thj 0 morpholinecarboxaflide, 12) CollaGenex Pharmaceuticals CMTr-3 (Metastat), 6-demethyl-6-deoxy- 4 dedimethylamiflotetracYcline, 13) Chiroscience D-2163, 2- [IS- acetylmfercaPto- 5- phthalimid0ipefltnoyl- L- leucyl) amino- 3- methylbutyl] imidazole, -408- HCI N-hydroxy-4- (phenylthio) phenyl] sulfonyl- 1- (2-propyny]- 4 -piperidinecarboxam~ide monohydrochlor ide, .OCF 3 H-OHN' HCI N-hydroxy-1- (2-znethoxyethyl) 4-Il4 (trifluoromethoxy) phenoxyl phenyJJ suJlfony1 1-4- piperidinecarboxa.fide monohydrochloride, N-hydroxy-l- (2-Inethoxyethy-) [4- (trifluoromethYJ-) pbenoxy3 phenyl3 sulfonylj -4- piper idinearoxamide, 17) HOHN AHCI 1-cyclopropy-Nhydroxy- 4 [4- (trifluoromethyl )phenoxy] phenyl) sulfonyl] -4- piper idinecarboxaflide monohydrochior ide, 1s) HI 4- [14- (cyclohexylthio)phell]sulf onyl) -N- hydroxy- (2 -propynyl) -4 -piperidinecarboxamfide monohydroch-oride, HOHN" chiorophenoxy) phenyl] sul fonyl] tetrahydro-N- hydroxy-2H-pyral-4-carboxamfide, -410- 0 I 0cl-0 0 N N-hydroxy-4- 114- (4- methoxyphefloxy)phenYl) sulfonyl (2- propynyl) 4 -piperidinecarb0xaide, 21) F HOHN IIi 1-cycloprOPY 2 4 fluorophelYl) thiolphel)sulfonlyJ]-N-hydrOxY- 4-~piperidineca-rboxaide, 22) HOHN S- j N. 1-ylpoy Nhdoy4[[4- (phenylthio)phelYll sulfony 1 l -4- piperidinecarboxaTnide, -411- HOHN' tetrahydro-Nhydroxy- 4 pyridinylthio) phenyl) sulfonyl] -2H-pyran-4- carboxamide, and HOWN tetrahydro -N-hydroxy- 4 4 4 (trifluoromethYl) phenoxy]pheljsulfonyl] -2H- pyran-4-carboxamide.

127. The combination of Claim 115 wherein the matrix metalloproteilase inhibitor is CH 3 N-hydroxy-.- (4-methy-phelyl) [[4-114- (trifluoromethyl )phenoxy] phenyl Isulfony1] -4- piperidinecarboxamide monohyd-rochloride. -412-

128. The combination of Claim 115 wherein the mnatri.x metalloproteinase inhibitor is 0 0 0CF 3 S0 H N H C HOC N l-cyclopropy1N-hydroxy- 4 [4- (trifluoromethOXY) phenoxy] phenyl] sulfoll-4- pieiieabxmd monohydxochloride.

129. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is H H HCI N N-hydlroxy-l- (phenylfethY-) [4- (trifluoromethoxy) phenoxyl -1- piperidillsulfonyll- 4 -piperidinecarboxamide monohydrochioride.- -413-

130. The combinlationl of Claim 115 wherein the matrix metalloProteiflase inhibitor is H NCF 3 H HCI N 00 H 3 C-- N-hydroxy--- (4-pyriilIfethyl) 4- 14- (tri fluoromethyl) phenoxyl phenyl) su2.f nyl) -4- piperidinecarboxaInide dihydlrochloride.

131. The combination of Claim 115 wherein the matrix metalloProteilase inhibitor is 0 0 0 CF 3 H 00 H 3 C CH 3 N-hydroxy-2 3 -dimethoxy- 6 14- (trjfluoromethyl)phenoxy3-1- piperidil)sulfonyl Ibenzamide. -414-

132. The combinationl of Claim 115 wherein the matrix metalloproteilase inhibitor is, HCI N-hydroxy-1- (4-pyridiflYlmethyl) [4- (trif luoromethYl) phenoxy] phenyl] sulf onyll -4- piperidifecarboxaride dihydrochioride.

133. The combination of Claim 115 wherein the matrix metalloproteiflase inhibitor is HOHN' HCI HCI N-hydroxy-l (3-pyridiflylmethYl) (trifluoromethYl) phenoxY) phenyl I sulfonyl) -4- piper idinecarboxamfide dihydrochioride. -415-

134. The combination of Claim 115 wherein the matrix metalloproteiflase inhibitor is 0 0 o HOHN CF 3 I 0 N N HCI N-hydroxy-l- (2-.pyridilmlethyl) [14- [4- (trifluoromethy) )phenoxy] phenyl) sulfonyll -4- piperidiiecarboxamilde monohydrochioride.

135. The combination of Claim 115 wherein the matrix mnetal lopro teiflase inhibitor is H-OHN N N CH3 J-i British Biotech BB-2516 (Marimastat), N4-112,2- dimethyl.- 1-11(inethylaino) carbolyl] propyl] N1,2 -dihydroxy-3 methyJlpropy].)i 12S- 1N4(R*) -416-

136. The com'binlationl of Claim 115 wherein the matrix metal].Oproteiflase inhibitor is Bayer Ag Bay-12- 9 S 66 4-[(4,-chloro[l~l'- iphenyll 4-yl) oxy) -2- (phenylthio)mfethylbutnoic acid.

137. The combination of Claim 115 wherein the matrix metal2-oproteiflase inhibitor is HOHN 0 NO 0 S S z N Agouroi Pharmaceuticals AG-33 4 O, Nq-hydroxy- 2,2-dimethyl- 4 -E E4-(4- pyridinYloxy)phenyl] sulfoay-)- 3-

138. The combination of Claim 115 wherein the matrix metalloproteiflase inhibitor is CollaGerlex Pharmaceuticals CMT-3 (Metastat), 6-demethyli6-deoxy- 4 dedimethylamfiflotetracycline.

139. The combinationi of Claim 115 wherein the matrix metalloproteiflase inhibitor is Chiroscieice D- I -417- 2163, 2- [lS- acetylmercapto- phthalimido]pentanoyl- L- leucyl)amino- 3- methylbutyl imidazole.

140. The method of antineoplastic agent is

141. The method of antineoplastic agent is

142. The method of antineoplastic agent is Claim 1 wherein the anastrozole. Claim 1 wherein the calcium carbonate. claim 1 wherein the exemestane.

143. The method is administered in a of Claim 58 wherein the combination sequential manner.

144. The method of Claim 58 wherein the combination is administered in a substantially simultaneous manner.

145- The method of claim 1 wherein the antineoplastic agent is exemestane.

146. A method for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, which method comprises administering to said mammal a therapeutically-effective amount of a combination of a cyclooxygenase- 2 inhibitor and a matrix metalloproteinase inhibitor, wherein said matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: -418- HCI OH 3 N-hydroxy-l- (4-methylphelYl) 114- [4- (trifluoromethyl) phenoxylphellsulfonyll -4- piperidinecarboxamride monohydroch-oride, HN 0 0 CF 3 H N HCL N 1-cyclopropyJl-N-hydroxy- 4 (trifluoromethoxy) phenoxyphel]sulfonyl] -4- piperidinecarboxamide monohydxoch-oride, -419- N-hydro2Cy- 1 (phenyl~methY-) [4- (trifluoromTethoxy)phenoxy) -1- piperidiny-]sulfonyl 4-piperidifecarboxamide mnonohydrocb2-oride, HCO N H 3 Cl0 N-hydroxy-l (4-pyridinylmfethYl) [[4-114- (trifluoromethY-) phenoxy] phenyl) sulfonYl3 -4- piperidifleca-rboxamide dihydrochioride, -420- H N-byclroxy- 2 3-dimeth~xy- 6 4( [4- (trif luoromethyl phenoxY] 1 piperidinyl]I sulf onyl] benzam~ide, HOHN HCI N-hydroxy-1- (4-pyridinylmethY]-) 4- 4- (trif luoromethyl )phenoxy] phenyl]I sulfonyl 1 -4- piperidinecarboxamfide dihydrochioride, HOHN' HCI N-hycdZOXY-l-(3-pyridilrethYl) -4-[[14-114- (trifluoromfethYl )pherioxyJ phenyl] sulfonyl-]-4- piperidinecarboxanide dihydrochioride, -42 1- :z CF 3 HOHN N N-hydroxy---(2-pyridiny]-methYl) j4- [4- (trifluoromethyl) phenoxy] phenyl) sulfonyl) -4- piper idinecarboxafide monohydrochloride, 9) 0 HH0 HOHNK NCH =ix H OH0 British Biotech BB-2516 (Marimastat), N4-[2,2- dimethyl- 1-[E(methylamtino) car:bonyl) propyl] N1,2 -dihydroxy-3 (2-iethylpropyl)-, t2S- ,2R*,3S* -422- Bayer Ag Bay-12- 9 5 6 6, 4-t(4'-chl.oro[1,l'- iphenyl3 4-yl)oxyI -2- [(phenylthio)methy1)butanoic acid, HOHN 0 N ZN Agouron Pharmaceuticals AG-334 0, N-hydroXY-2,2 dimethyl- 4 4-(4- pyridinyloxcy)phenyl) sulfonyll 3- thiomorpholiflecarboxamide, 12) CollaGefleX Pharmaceuticals CMT-3 (Metastat), 6 -demetbyl -6 -deoxy- 4- dedimnethyJl8miflotetracycline, 13) ChirosCieriCe D-2163, 2- [lS- acetylmercapto- 5- phthalimido ]pentafloyl- L- leucyl) amino- 3- methylbutyll imidazole, -423- HCI 'N'~O N-hydZoxy- 4 (pheflylthiO)phellsultOnYll 1- (2-propyl)- 4 -piperidifecaboxamide xnonohydrochloridler HOHN CF 3 N HC1 N-hydr~xy-l (2-methoxyethyl) (trifluoZ'omethoxy) phenoxY) phenYl] sulfofl] 4 pi.peridinec~rboxiae monohydrochlorider HOHN' A-1 N-bydrOxYl -(2-methoxyethyl) -4 [4- (trifluoromethYl) phenoxyl phenyl) sulfonyl) -4- pieiie~roaie -42 4- HOHN CF 04fC 1-cyclopropyl-N-hyd~rOXY- 4 E 4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyll -4- piperidinecarboxa'fide zonohydrochl1Oride, HOHN 7~ii N HCI 4-f (cyclohexyl thio)phenYl] sulfonYll -N- hydroxy-l-(2 -propynyl) -4 -piperidinecarboxamide monohydrochioride, HOHN 00 4-f f4-(4- chiorophenoxy) phenyl) sulfonyll tetrahydro-N- hydro~xy 2-pyran -4-c arboxamide, -425- HOHN S OCH N N-hydroxy- 4 II[4- (4- methoxyphelcxy)phelYl) sulfonyl) propyny-4-piperidilecarboxamide, 21) HOHN SF N i-cyclopropyl- 4 fluorophelyl) thic Ipheny. IsulfonYl I-N-hydroxy- 4-.piperidinecarboxamfide, 22) tiI 1-cyclopropyl1N-hydroxy- 4 (phenylthio) phenyl) sulfonyll -4- piperidinecarboxanide, -42 6- 23) HOHN S N S N tetrahydro-N-hydroxy- 4 I 4- (4- pyridinyithic) phenyl] sulfolyl] -2H-pyral-4- carboxamide, and 24) HOHN F 3 00 tetrahydroN-hydrozy- 4 £4- (trifluoromethyl) phenoxy] phenyl] sulfolyl)-211- pyran-4-carboxamide.

147. The method of Claim 146 comprising administerinlg to said mammiial a therapeutically-effective amount of a comb ination of an cyclooxygeflase- 2 inhibitor, a matrix metalloproteinase inhibitor, and an antineoplastic agent,.wherein the antineoplastic agent is selected from the group consisting of anastrozole, calcium carbonate, capecitabile, carboplatin, cisplatin, Cell Pathways CP-461,. docetaxel, doxorubicin, etoposide, fluorouracil fluoxymestrine, gexncitabine, gosereli', irinotecai, ketocoflazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrole, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecai, toremifene, vinorelbine, vinbiastile, vincristine, selenium (selenonethioflie), -427- ursodeoxycholic acid, sulindac suif one and eflornithile (DFMO).

148. The method of Claim 146 comprising administering to said mammal a therapeuticallY-effective amount of a combination of radiation, a cyclooxygenase- 2 inhibitor-and a matrix metalloproteinase inhibitor.

149. A combination comprising a cyclooxygeflase- 2 inhibitor and a matrix metalloproteiflase inhibitor, wherein said matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: %VS CF 3 HC1 N CH- 3 N-hydroxy-1-4methylphenyl) -4-f (trifluoromethyl) phenoxyl phenyl) sulfonyl] -4- piperidinecarboxamfide monohydrochioride, 2) -42 8- HCI N 1-cyclopropyl-N-hydrOXY- 4 [4- (trifluoroxnethoxy) phenoxylphelyll sulfonyl] -4- piperidinecarboxamlide monohydrochioride, 0 00 CF 3 H 10 N S N0 H HO N N-hydroxy-1- (phenylmethyl) [4- (trifluoromethoxY) phenoxyl -1- p iperidiny]Jsul fonyl] -4 -piperidinecarboxamfide monohydrochloride, H 1- 1N' H HCI -429- N-hydroxy-l (4-pyridiflYlmethYl) -4-[E[4-IA- (trifluoromfethY-) phenoxy3 phenyl) sulfonyl] -4- piperidinecarboxamide dihydrophloride,. 00 0 CF 3 H H 3 C 0 CHS N-hydroxy-2, 3-dimethoxy-6-[t 4- [4- (trifluoromfethYl) phenoxy) -1- piperidinyl-)sulfonyllIbenzamide, HOHN CF 3 HOHN HCI N N-bydroxy-l- (4-pyridiflmethyl) [4- (trifJluoromfethyl )phenoxy) phenyl] sulfoflyll -4- piperidinecarboxanide dihydrochioride, HOWN HCI HCI -430- N-hydrOxY- I -Qpyridinymethyl) 4- [4 [4 (trif luoromethyl phenoxy]I phenyl I suJ1 f ony -4 piperidinecarboxaie dihydroch1oride, 8) HOHN 0CF 3 No N HCI N-hydroxy-l (2-pyridiny3lmethyl) -4 -1 4- [4- (trif luoromethyl) phenoxylphenyl.Il uf onyl1 4 piperidinecarboxamide zonohydrochloride, 9) British BoehB-56(marimastat), N4-.[2, 2 dimethyl- 1-(methylaifo) carboflyl Ipropyl] N1, 2 -dihydroxy- 3 (2-methylpropy))-, [2S- ,2R*,3S*II) -431- Bayer Ag BaY-12- 9 5 6 6, 4-(4-chlorO[1,1'- iphenyl]- 4-yl)oxy]- 2 (phenylthio)methyllbutanoic acid, 11) HOHN 0 0 C 0 Agouron Pharmaceuticals AG-3 340, N-hydroxy- 2 2 dimethyl-4-[[4- (4- pyridinyloxy) phenyll sulfolylI 3- thiomorpholiflecarboxamide, 12) CollaGeleX Pharmaceuticals CMT-3 (Metastat), 6 -demethyl -6-deoxy-4- dedimethy-amnfotetracyc line, 13) ChiroscieiCe D-2163, 2- tis- acetylmercapto- 5- phthalimido) pentafloyl- L- leucyl) amino- 3- methylbutyli imidazole, -432- HOHN- H-CI N N-hydroxy- 4 (pheny3-thio)phen~yls ulffonyl 1- (2 -propylyl) -4-piperidiflecarboxamide monohydxochi or ide, HOI N-hydroxy-l (2-methoxyethYl) (trifluoromethoxy) phenoxy] phenyll)sulfonyll -4- piperidiflecarboxamide monohydrochloride, 16) HOHN' N-hydroxy-l (2-mnethoxyethYl) [4- (trifluoromlethYl)phenoxYlphenylJ sulfonyJ-4- piperidinearboxamide, -4:j3- HOHN 2 ~J% AHCI I-cyclopropy -Nhydroxy 4 -4 4 (trif luoromethyl) pheloxyl phenyl]1 sulf oryl 3 -4 piperidinecarboxanide monohydrocbioride, ock\,, N HCI (cyclohexylthio)phellsulfonYl] -N- hydroxy-l- (2 -propynyl) -4 -piperidinecarboxamtide monohydrochioride, HOHN 00 4- chlorophenoxcy) phenyl] sul fonyl] tetrahydro-N- hydroxy-2H-pyra 4 -carboxamide, -434- HOHW N N-hydroxy-4- (4- methoxyphenoxy)phenyl) sulfonyl] -1 propynyl) -4-piperidinecarboxamide, HOHN' A 1-cyclopropyl-4- fluorophenyl) thiol phenyl] sulfonyl] -N-hydroxy- 4 -piperidinecarboxamide, 22) 1-cyclopropyl-N-hydroxy-4- (phenylthio) phenyl) sulfonyl] -4- piperidinecarboxamide, -43 HOWN( I tetrahydro-N-hydroxy-4-[4- (4- pyridinyithio) phenyl] sul1Eonyl1 -2H-pyral-4- carboxamide, and tetrahydro-N-hYdroxy- 4 d t4- [4- (trifluoromethyl) phenoxyj phenyl) sulfonyll -2H- pyran-4-carboxamide. 436 ,150. A method for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, which method comprises administering to said mammal a therapeutically-effective amount of a combination of a cyclooxygenase- 2 selective inhibitor and a matrix metalloproteinase inhibitor, wherein the cyclooxygenase- 2 selective inhibitor is a compound having the formula R CH 2 COOH NH RI R R 2 R4 R3 wherein R is methyl or ethyl; R 1 is chloro or fluoro; R 2 is hydrogen or fluoro; R 3 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R 4 is hydrogen or fluoro; and R 5 is chloro, fluoro, trifluoromethyl or methyl; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug ester thereof.

151. The method of Claim 150 wherein, the combination is administered in a sequential manner.

152. The method of Claim 150 wherein the combination is administered in a substantially simultaneous manner.

153. The method of Claim 150 wherein the combination further comprises an antineoplastic agent selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways 437 CP-461, docetaxel, doxorubicin, etoposide, fluorouracil, fluoxyrnesterone, gemcitabine, goserelil, irinotecai, ketoconazo.e, letrozole, leucovorin, levamisole, ynegestrol, mitoxantrofle, paclitaxel, raloxifele, retinoic acid, tamoxif en, thiotepa, topotecan, toremif ene, vinorelbine, vinbiastine, vincristile, selenomethionile, ursodeoxycholiC acid, sulindac suif one, exeinestarle and eflornithile.

154. The method of Claim 153 wherein the combination further comprises radiation.

155. The method of Claim 150 wherein, in the formula for the cyclooxygelase- 2 selective inhibitor, R is methyl, R 1 is f luoro, R 2 is hydrogen, R 3 is hydrogen, R 4 i1s hydrogen, and R 5 is chioro.

156. The method of Claim 150 wherein the neoplasia disorder is selecte d from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.

157. The method of Claim 150 wherein the neoplasia disorder is selected from the group consisting of acral lentigirious melanoma, actinic keratoses, adenocarciomfa, adenoid cystic carcinoma, adenaomas, adenosarcomfa, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary neoplasia, carcinoids, carcinoma, carcinosarcoma, cavernous neoplasia, cholang iocarciloma, chondrosarcoma, corioid plexus papilloma/carcinoma, clear cell carcinoma, cystadenomta, endodermal sinus tumor, endometrial hyperplasia, endometrial strona. sarcoma, endometrioid adenocarciloa, ependymal neoplasia, epitheloid neoplasia, Ewing's sarcoma, fibrolamellar neoplasia, focal nodular hyperplasia, gastrinona, germ cell tumors, glioblastoma, glucagonoma, -438- hemangioblastomas, heinangioendothelioma, heinangiomas, hepatic adenoma, hepatic aderioratosis, hepatocellular carcinoma, insulinona, intraepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, lejomyosarcona, lentigo inaligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastorma, mredulloepithelioma, mnelanioma, meningeal neoplasia, mesothelial neoplasia, metastatic carcinoma, iucoepidermoid carc Iinoma, neuroblastona, neuroepitheli al adenocarcinoma, nodular melanoma, oat cell carcinoma, oligodendroglial neoplasia, osteosarcoma, papillary serous adenocarcinoma, pineal cell neoplasia, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinomha, retinoblastona, rhabdomyo sarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft -tissue carcinomas, soatostatin-s ecreting tumor, squamous cell1 carcinoma,- submesothelial neoplasia, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipona, well differentiated carcinoma, and Wilmn's tumor.

158. A composition comprising a cyclooxygenase-2 selective inhibitor and a matrix metalloproteinase inhibitor, wherein the cyclooxgenase-2 selective inhibitor is a compound the formula 439 wherein R is methyl or ethyl; R' is chioro or fluoro; R2 is hydrogen or fluoro; R3 is hydrogen, fluoro, chioro, methyl, ethyl, methoxy, ethoxy or hydroxy; R 4 is hydrogen or fluoro; and R5 is chioro, fluoro, trifluoromethyl or methyl; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug ester thereof.

159. The composition of Clai m 158, further comprising an antineoplastic agent selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461, docetaxel, doxorubicin, etoposide, fluorouracil, fluoxymesterrle, gemcitabine, goserelin, irinotecan, ketoconazole, letrozole, leucovorin, levainisole, megestrol, mitoxantrone, paclitaxe-, raloxifene, retinoic acid, tamoxif en, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, viricristine, selenomethionine, ursodeoxycholic acid, sulindac sulfone, exemestane and eflornithile.

160. The composition of Claim l58wherein, in the formula for the cyclooxygenase- 2 selective inhibitor, R is methyl, R 1 is fluoro, R 2 is hydrogen, R 3 is hydrogen, R' is hydrogen, and R5 is chioro. 440

161. The use of a combination comprising a cyclooxygenase- 2 selective inhibitor and a matrix metalloproteinase inhibitor for the preparation of a medicament for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, wherein the cyclooxygenase-2 selective inhibitor is a compound having the formula R CH 2 COOH NH F11 ,R R 2 R2* R4 R 3 wherein R is methyl or ethyl; R 1 is chloro or fluoro; R 2 is hydrogen or fluoro; R 3 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R 4 is hydrogen or fluoro; and R 5 is chloro, fluoro, trifluoromethyl or methyl; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug ester thereof. I 441

162. The use of a combination comprising a cyclooxygenase- 2 selective inhibitor and a matrix metalloproteinase inhibitor for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, wherein the cyclooxygenase- 2 selective inhibitor is a compound having the formula R CHCOOH NH R1 R R2 R4 R 3 wherein R is methyl or ethyl; R 1 is chloro or fluoro; R 2 is hydrogen or fluoro; R 3 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R 4 is hydrogen or fluoro; and R 5 is chloro, fluoro, trifluoromethyl or methyl; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug ester thereof.

163. A combination comprising a cyclooxygenase-2 selective inhibitor and a matrix metalloproteinase inhibitor, when used in the method of any one of claims 150 to 157, wherein the cyclooxygenase- 2 selective inhibitor is a compound having the formula 442 P N, M 2 L;Uflr RH R R 2 R p 3 wherein R is methyl or ethyl; R' is Ichioro or fluoro;R2 is hydrogen or fluoro; R 3 is hydrogen, fhioro, chioro, methyl, ethyl, methoxy, ethoxy or iaydroxy; R 4 is hydrogen or fluoro; and R 5 is chioro, fluoro,.trifluoromethyl or 1methyl; or 'a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug ester thereof.

164. The combination of Claim 163, further comprising an antineoplastic agent selected from the group consisting of anastrozole, calcium carbonate, capecitabile, carboplatin, cisplatin, Cell Pathways CP-461, docetax1l, doxorubicin, etoposide, fluorouracil, fluoxymesterone, gemcitabile, goserelil, irinotecan, ketoconazo)le, letroz ole, leucovorin, levainisole, megestrol, mitoxantrole, paclitaxel, raloxifene, retiloic acid, tamoxif en, thiotepa, topotecal1 toremifele, vinorelbile, vinblastile, vincristile, selenolethiolifle, ursodeoxycholic acid, sulindac sulfone, exemestale arid eflornithifle. -443-

165. The combination of Claim 163 wherein, in the formula for the cyclooxygenase- 2 selective inhibitor, R is methyl, R' is f luoro, R 2 is hydrogen, R 3 is hydrogen, R 4 hydrogen, and R 5 is chioro. Dated this 10th day of September 2004 G.D. SEARLE CO. By their Patent Attorneys GRIFFITH HACK