MXPA01006489A - Method of using a cyclooxygenase-2 inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia - Google Patents

Abstract

Thepresent invention provides methods to treat or prevent neoplasia disorders in a mammal using a combination of a cyclooxygenase-2 inhibitor and an antineoplastic agent.

Description

METHOD FOR USING A CICLOOXYGENASE-2 INHIBITOR AND ONE OR MORE ANTINEOPLASTIC AGENTS AS A THERAPY OF COMBINATION FOR THE TREATMENT OF NEOPLASIA FIELD OF THE INVENTION The present invention relates to combinations and methods for the treatment or prevention of neoplasia disorders in a mammal using two or more components with at least one component being a cyclooxygenase-2 inhibitor.

BACKGROUND OF THE INVENTION A neoplasm, or tumor, is a proliferation of abnormal cell growth, unregulated and disorganized. 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 the surrounding tissue, typically breaking the basal laminae that define tissue boundaries, thus entering commonly into the body's circulatory system. Metastasis typically refers to the spread of tumor cells by lymphatics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or spaces Ref: 130978 subarachnoid or others. Through the process of metastasis, the migration of tumor cells to others of the body establishes neoplasms in areas far from the site of initial appearance. Cancer is now the second leading cause of death in the United States and more than 8,000,000 people in that country have been diagnosed with cancer. In 1995, cancer accounted for 23% of all deaths in the United States. (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 at the molecular level. It is known that the exposure of a cell to a carcinogen such as certain viruses, certain chemicals or radiation, leads to a DNA alteration that inactivates a "suppressor" gene or activates an "oncogene". The suppressor genes are growth regulating genes, which after the mutation can no longer control cell growth. The oncogenes are initially normal genes (called protooncogenes) that by means of the mutation or the altered context of the expression become genes in transformation. The products of genes in transformation cause inadequate cell growth. More than twenty different normal cellular genes can become oncogenes by genetic alteration. Transformed cells are different from normal cells in many ways, including cell morphology, cell-cell interactions, membrane content, cytoskeletal structure, secretion of proteins, gene expression and mortality (transformed cells can grow indefinitely). Cancer is now mainly treated with one or a combination of three types of therapies: surgery, radiation and chemotherapy. Surgery includes the complete removal of diseased tissue. Although surgery is sometimes effective in removing localized tumors in certain sites, for example, in the breast, colon and skin, it can not be used in the treatment of tumors located in other areas, such as the spine, or the treatment of conditions. disseminated neoplasms such as leukemia. Chemotherapy includes the interruption of cell replication or cell metabolism. It is very commonly used in the treatment of breast, lung and testicular cancer. The adverse effects of systemic chemotherapy used in the treatment of neoplastic diseases are greatly 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 rescue therapy or radiation of the bone marrow; alopecia (hair loss); cutaneous complications (see MD Abeloff, et al: Alopecia and Cutaneous Complications, P. 755-56, In Abeloff, MD, Armitage, JO, Lichter, AS, and Niederhuber, JE (eds) Clinical Oncology, Churchill Livingston, New York, 1992, for cutaneous reactions to chemotherapy agents), such as pruritus, urticaria and angioedema; neurological complications; pulmonary and cardiac complications in patients receiving radiation or chemotherapy; and reproductive and endocrine complications. The side effects induced by chemotherapy have a significant impact on the quality of life of the patient and can dramatically influence the patient's response to treatment. In addition, the adverse side effects associated with chemotherapeutic agents are generally the great dose limiting toxicity (DLT) in the administration of these drugs. For example, mucositis is one of the main dose limiting toxicities for several anticancer agents, including the cytotoxic agents antimetabolite 5-FU, methotrexate and antitumor antibiotics, such as doxorubicin. Many of these side effects induced by chemotherapy, if severe, can lead to hospitalization, or require treatment with analgesics for the treatment of pain. Adverse side effects induced by chemotherapeutic agents and radiation therapy have become of great importance for the clinical management of patients with cancer. FR 27 71 005 describes compositions containing a cyclooxygenase-2 inhibitor and an N-methyl-d-aspartate (NMDA) antagonist used to treat cancer and other diseases.

WO 99/18960 discloses a combination comprising a cyclooxygenase-2 inhibitor and a nitric oxide synthase (NOS) inhibitor which can be used to treat colorectal and breast cancer. WO 98/13799 describes the combination of a cyclooxygenase-2 inhibitor and an opioid analgesic. WO 98/41511 describes 5- (4-sulfunyl-phenyl) -pyridazinone derivatives used to treat cancer. WO 98/41516 describes (methylsulfonyl) phenyl-2- (5H) -furanone derivatives which can be used in the treatment of cancer. WO 98/16227 describes the use of cyclooxygenase-2 inhibitors in the treatment or prevention of neoplasia. WO 97/36497 describes a combination comprising a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor useful in the treatment of cancer. WO 97/29776 describes a composition comprising a d9 cyclooxygenase-2 inhibitor in combination with a leukotriene B4 receptor antagonist and an immunosuppressant drug. WO 97/29775 describes the use of a cyclooxygenase-2 inhibitor in combination with an inhibitor of leukotriene A4 hydrolase and an immunosuppressant drug. WO97 / 29774 describes the combination of a cyclooxygapase-2 inhibitor and prostaglandin or an antiulcer agent, useful in the treatment of cancer.

WO 97/11701 describes a combination comprising a cyclooxygenase-2 inhibitor and a B4 receptor antagonist of leukotriene, useful for treating colorectal cancer. WO 96/41645 describes a combination comprising a cyclooxygenase-2 inhibitor and a leukotriene A hydrolase inhibitor. WO 96/03385 describes 3,4-disubstituted pyrazole compounds which are administered alone or with combination NSAIDs, steroids, 5-LO inhibitors, LTB 4 antagonists or LTA 4 hydrolase inhibitors which may be useful in the treatment of cancer. WO 98/47890 describes substituted benzopyran derivatives which may be used alone or in combination with other active ingredients. WO 98/16227 describes a method for using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia. The patent of E.U.A. No. 5,854,205 discloses an isolated endostatin protein that is an inhibitor of endothelial cell proliferation and angiogenesis. The patent of E.U.A. No. 5,843,925 discloses a method for inhibiting angiogenesis and proliferation of endothelial cells using a 7- [substituted amino] -9 - [(substituted glycyl-10-amido] -6-demethyl-6-deoxytetracycline) U.S. Patent No. 5,863,538 describes methods and compositions to reach the tumor vasculature of solid tumors using immunological reagents and based on growth factors in combination with chemotherapy and radiation.

The patent of E.U.A. No. 837,682 describes the use of fragments of an inhibitor of endothelial cell proliferation, angiostatin. The patent of E.U.A. No. 5,861, 372 discloses the use of an aggregated endothelial inhibitor, angiostatin, and its use to inhibit 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 cinoline derivatives for use in the production of an anti-angiogenic and / or vascular permeability reducing effect. PCT / US97 / 09610 describes the administration of a monoclonal antibody to antigene, or fragments thereof, which is conjugated to at least one angiogenesis inhibitor or antitumor agent for use in the treatment of tumors and diseases associated with angiogenesis. PCT / IL96 / 00012 describes a fragment of the B chain of thrombin for the treatment of cancer. PCT / US95 / 16855 describes compositions and methods for removing selected turnoral cells using recombinant viral vectors. Ravaud, A. et al. describes the efficacy and tolerance of interleukin-2 (IL-2), interferon alfa-2a and fluorouracil in patients with metastatic renal cell carcinoma.

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. Rosenberg, S.A. et al. describes the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. Elias, L. Et al. describes the use of 5-f luorouracil, interleukin-2 infusions and subcutaneous interferon alpha to treat advanced renal cell carcinoma. Tourani, J.M. et al. describes the treatment of renal cell carcinoma using interleukin-2 and interferon alfa-2a administered in combination with fluorouracil. Majewski, S. describes the anti-cancer action of retinoids, vitamin D3 and cytokines (interferons and interleukin-12) as related to antiangiogenic and antiproliferative effects. Ryan, C.W. describes the treatment of patients with metastatic renal cell cancer with GM-CSF, interleukin-2 and interferon alpha plus oral cis-retinoic acid in patients with metastatic renal cell cancer. Tai-Ping, D. describes potential anti-angiogenic therapies. Brembeck, F.H. describes the use of 13-cis retinoic acid and interferon alfa to treat UICC pancreatic cancer stage III / IV.

Brembeck, F.H. describes the use of 13-cis retinoic acid and interferon alfa in patients with advanced pancreatic carcinoma. Mackean, M.J. describes the use of roquinimex (Linomide) and interferon alfa in patients with advanced malignant melanoma or renal carcinoma. Jayson, G.C. describes the use of interleukin-2 and interleukin-interferon alpha in advanced renal cancer. Abraham, J.M. describes the use of interleukin-2, interferon alfa and 5-fluorouracil in patients with metastatic renal carcinoma. Soori, G.S. describes the use of chemo-biotherapy with chlorambucil and interferon alfa in patients with non-Hodgkin's lymphoma. Enschede, S.H. describes the use of interferon alfa added to an anthracycline-based regimen to treat low-grade and intermediate-grade non-Hodgkin's lymphoma. Schachter, J. describes the use of a sequential multiple drug chemotherapy and biotherapy with interferon alfa, a four-drug chemotherapy regimen and GM-CSF. Mross, K. describes the use of retinoic acid, interferon alpha and tamoxifen in patients with metastatic breast cancer. Muller, H. describes the use of suramin and tamoxifen in the treatment of metastatic and advanced pancreatic carcinoma. Rodríguez, M.R. describes the use of taxol and cisplatin, and taxotera and vinorrelbine in the treatment of metastatic breast cancer.

Formenti, C. describes paclitaxel and concurrent radiation therapy in patients with locally advanced breast cancer. Durando, A. describes combination chemotherapy with paclitaxel (T) and epirr jbicin (E) for metastatic breast cancer. Osaki, A. describes the use of a combination therapy with mitomycin-C, etoposide, doxifluridine and medroxyprogesterone acetate as a second-line therapy for advanced breast cancer.

DESCRIPTION OF THE INVENTION A method is provided for treating or preventing a neoplasm disorder in a mammal, including a human, that requires such treatment or prevention. The method comprises treating the mammal with a therapeutically effective amount of a combination comprising two or more components, the first component is cyclooxygenase-2 inhibitor, and the additional component or components are optionally selected from a) an anti-angiogenesis agent; b) an antineoplastic agent; c) an adjunctive agent; d) an immunotherapeutic agent; e) a device; f) a vaccine; g) an analgesic agent and h) a radiotherapeutic agent; provided that the additional component or components are not the cyclooxygenase-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 and an antineoplastic agent. Apart from being useful for the treatment of humans, the present invention is also useful for the veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents / the like. The most preferred animals include horses, dogs and cats. The methods and combinations of the present invention can be used for the treatment or prevention of neoplasia disorders including acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cystic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, Bartholin gland carcinoma, carcinoma of basal cell, carcinomas of the bronchial gland, capillary, carcinoid, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, condosarcoma, papilloma / carcinoma of the chorioid plexus, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrioma stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasia ial, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo malignant melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal carcinoma, mesothelial carcinoma, mucoepidermoid carcinoma, neuroblastoma, nodular melanoma due to neuroepithelial adenocarcinoma, oat cell 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 cell carcinoma, squamous cell carcinoma, submesothelial superficial 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 with the compounds, compositions, agents and therapies of the present invention are useful for treating and preventing neoplasia disorders. Preferably, the inhibitors, of COX-2 and the compounds, compositions, agents and therapies of the present invention are administered in combination at a low dose, ie, at a lower dose than that which has been conventionally used in clinical situations. A benefit of decreasing 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 doses. For example, by decreasing the dose of an agent chemotherapy such as metrotrexate, the result will be a reduction in the frequency and severity of nausea and vomiting compared to that observed at more doses. high Additional benefits are contemplated for the compounds, compositions, agents and combination therapies with the COX-2 inhibitors of the present invention. The additional benefits of decreasing the incidence of adverse effects include an improvement in the patient's response, a reduction in the number of hospitalizations that are required for the treatment of adverse effects, and a reduction in the administration of analgesic agents necessary to treat pain. associated with 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 that are administered at the same time or at different times, or the therapeutic agents can be administered as a single composition. When used as a therapeutic agent the components 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 vehicles include, but are not limited to, water, saline, physiologically regulated pH solution. Additional examples are provided below.

The term "pharmaceutically acceptable" is used as an adjective herein to indicate that the modified noun is suitable for use in a pharmaceutical product. The pharmaceutically acceptable cations include metal ions and organic ions. Preferred metal ions include, but are not limited to, alkali metal salts, suitable alkaline earth metal salts and other physiologically acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their normal valencies. 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, methansulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, 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 be administered orally, parenterally, by spraying for inhalation, rectally or topically in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as want. Topical administration may also include the use of transdermal administration such as transdermal patches or iontophoresis devices. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular injections, intrasternal injection or infusion techniques. Drug formulation is described in, for example, Hoover, John E., Reminqton's Pharmaceutical Sciences. Mack Publishing Co., Easton, Pennsylvania; 1975. Another example includes Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosaqe Forms; Marcel Decker, New York, N.Y., 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 non-toxic parenterally acceptable diluent or solvent., for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and nonionic detergents and polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those described above are also useful.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and that will therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In those solid dose forms, the compounds of this invention are ordinarily combined with one or more adjuvants suitable for the indicated route of administration. If peroids are administered, a contemplated aromatic sulfone hydroximate inhibitor compound may be mixed with lactose, sucrose, powdered starch, 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 tabletted or encapsulated for convenient administration. Said capsules or tablets may contain a controlled release formulation as provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise pH regulating agents such as sodium citrate, carbonate or magnesium or calcium bicarbonate. Tablets and pills can also be prepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration may be in the form of sterile, aqueous or non-aqueous isotonic injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the aforementioned carriers or diluents for use in the formulations for oral administration. A contemplated aromatic sulfone hydroxymate inhibitor compound contemplated 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 water regulators. pH. Other adjuvants and modes of administration are well known and widely used in the pharmaceutical art. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, syrups and elixirs containing inert diluents commonly used in the art, such as water. These compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfume agents. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending on the mammalian host treated and the particular mode of administration. The present invention further includes kits comprising a COX-2 inhibitor and an antineoplastic agent.

The term "treatment" refers to any procedure, action, therapy or the like, in which a mammal, including a human being, is subject to medical assistance for the purpose of improving the condition of the mammal, directly or indirectly. The term "inhibition", in the context of neoplasia, tumor growth or growth of tumor cells, can be determined by the delayed appearance of primary or secondary tumors, the slow development of primary or secondary tumors, the diminished occurrence of primary or secondary tumors, decreased or slower severity of side effects of the disease, arrested tumor growth and regression of tumors, among others. In the excerpt, complete inhibition is referred to herein as prevention or chemoprevention. The term "prevention" includes either prevent the onset of clinically evident neoplasia completely or prevent the appearance of a stage of neoplasia preclinically evident in individuals at risk. It is also attempted to embrace with this definition the prevention of the start of malignant cells or stop or reverse the progression of premalignant cells to malignant cells. This includes the prophylactic treatment of those at risk of developing neoplasia. The term "angiogenesis" refers to the process by which tumor cells trigger the abnormal growth of blood vessels to create their own source of blood, and is one of the main objectives of cancer research. It is believed that angiogenesis is the mechanism whereby tumors get the nutrients they need to grow and metastasize to other places in the body. Antiangiogenic agents interfere with these processes and destroy or control tumors. Angiogenesis is an attractive therapeutic goal because it is a multi-step process that occurs in a specific sequence, thus providing several possible targets for the action of the drug. Examples of agents that interfere with several of these steps include thrombospondin-1, angiostatin, endostatin, interferon alpha, and compounds such as matrix metalloproteinase inhibitors (MMPs) that block the actions of enlightening enzymes and create pathways for vessels to follow. newly formed blood compounds, such as avß3 inhibitors, that interfere with molecules that blood vessel cells use to form a 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 protein-based compounds that simultaneously interfere with several of these objectives. Antiangiogenic therapy can offer several advantages over conventional chemotherapy for the treatment of cancer. Antiangiogenic agents have low toxicity in preclinical tests; and the development of drug resistance has not been observed (Folkman, J., Seminars in Medicine of the Beth Israel Hospital, Boston 333 (26): 1757-1762., 1995). Since angiogenesis is a complex process, formed by Several stages that include invasion, proliferation and migration of endothelial cells, it can be anticipated that the combination therapies will be very effective. Kumar and Armstrong describe antiangiogenesis therapy used as an adjunct to chemotherapy, radiation therapy or surgery. (Kumar, CC, and Armstrong, L., Tumor-induced angiogenesis: a novel target for drug therapy ?, Emerging Drugs (1997), 2, 175-190). The phrase "therapeutically effective" attempts to qualify the amount of each agent that will achieve the goal of improving the severity of the neoplastic disease and the frequency of the neoplastic disease on the treatment of each agent in itself, while avoiding associated adverse side effects. typically with alternative therapies. A "therapeutic effect" or "effective therapeutic amount" is designed to qualify the amount of an anti-cancer agent that is required to alleviate to some degree one or more of the symptoms of a neoplasia disorder, but is not limited to: ) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (ie, reduction to a certain degree, preferably arrest) of the infiltration of cancer cells into peripheral organs; 4) inhibition, to a certain degree, of tumor growth; 5) relief or reduction to some degree of 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") encompasses the administration of a cyclooxygenase-2 inhibitor and an antineoplastic agent as part of a specific treatment regimen designed 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. The administration of these therapeutic agents in combination is typically carried out for a defined period of time (typically minutes, hours, days or weeks depending on the combination selected). "Combination therapy" generally does not attempt to encompass administration of two or more of these therapeutic agents as part of separate monotherapy regimens that accidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" attempts to encompass the administration of these therapeutic agents in a sequential manner, ie, wherein each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in several individual capsules for each of the therapeutic agents. The sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable 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 through different routes. For example, a first therapeutic agent of the selected combination can be administered by intravenous injection while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not strictly critical. "Combination therapy" may also encompass the administration of therapeutic agents such as those described above in additional 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). When the combination therapy further comprises treatment with radiation, the radiation treatment can be carried out at any suitable time as long as a beneficial effect is achieved from the co-action of the combination of the therapeutic agents and the radiation treatment. . For example, in appropriate cases, the beneficial effect is achieved even when the radiation treatment is temporarily withdrawn from the administration of the therapeutic agents, perhaps for days or even weeks. The phrases "low dose" or "low dose amount", to characterize the therapeutically effective amount of the antiangiogenesis agent and the antineoplastic agent or therapy in the combination therapy, defines an amount of said agent, or a quantity scale of said agent , which is able to relieve the severity of the neoplastic disease or by avoiding at the same time reducing one or more side effects induced by antineoplastic agents, such as myelosuppression, cardiac toxicity, alopecia, nausea or vomiting. The phrase "adjunctive therapy" encompasses the treatment of a subject with agents that reduce or avoid the 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 anti-cancer drugs, for example, inhibitors of bone resorption, cardioprotransport agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or surgery; or reduce the incidence of infections associated with the administration of myelosuppressive anti-cancer drugs. The phrase "immunotherapeutic agent" refers to agents used to transfer the immunity of an immune donor, for example, another person or an animal to a host by inoculation. The term encompasses the use of serum or gammaglobulin containing preformed antibodies produced by another individual or an animal; non-specific systemic stimulation; adjuvants; active specific immunotherapy and adoptive immunotherapy. Adoptive immunotherapy refers to the treatment of a disease by therapy or agents that include inoculation in the host of sensitized lymphocytes, transfer factor, immune RNA or antibodies in serum or gamma globulin. The phrase "device" refers to any apparatus, usually mechanical or electrical, designed to perform a particular function.

The phrase "vaccine" includes agents that induce the patient's immune system to develop an immune response against the tumor by attacking cells that express tumor-associated antigens (TAAs). The phrase "multifunctional proteins" encompasses a variety of pro-angiogenic factors that include basic and acidic fibroblast growth factors (bFGF and aFGF) and vascular endothelial growth factor / vascular permeability factor (VPF / VEGF) (Bikfalvi, A. et al., Endocrine Reviews 18: 26-45, 1997). Several endogenous antiangiogenic factors have also been characterized as multifunctional 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. (Ezakowitz et al, N. Engl. J Med., May 28, 326 (22) 1456-1463, 1992), thrombospondin (Good et al, Proc Nati 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 "analgesic agent" refers to an agent that relieves pain without producing anesthesia or loss of consciousness by generally altering the perception of nociceptive stimuli. The phrase "radiotherapeutic agent" refers to the use of electromagnetic or particle radiation in the treatment of neoplasia. The term "pBATT encompasses" or "protein-based antitumor therapies" refers to protein-based therapeutics for solid tumors. The pBATTs include proteins that have shown efficacy against tumors in models with animals or in humans. The protein is then modified to increase its efficacy and toxicity profile, improving its bioavailability and direction. "Angiostatin" is a 38 kD protein that comprises the first three or four kringle domains of plasminogen and was first described in 1994 (O'Reilly, MS et al., Cell (Cambridge, Mass.) 79 (2): 315- 328, 1994). Mice carrying primary tumors (Lewis metastatic lower lung carcinoma) did not respond to angiogenic stimuli such as bFGF in a corneal microcavity test, 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 also showed to inhibit the growth of endothelial cells in vitro. Human angiostatin can be prepared by the digestion of plasminogens by porcine elastase (O'Reilly, et al., Cell 79 (2): 315-328, 1994) or with human metalloelastase (Dong et al., Cell 88, 801-810). , 1971). Angiostatin produced by porcine elastase digestion inhibited the growth of metastases and primary tumors in mice. O'Reilly et al., (Cell 79 (2): 31-5-328, 1994) demonstrated metastasis inhibited by human angiostatin from Lewis lung carcinoma in SCID mice. The same group (O'Reilly, MS et al., Nat. Med. (NY) 2 (6): 689-692, 1996) subsequently showed that human angiostatin inhibited the growth of human tumors PC3 prostate carcinoma, carcinoma of colon from clone A and MDA-MB breast carcinoma in SCID mice. Human angiostatin also inhibited the growth of tumors of mouse Lewis lung carcinoma, T241 fibrosarcoma and M5076 reticulum cell carcinoma in C57B1 mice. Because these enzymatically prepared angiostatins are not well characterized biochemically, the exact composition of the molecules is unknown. Angiostatins of known composition can be prepared by means of recombinant DNA expression and technology in heterologous cell systems. Recombinant human angiostatin comprising Kringle domains one to four (K1-4) has been produced in the yeast of Pichia pastoris (Sim et al., Cancer Res 57: 1329-1334, 1997). The recombinant human protein inhibited the growth of endothelial cells in vitro, and inhibited the metastasis of Lewis lung carcinoma in C57B1 mice. Recombinant murine angiostatin (K1-4) has been produced in insect cells (Wu et al., Biochem Biophys Res Comm 236: 651-654, 1997). The recombinant mouse protein inhibited the growth of endothelial cells in vitro and the growth of primary Lewis lung carcinoma in vivo. These experiments demonstrated that the first four Kringle domains are sufficient for angiostatin activity but did not determine which Kringle domains are necessary. Cao et al. (J. Biol. Chem. 271: 29461-29467, 1996), produced fragments of human plasminogen by proteolysis and by the expression of recombinant proteins in E. coli. These authors showed that the kringle one and to a lesser extent the four kringle of plasminogen were responsible for the inhibition of endothelial cell growth in vitro. Specifically, kringles 1-4 and 1-3 inhibited at similar concentrations, whereas K1 only inhibited the growth of endothelial cells at four times higher concentrations. The kringles two and three inhibited to a lesser degree. More recently Cao et al. (J. Biol. Chem. 272: 22924-22928, 1997), showed that five kringle of mouse or recombinant human inhibited endothelial cell growth at lower concentrations than angiostatin (K1-4). These experiments demonstrated angiostatin-like activity in vitro but did not touch the in vivo action against tumors and their metastases. PCT publication WO 95/29242 describes the purification of a blood and urine protein by HPLC which inhibits the proliferation of endothelial cells. The protein has a molecular weight of between 38 kilodaltons and 45 kilodetons, and an amino acid sequence substantially similar to that of a murine plasminogen fragment starting at amino acid number 79 of a murine plasminogen molecule. PCT publication WO 96/41194 describes compounds and methods for the diagnosis and monitoring of angiogenesis-dependent diseases. PCT publication WO 96/35774 describes the structure of protein fragments, generally corresponding to kringle structures that occur in angiostatin. It also describes aggregated forms of angiostatin, which have cell inhibitory, endothelial activity, and provides a means to inhibit tumor angiogenesis and will treat diseases mediated by angiogenesis.

"Endostatin" is a 20 kDa carboxy fragment (184 amino acids) of collagen XVIII, is an angiogenesis inhibitor produced by a hemangioendothelioma (O'Reily, MS 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. Drimary tumors treated with non-refolded suspensions of endostatin derived from E. Coli returned to dormant microscopic lesions. No toxicity was observed, and immunohistochemical studies revealed a blockage of angiogenesis accompanied by high balanced proliferation by apoptosis in turnoral cells. "Interferon .alpha." (IFN.alpha.) Is a family of highly homologous species specific proteins that possess complex antiviral, antineoplastic, and immunomodulatory activities (reviewed extensively in the monograph "Antineoplastic agents, interferon alfa", American Society of Hospital Pharmaciets, Inc., 1996 ). Interferon .alpha also has antiproliferative and antiangiogenic properties, and has specific effects on cell differentiation (Sreevalsan, in "Biologic Therapy of Cancer", pp. 347-364, (eds. VT DeVita Jr., S. Hellmsn, and SA Rosenberg), JB Lippincott Co, Philadelphia, PA, 1995). 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 the IFN.alfa. exerts its antitumor activity is not completely clear, and can be different based on the type of tumor or stage of the disease. The antiproliferative properties of IFN.alpha., Which can result from the modulation of the expression of oncogenes and / or proto-oncogenes, have been demonstrated both in tumor cell lines and in human tumors that grow in bald mice (Gutterman, JU , Proc. Nati, Acad. Sci., USA 91: 1198-1205, 1994). Interferon is also considered an anti-angiogenic factor, as has been demonstrated through the successful treatment of hemangiomas in infants (Ezekowit .: et al, N. Engl. J. Med., May 28, 326 (22) 1456-1463, 1992 ) and the effectiveness of INF. alpha, against Kaposi's sarcoma (Krown), Semin Oncol 14 (2 Suppl 3): 27-33, 1987). The mechanism underlying these antiangiogenic effects is not clear, and may be the result of IFN.alpha action. in the tumor (decreasing the secretion of proangiogenic factors) or in the neovascul atura. IFN receptors have been identified in a variety of cell types (Navarro et al., Modern Pathology 9 (2): 150-156, 1996). U.S. Patent 4,530,901, by Weissmann, describes the cloning and expression of IFN.alpha molecules. in transformed host strains. U.S. Patent 4,503,035, Pestka, describes an improved process for purifying 10 species of human leukocyte interferon using preparative high performance liquid chromatography. U.S. Patent 5,231,176, Goeddel, describes the cloning of a different and novel family of human leukocyte interferons which contain in their mature form more than 166 and no more than 172 amino acids.

U.S. Patent 5,541, 293, by Stabinsky, describes the synthesis, cloning and expression of human interferons in consensus. These are analogs that occur not naturally of interferon .alpha, human (leukocytes) 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 in each position. These variants are different from the natural forms in terms of the identity and / or location of one or more amino acids, and one or more biological and pharmacobiological properties (e.g., antibody reactivity, potency and / or duration effect) but retain other of those properties. "Thrombospondin-1" (TSP-1) is a trimer that contains 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. 3 (5): 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 Inés, J Cell Biol. 103 (5): 1635-1648, 1986). Native TSP-1 has been shown to block endothelial cell migration in vitro and neovascularization in vivo (Good et al, Proc Nati Acad Sci USA 87 (17): 6624-6628, 1990). The expression of TSP-1 in tumor cells also suppresses tumorigenesis and tumor-induced angiogenesis (Sheibani and Frazier, Proc Nati 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 shown 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 CSVTCG sequence that appears to mediate the binding of TSP-1 to some types of tumor cells (Tuszynski and Nicosia, Bioessays 18 (1): 71-76, 1996). These results suggest that CSVTCG, or related sequences, can be used to direct other portions to tumor cells. Taken together, the available data indicate that TSP-1 plays a role in the growth and vascularization of tumors. The subfragments of TSP-1 may then be useful as anti-angiogenic components of chimeras and / or to direct other proteins to specific tumor cells. The subfragments can 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 to verify antiangiogenic or antitumor activities by methods known in the art ( Tolsma et al, J Cell Biol. 122 (2): 497-511, 1993; Tuszynski and Nicosia, Bioessays 18 (1): 71-76, 1996). The phrase "matrix metalloproteinase inhibitor" or "MMP inhibitor" includes agents that specifically inhibit a class of enzymes, zinc metalloproleinases (metalloproteases). Zinc metalloproteinases are involved in the degradation of connective tissue or connective tissue components. These enzymes are released from resident tissue cells and / or invasive inflammatory or tumor cells. Blocking the action of J.

Zinc metalloproleinases interfere with the creation of pathways that follow newly formed blood vessels. Examples of MMP inhibitors are described in Golub, LM, Inhibition of Matrix Metalloproteinases: Therapeutic Applications (Annals of the New York Academy of Science, Vol. 878). Robert A. Greenwald and Stanley Zucker (Eds.), June 1999), and is incorporated herein by reference. The phrase "integrin antogonist" includes agents that impair adhesion of endothelial cells by different integrins. Integrin antagonisms induce inadequate proliferation of endothelial cells to die, interfering with molecules that the cells of blood vessels use to establish a bridge between a blood vessel of origin and a tumor. Adhesion forces are critical for many normal physiological functions. Interruptions in these forces, through alterations in cell adhesion factors, are implicated in a variety of disorders, including cancer, stroke, osteoporosis, restenosis and rheumatoid arthritis (AF Horwitz, Scientific American, 276: (5): 68 -75, 1997). Integrins are a large family of cell surface glycoproteins that mediate cell adhesion and play central roles in many adhesion phenomena. Integrins are heterodimers composed of sub-units of polypeptides a and b linked non-covalently. Currently, eleven subunits have been identified and have been identified six different ß subunits. The different a subunits can be combined with several subunits b to form different integrins. An integrin known as av > 3 (or the vitronectin receptor) is normally associated with endothelial cells and smooth muscle cells. The integrins Av > 3 can promote the formation of blood vessels (angiogenesis) in tumors. These vessels feed the tumors and provide access routes to the bloodstream for metastatic cells. It is also known that the integrin avb3 plays a role in several other conditions or conditions of disease 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 migration of smooth muscle cells (eg, restenosis). Invasion of tumor cells occurs through a three-step process: 1) attachment of tumor cells to extracellular matrices; 2) proteolytic dissolution of the matrix and 3) movement of the cells through the loose barrier d. This procedure can occur repeatedly and may result in metastases in places far from the original tumor. The integrin avfc > 3 and a variety of other integrins containing av bind to a number of matrix macromolecules containing Arg-Gly-Asp (RG). The compounds containing the RGD sequence mimic the ligands of the extracellular matrix and bind to receptors on the surface of the cell. Fibronectin and vitronectin are among the main binding partners of the integrin avD3. Other proteins and peptides also bind to the avb3 ligand. These include disintegrins (M. Pfaff et al., Cell Hades, Common 2 (6): 491-501, 1994), peptides derived from phage display libraries (Healy, JM et al., Protein Pept. Lett. 3 (1): 23-30, 1996; Hart, SL et al., J. Biol. Chem 269 (17): 12468-12474, 1994) and small cyclic RGD peptides (M. Pfaff et al., J. Biol. .. Chem., 269 (32): 20233-20238, 1994). The monoclonal antibody LM609 is also an avb3 integrin antagonist (D.A. Cheresh et al., J. Biol. Chem., 262 (36): 1 7703-17711, 1987). Avfc inhibitors > 3 are being developed as potential anticancer agents. Compounds that affect the adhesion of endothelial cells by means of the integrin avb3 induce the endothelial cells of inadequate proliferation to die. Integrin avb3 has been shown to play a role in the invasion of melanoma cells (Seftor et al., Proc. Nati, Acad Sci. USA, 89: 1557-1561, 1992). The avb3 integrin expressed in human melanoma cells has also been shown to promote a survival signal, protecting the cells against apoptosis (Montgomery et al., Proc. Nati, Acad. Sci. USA, 91: 8856-8860, 1994). Mediating the metastatic pathway of tumor cells by interfering with the avD3 integrin cell adhesion receptor to prevent tumor metastasis could be beneficial. The avb3 antagonists have shown to provide a therapeutic approach for the treatment of neoplasia (inhibition of the growth of solid tumors) because the systemic administration of avb3 antagonists causes a dramatic regression of several histologically distinct human tumors (Brooks et al., Cell, 79: 1157- 1164, 1994). The adhesion receptor identified as integrin avb3 is a marker of angiogenic blood vessels in chicken and man. This receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle cells and endothelial cells by new blood vessels. The avb3 antagonists inhibit this process by selectively promoting cell apoptosis 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, avb3 antagonists may be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, 264: 569-571, 1994). The cell surface receptor avD3 is also the main integrin in osteoclasts responsible for binding to the bone matrix. Osteoclasts cause bone resorption and when that resorption activity (of bone exceeds the activity of bone formation, the result is osteoporosis (a loss of bone), which leads to an increased number of bone bone fractures, incapacitation and increased mortality. AvD3 antagonists have been shown to be potent inhibitors of osteoclast activity both in vitro (Sato et al., J Cell., 111: 1713-1723, 1990) and in vivo (Fisher et al., Endocrinology, 132: 1411-1413 , 1993). Antagonism of avb3 leads to decreased bone resorption and therefore helps to restore a normal balance of bone formation and resorption activideid. Thus, it would be beneficial to provide avb3 osteoclast antagonists that were effective inhibitors of bone resorption and that were therefore useful in the treatment or prevention of osteoporosis. The international PCT application WO 97/08145 by Sikorski et al. Discloses metaguanidine, urea, thiourea or azocyclic amino benzoic acid derivatives as highly spic avb3 integrin antagonists. The international PCT application WO 96/00574 A1 960111 by Cousins, R.D. et al., describes the preparation of derivatives and analogs of 3-oxo-2,3,4,5-tet? ahydro-1 H-1,4-benzodiazepine and -2-benzazepine as antagonists of the vitronectin receptor. The international PCT application WO 97/23480 A1 970703 by Jadhav, P.K. et al. describes ringed pyrazoles as novel integrin receptor antagonists. The novel heterocycles include 3- [1- [3- (imidazol-2-ylamino) propyl] indazol-5-ylcarbonylamino] -2- (benzyloxycarbonylamino) -propionic acid, which are useful as antagonists of the integrin avb3 and of receptors of adhesive protein to cell surface related.

The international PCT application WO 97/26250 A1 970724 by Hartman, G.D. et al., describes the preparation of arginine dipeptide mimics as integrin receptor antagonists. Selected compounds showed binding to human integrin avb3 with EIB < 1000 nM and ensures that they are useful compounds to inhibit the binding of fibrinogens to blood platelets and to inhibit the aggregation of blood platelets. The international PCT application WO 97/23451 by Diefenbach, B. et al. describes a series of tyrosine derivatives used as inhibitors of alpha v-integrinei to treat tumors, osteoporosis, osteolytic disorder and to suppress angiogenesis. The international PCT application WO 96/16983 A1 960606 by Vuori, K. and Ruoslahti, E. describes cooperative combinations of integrin ligand vD3 and second ligand contained within a matrix, and the use in wound healing and tissue regeneration . The compounds contain a ligand for the integrin avb3 and a ligand for the insulin receptor, the PDGF receptor, the IL-4 receptor or the IGF receptor, combined in a biodegradable polymer matrix (e.g., hyaluronic acid). The international PCT application WO 97/10507 A1 970320 by Ruoslahti, E; and Pasqualini, R. describes peptides that are housed in an organ or tissue selected in vivo, and methods for identifying them. A brain-hosted peptide, of nine amino acid residues long, for example, directs red blood cells to the brain. The use of panning in vivo to identify peptides that are housed in a breast tumor or a melanoma is also described.

The international PCT application WO 96/01653 A1 960125 by Torpe, Philip E; Edgington, Thomas S. describes bifunctionals for the spic inhibition of tumors by the coagulation of blood in the vasculature of tumors. The described biospic binding ligands are linked through a first binding region to a target cell related to the disease, eg, Lina tumor cell or tumor vasculature; the second region has coagulation promoting activity or is a binding region for a coagulation factor. The biospic binding ligand described may be a bispic antibody (monoclonal), or the two ligands may be connected by a covalent bond (selectively cleavable), a chemical binding agent, an avidin-biotin bond, and the like. The target of the first binding region may be an inducible component of cytokine, and the cytosine may be released in response to a leukocyte activation antibody; this may be a bispic antibody that interlaces activated leukocytes with tumor cells. The phrase "cyclogenase-2 inhibitor" or "COX-2 inhibitor" or "(cyxygenase-M) inhibitor includes agents that specifically inhibit one class of enzymes, cyxygenase-2, with the least significant inhibition of cyxygenase-1, preferably including compounds having an IC 50 of cyxygenase-2 of less than about 0.2. μM, and also have a selectivity ratio of cyxygenase-2 inhibition on cyxygenase-1 inhibition of at least 50, and most preferably of at least 100. Even more preferably, the compounds have an IC50 of cyxygenase-1 of more about 1 μM, and most preferably more than 10 μM.

Studies indicate that prostaglandins synthesized by cyoxygenases play a critical role in the initiation and promotion of cancer. In addition, COX-2 is overexpressed in neoplastic lesions of the colon, sinuses, lung, prostate, esophagus, pancreas, intestine, cervix, ovaries, urinary bladder and head and neck. In several in vitro and animal models, COX-2 inhibitors have inhibited the growth and metastasis of tumors. 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 mouse and rat, COX-2 inhibitors markedly inhibited neo-vascularization induced by bFGF. The usefulness 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, incorporated herein by reference). Amplification and / or overexpression of HER-2 / nue (ErbB2) occurs in 20-30% of breast and cvarian cancers in humans, as well as in 5-15% of gastric and esophageal cancers, and is associated with a prognosis deficient. Furthermore, it has recently been discovered in vitro that the expression of COX-2 is upregulated in cells overexpressing the HER-2 / neu oncogene. (Subbaramaiah et al., Increased expression of cyxygenase-2 in HER-2 / neu-overexpressing breast cancer.Cancer Research (presented in 1999), incorporated herein by reference). In this study, markedly increased levels of production of PGE2, COX-2 protein and mRNA were detected in mammary epithelial cells transformed with HER-2 / neu in comparison with a line of non-transformed partner cells. The products of COX-2 activity, that is, prostaglandins, simulate proliferation, increase the invasiveness of malignant cells and improve the production of vascular endothelial growth factor, which promotes angiogenesis. In addition, HER-2 / neu induces the production of angiogenic factors such as vascular endothelial growth factor. Accordingly, it is contemplated that the administration of a COX-2 inhibitor in combination with an anti-HER-2 / neu antibody such as trastuzumab (Herceptin®) and other therapies directed to inhibit HER-2 / neu treats cancers in which HER -2 / neu is overexpressed. Likewise, 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 The products of COX-2 activity stimulate cell proliferation, inhibit immune surveillance, increase the invasiveness of malignant cells and promote angiogenesis. Accordingly, it is contemplated that the administration of a COX-2 inhibitor in combination with an agent or agents that inhibit or suppress oncogenes prevents or treats cancers in which the oncogenes are overexpressed. Accordingly, there is a need for a method to treat or prevent cancer in a patient, which overexpresses COX-2 and / or an oncogene. The 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 (WO 98/16227) and several models with animals reduce angiogenesis driven by various growth factors (WO 98/22101). Anti-angiogenesis was achieved with a COX-2 inhibitor in rats implanted with bFGF, vascular endothelial growth factor (VEGF) or carrageenan, proteins with well-known angiogenic properties. (Masferrer, et al., 89th Annual Meeting of the American Association for Cancer Research, March 1998). The pyrazoles can be prepared by methods described in WO 95/15,316. The pyrazoles can be further prepared by the methods described in WO 95/15315. Pyrazoles can also be prepared by the methods described in WO 96/03385. Thiophene analogues can be prepared by the methods described in WO 95/00501. The preparation of thiophene analogs is also described in WO 94/15932. Oxazoles can be prepared by the methods described in WO 95/00501. The preparation of oxazoles is also described in WO 94/27980. The isoxazoles can be prepared by the methods described in WO 96/25405. Imidazole can be prepared by the methods described in WO 96/03388. The preparation of imidazoles. it 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. The preparation of cyclopentane inhibitors COX-2 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. The preparation of pyridine compounds is also described in WO 96/24,585. Non-limiting examples of COX-2 inhibitors that can be used in the present invention are identified below in Table 1.

Table No. 1 Cyclooxyquinase inhibitors The following references listed below in Table No. 2, incorporated in this manner individually as a reference, describe various COX-2 inhibitors suitable for use in the present invention described herein and the processes for their preparation.

Table 2 COX-2 inhibitors The celecoxib used in the therapeutic combinations of the present invention can be prepared in the manner described in the US patent. No. 5,466,823. The valdcoxib used in the therapeutic combinations of the present invention can be prepared in the manner described in the US patent. No. 5,633,272. Parecoxib used in the therapeutic combinations of the present invention can be prepared in the manner described in the US patent. No. 5,932,598. The rofecoxib used in the therapeutic combinations of the present invention can be prepared in the manner described in the US patent. No. 5,968,974. The Japanese Tobacco JTE-522 used in the therapeutic combinations of the present invention can be prepared in the manner described in the patent JP 90 / 52,882. Preferred COX-2 inhibitors that can be used in the present invention include, but are not limited to: C1) JTE-522, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide; C2) 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine; C3) 2- (3,5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one; C4) 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1 -yl] -benzenesutfonamide; C5) C6) 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide; C7) N - [[4- (5-methyl-3-phenylisoxazol-4-yl] phenyl] sulfonyl] propanamide; C8) 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yljbenzenesulfonamide; C9) C10) C11) 6 - [[5- (4-chlorobenzoyl) -1,4-dimethyl-1 H -pyrrol-2-yl] methyl] -3 (2 H) -pyridazinone; C12) N- (4-nitro-2-phenoxyphenyl) metasulfonamide; C13) C14) 3- (3,4-difluorophenoxy) -5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone; C15) N- [6 - [(2,4-difluorophenyl) thio] -2,3-dihydro-1 -oxo-1 H -inden-5-yl-methanesulfonamide; C16) 3- (4-chlorophenyl) -4- [4- (methylsulfonyl) phenyl] -2 (3H) -oxazolone; C17) 4- [3- (4-fluorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; C18) 3- [4- (methylsulfonyl) phenyl] -2-phenyl-2-cyclopenten-1-one; C19) 4- (2-methyl-4-phenyl-5-oxaxolyl) benzenesulfonamide; C20) 3- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (3H) -oxazolone; C21) - (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; C22) 4- [5-phenyl] -3- (trifluoromethyl) -1 H -pyrazol-1-yl) benzenesulfonamide; C23) 4- [1-phenyl-3- (trifluoromethyl) -1 H -pyrazol-5-yl] benzenesulfonamide; C24) 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-ylbenzenesulfonamide; C25) N- [2 - (- cyclohexyloxy) -4-nitrophenyl] methanesulfonamide; C26) N- [6- (2,4-difluorophenoxy) -2,3-dihydro-1-oxo-1 H -inden-5-yl-methanesulfonamide; C27) 3- (4-chlorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; C28) 3- (4-fluorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; C29) 3 - [(1-methyl-1 H-imidazol-2-yl) thio] -4 [(methylsulfonyl) amino] -benzenesulonamide; C30) ,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -3-phenoxy-2 (5H) -furanone; C31) N- [6 - [(4-ethyl-2-thiazolyl) thio] -1,3-dihydro-1-oxo-5-isobenzofuranyl] -methanesulfonamide; C32) 3 - [(2,4-dichlorophenyl) thio] -4 - [(methylsulfonyl) amino] benzenesulfonamide; C33) 1-fluoro-4- [2- [4- (methylsulfonyl) phenyl] cyclopenten-1-yl] benzene; C34) 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1 H -pyrazol-1-yl-benzenesulfonamide; C35) 3- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazol-2-yl] pyridine; C36) 4- [2- (3-pyridinyl) -4- (trifluoromethyl) -1 H -imidazol-1-yl-benzenesulfonamide; C37) 4- [5- (hydroxymethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; C38) 4- [3- (4-chlorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; C39) 4- [5- (difluoromethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; C40) [1, 1 *: 2 \ 1"-terphenyl] -4-sulfonamide; C41) 4- (methylsulfonyl) -1, 1 \ 2], 1"-terphenyl, C42) 4- (2-phenyl-3-pyridinyl) benzenesulfonamide; C43) N- (2,3-dihydro-1,1-dioxido-6-phenoxy-1,2-benzisothiazol-5-yl) methanesulfonamide; Y C44) N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl-methanesulfonamide; Four. Five) 46) 47) 48) The COX-2 inhibitors that can be used in the present invention are selected from the group consisting of: C1) JTE-522, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide; C2) 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine; C3) 2- (3,5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1 -one; C4) 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1-yl] -benzenesulonamide; C5) rofecoxib, 4- (4- (methylsulfonyl) phenyl] -3-phenyl-2- (5H) -furanone; 6) 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesufonamide; C7) N - [[4- (5-methyl-3-phenylisoxazol-4-yl] phenyl] sulfonyl] propanamide; C8) 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1 H) -pyrazol-1-yl] benzenesulfonamide; Even 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 JTE-522 Snuff Japanese. The isomeric forms are also included in the combination of the invention; and tautomers of the disclosed compounds and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts Illustrative from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic are prepared, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (Pamoic) methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metal ion salts and organic ion salts. More preferably, the metal ion salts include, but are not limited to, suitable alkali metal salts (group a), alkaline earth metal (group lia) and other physiologically suitable metal ions. These salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. The 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 in the art by conventional means from the corresponding compounds of the present invention. A COX-2 inhibitor of the present invention can be formulated as a pharmaceutical composition. That composition can be administered orally, parenterally, by inhalation spray, rectally or topically in dosage unit formulations containing conventional pharmaceutically acceptable and non-toxic vehicles, auxiliaries and carriers as desired. Topical administration may also include the use of transdermal administration such as transdermal patches or iontophoresis devices. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intramuscular or infusion techniques. Drug formulation is described, for example, in Hoover, John E., Reminqton's Pharmaceutical Sciences, Mack Publishing, Co., Easton, Pa., 1975. Another description of the drugs can be found in Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms. Marcel Decker, New York, N. Y., 1980. Injectable preparations, for example, injectable and sterile aqueous or oleaginous suspensions can be formulated according to the known art by the use of dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a suitable parenterally non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and suitable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed and sterile oils are conventionally employed as a solvent or suspending medium. For this purpose any soft fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful for the preparation of injectables. Dimethylacetamide, surfactants including ionic and nonionic detergents, polyethylene glycols, can be used. Mixtures of solvents and wetting agents such as those described above are also useful.

Suppositories can be prepared for rectal administration of the drug by mixing the drug with a suitable non-irritating excipient such as cocoa butter, mono-, di or synthetic triglycerides, fatty acids and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and therefore they will melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more auxiliaries suitable for the indicated route of administration. If administered per os, a contemplated aromatic sulfone hydroximate inhibitor compound may be mixed with lactose, sucrose, powdered starch, alkali esters, alkanoic acid esters, cellulose alkyl esters, talc, stearyl acid, magnesium stearate, magnesium, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then encapsulated for convenient administration. Said capsules or tablets may contain a controlled release formulation as may be provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise pH regulating agents such as sodium citrate, carbonate or magnesium or calcium bicarbonate. Tablets or pills with enteric coatings can also be prepared.

For therapeutic purposes, formulations of parenteral administration may be in the form of sterile and isotonic, aqueous or non-aqueous solutions or suspensions for injection. These solutions and suspensions may be prepared from sterile powders or granules containing one or more of the mentioned carriers or diluents for use in the formulations for oral administration. A contemplated 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 pH regulators . Other adjuvants or modes of administration are well known and widely in the pharmaceutical art. Liquid dosage forms for oral administration may include pharmaceutically suitable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Said compositions also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfume agents. The amount of active ingredient that can be combined with the carrier materials to produce a single dose varies depending on the host treated and the particular mode of administration.

Dose of COX-2 inhibitors Dose levels of COX-2 inhibitors in the order of about 0.1 mg to about 10,000 mg of the ingredient compound} Active antiangiogenic agents are useful in the treatment of the above conditions, with preferred levels of about 10 mg to about 1,000 mg. The amount of the active ingredient that can be combined with other anti-cancer agents to produce a single dosage form can vary depending on the host treated and the particular mode of administration. It is understood, however, that a specific dose level for any particular patient may depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration , rate of excretion, combination of drugs and the severity of the particular disease being treated and the form of administration. Treatment doses can usually be titrated to optimize safety and efficacy. Typically, in vitro dose-effect relationships may provide useful guidance at appropriate doses for administration to patients. Studies with animal models can also be used generally for guidance regarding the effective doses for the treatment of cancers according to the present invention. In terms of treatment protocols, it should be appreciated that the dose to be administered will depend on several factors, including the particular agent that will be administered, the route administered, the condition of the patient in particular, etc. Generalizing, one will want to administer a quantity of the compound that is effective to achieve a serum level proportional to the concentrations found to be effective in vitro. Thus, when a compound is found to demonstrate in vitro activity at, for example, 10 μM, it will be desirable to administer a quantity of the drug that is effective to provide approximately a concentration of 10 μM in vivo. The determination of these parameters is among the skills of the technique. These considerations, as well as the effective administration formulations and procedures are well known in the art and are described in standard textbooks. The phrase "antineoplastic agents" includes agents that exert antineoplastic effects, that is, prevent the development, maturation or dispersion of neoplastic cells, directly in the tumor cell, for example, by cytostatic or cytocidal effects, and not indirectly through such mechanisms as a modification of the biological response. There are large numbers of antineoplastic agents available for commercial use, in clinical evaluation and in pre-clinical development, which can be included in the present invention for the treatment of neoplasia by drug combination chemotherapy. For convenience in the description, antineoplastic agents are classified into the following classes, subtypes and species: ACE inhibitors, alkylating agents, anigiogenesis inhibitors, angiostatin, anthracyclines / DNA intercalators, anti-cancer antibiotics or antimetabolite-type antibiotic agents, antimetastatic compounds, asparaginase, bisphosphonates, cGMP phosphodiesterase inhibitors, calcium carbonate, cyclooxygenase-2 inhibitors DHA derivatives, DNA topoisomerase, endostantin, genistein epipodophyllotoxins, hormonal anti-cancer agents, hydrophilic bile acids (URSO), immunological or immunomodulatory agents, integrin antagonists, antagonists or interferon agents, MMP inhibitors, various antineoplastic agents, monoclonal antibodies, nitrosoureas, NSAIDs, ornithine decarboxylase inhibitors, pBATTs, radio / chimer sensitizers / protectors, retinoids, selective inhibitors of proliferation and endothelial cell migration, selenium, stromelysin inhibitors, taxanes, vaccines and vinca alkaloids. The main categories in which some preferred antineoplastic agents enter include antimetabolite agents, alkylating agents, antibiotic type agents, hormonal anti-cancer agents, immunological agents, interferon-like agents, and a category of various antineoplastic agents. Some antineoplastic agents operate through multiple or unknown mechanisms, and in this way can be classified into more than one category.

A first family of antineoplastic agents that can be used in combination with the present invention consists of antimetabolite-type antineoplastic agents. Antimetabolites are typically inhibitors of reversible or irreversible enzymes, or compounds that would otherwise interfere with the replication, translation or transcription of nucleic acids. Suitable antimetabolite antineoplastic agents which can be used in the present invention include, but are not limited to, acanthuric acid, aminothiadiazole, anastrazole, bicalutamide, brequinar sodium, capecitabine, carmofur, Ciba-Geigy CGP-30694, cladribine, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, cytarabine ocphosphate, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine finasteride, floxuridine, fludarabine phosphate, N- (2'-furanidyl) -5-fluorouraion, Daiichi Seiyaku FO-152, fluorouracil (5-FU), 5-FU-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 PL-AC, stearate; Takeda TAC-788, thioguanine, thiazofurine, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, toremifene and uricitin.

The antimetabolite agents that can be used in the present invention include, but are not limited to, those identified below in Table No. 3.

Table No. 3 Antimetabolite Agents A second family of antineoplastic agents that can be used in combination with the present invention consists of alkylating agent type antineoplastic agents. The alkylating agents are believed to act by alkylating and crosslinking guanine and possibly other bases in DNA, preventing the division of coca. Typical alkylating agents include nitrogen mustards, ethylene imine compounds, alkyl sulfates, cisplatin and various nitrosoureas. A disadvantage with these compounds is that they not only attack malignant cells, but also other cells that divide naturally, such as those of the bone marrow, skin, gastrointestinal mucosa and fetal tissue. Suitable alkylating agent type antineoplastic agents that can be used in the present invention, include but are not limited to, Shionogi 254-S, analogs of aldo-phosphamide, altretamin, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitano, Wakunga CA-102 , carboplatin, carmustine (BiCNU), Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cynamid CL-286558, Sanofi CY-233, ciplatate, dacarbazine, Degussa D-19-384, Sumimoto DACHP (Myr) 2 , diphenylspiromustine, cytostatic diplatin, derivatives of Erba distamycin, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, sodium salt of estramustine phosphate, etoposide phosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230 , hepsul-fam, ifosamide, iproplatin, lomustine, mafosfamide, mitolactol, mycophenolate, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKine SK &F-101772, tiotepa, Yakult Honsha SN-22, spiromus-tina, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol. Alkylating agents that can be used herein include, but are not limited to, those identified below in Table No. 4.

Table No. 4 Alkylating agents A third family of antineoplastic agents that can be used in combination with the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents that can be used in the present invention, include but are not limited to, Taiho 4181 -A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, derivative of aeroplisinin, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-micin-A, bisucaberin, Bristol-Myers BL-6589, Bristol-Myers BMY-25067, Bristol-Myers BMY-2551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, briostatin-1, Taiho C-1027, calichemycin, chromoximicin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyov / a Hakko DC89-A1 , Kyowa Hakko DC92-B, Kyowa Hakko DC92-B, distrisarrubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbestatin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK -973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesaridodyns, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT- 5594, Kyowa Hakko KT-6149, American Cynamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKine M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalisin, oxaunomycin, peplomycin, pilatin, pirarubicin, porotramycin, pirindamicin A, Tobishi RA-I, rapamicin, rhizoxin, rodorubicin, sibanomycin, siwenmicin, Sumitomo SM -5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, Stefimycin B, Taiho 4181-2, Talisomycin, Takeda TAN-868A, terpentecin, trazine, tricrozarine A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF.3405, Yoshitomi Y-25024 and zorrubicin.

Preferred antibiotic anticancer agents that can be used in the present invention, include but are not limited to, the agents that are identified below in Table No. 5.

Table No. 5 Anti-cancer antibiotic agents A fourth family of antineoplastic agents that can be used in combination with the present invention consists of synthetic nucleosides. Several synthetic nucleosides that exhibit anticancer activity have been identified. A well-known nucleoside derivative with potent anticancer activity is 5-fluorouracil (5FU). 5-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. However, 5-fluorouracil causes serious adverse reactions such as nausea, alopecia, diarrhea, stomatitis, leukocytic thrombocytopenia, anorexia, pigmentation and edema. 5-fluorouracil derivatives with anti-cancer activity have been described in the U.S. patent. No. 4,336,381. Additional 5-fluorouracil derivatives have been described in the following patents listed in Table No. (3, hereinafter individually incorporated by reference.

Tabl a No. 6 Derivatives of 5-Fu The patent of E.U.A. No. 4,000,137 discloses that the oxidation product of inosine, adenosine or cytidine peroxidate with methanol or ethanol It has activity against lymphocytic leukemia. Cytosine arabinoside (also known as cytarabine, 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 leukemia acute myeloid It is also active against acute lymphocytic leukemia, and to a lesser degree, is useful in chronic myelocytic leukemia and non-Hodgkin's lymphoma. The primary action of araC is the inhibition of nuclear DNA synthesis. Handschumacher, R, and Cheng, Y., "Purine and Pyrirmidine Antimetabolites", Cancer Medicine, Chapter XV-1, 3rd Edition, Edited by J. Holland, et al., Lea and Febigol editors. 5-Azacitidine is a cytidine analog that is used primarily in the treatment of acute myelocytic leukemia and myelodysplastic syndrome. 2-Fluoroadenosin-5'-phosphate (Fludara, also known as pharaoh) is one of the most active agents in the treatment of acute lymphocytic leukemia. The compound acts by inhibiting DNA synthesis. The treatment of cells with F-araA is associated with the accumulation of cells in the limit; of the G1 / S phase and in the S phase; in this way, this is a specific drug for the G1 / S phase of the cell cycle. The incorporation of the active metabolite, F-araATP, delays the lengthening of the DNA chain. F-araA is also a potent inhibitor of ribonucleotide 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-Hodgkin's lymphoma and cell-hairy leukemia. The spectre of activity is similar to that of Fludara. The compound inhibits DNA synthesis in growing cells and inhibits DNA repair in dormant cells. A fifth family of antineoplastic agents that can be used in combination with the present invention consists of hormonal agents. Hormonal-type antineoplastic agents that can 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-041 R; Avorelina; aseranox; Sensus B2036-PEG; Bicalutamide; buserelin; BTG CB-7598; BTG CB-7630; Casodex; cetrolix; clasped; disodium clodronate; Cosudex; Rotta Research CR-1505; citradren; crinone; deslorelin; droloxifene; dutasteride; Eliminate; Laval University EM-800; Laval Uni-ersity EM-652; epithioestanol; epristerida; Mediolanum EP-23904; EntreMed 2-ME; exemestane; fadrozole; Finasteride; Flutamide; formestane; Pharmacia & Upjohn FCE-24304; ganirelix; goserelin; Shire gonadorelin agonist; Glaxo Wellcome GW-5638; Hoechst Marion Roussel Hooe-766; NCI hCG; idoxifen; isochordoin; Zeneca ICI-182780; Zeneca ICI-118630; Tulane University J015X; Shering Ag J96; ketanserin; lanreotide; Milkhaus LDI-200; letorzole; leuprolide; leuprorelin; liarozole; lisuride hydrogen maleate; loxiglumide; Mepitiostan; Leuprorelin; Ligand Pharmaceuticals LG-1127; LG-1447; LG-2293; LG-2527; LG-2716; Bone Care International LR-103; Lilly LY-326315; Lilly LY-353381-HC1; Lilly LY-326391; Lilly LY-353381; Lilly LY-357489; Miproxifene phosphate; Orion Pharma MPV-2213ad; Tulane University MZ-4-71; nafarelin; nilutamide; Snow Brand NKS01; octreotide; Azko Nobel ORG-31710; Azko Nobel ORG-31806; orimeten; Orimeteno; Orimetin; ormeloxifene; osaterone; Smithkiine Beecham SKB-105657; Tokyo University OSW-1; Peptech PTL-03001; Pharmacia & Upjohn PNU-156765; quinagolide; ramorelix; Raloxifen; statin; Sandostatin LAR; Shionogi S-1064; Novartis SMT-487; somavert; somatostatin; tamoxifen; tamoxifen methylodide; teverelix; toremifen; tripotorelin; TT-232; vapreotide; vorozole; Yamanouchi YM- 116; Yamanouchi YM-511; Yamanouchi YM-55208; Yamanouchi YM-53789; Schering AG ZK-1911703; Schering AG ZK-230211 and Zenca ZD-182780. Preferred hormonal agents that can be used in the present invention include, but are not limited to, those identified below in Table No. 7.

Table No. 7 Hormone agents A sixth family of antineoplastic agents which may be used in combination with the present invention consists of a diverse family of antineoplastic agents including, but not limited to, alpha-carotene, alpha-difluoromeítil-arginine, acitretin, Biotec AD-5, Kiorina AHC-52, alstonin, amonafide, amphetamine, amsacrine, Angiostat, anquinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, afidicolin glycinate, asparaginase, Avarol, bacarin, batracilins, benfluron, Benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamida, Wellcome BW-502, Wellcome BW-773, calcium carbonate, Calcet, Calci-Chew, Calci-Mix, tablets calcium carbonate Roxane, caracemide, hydrochloride carmetizol, Ajinomoto CDAF, clorslfaquinoxalona, Cheme CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner -Lambert CI-958, cla nfenur, claviridenona, compound 1259 ICN compound 4711 ICN, Contracan, routes Cellular CP-461, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, citarabian, citocitina, Merz D-609, maleate Dabis, dacarabizine, datelliptinio, DFMO, diemin-B, dihematoporfirínico ether, dihidrolenperona, dinalina, distamycin, Toy Pharm DM-341, Toy Pheirm DM-75, Daiichi Seyaku DN-9693, docetaxel, Encore Pharmaceuticals E7869, eliprabina, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, Eulexin®, Cell Pathways Exisulind® (sulfone sulindac or CP-246), fenretinide, Merck Research Labs Finasteride, Florical, Fujisawa FR-57704, gallium nitrate, gemcitabine, genkwadafnin, Gerimed, Chugai GI A-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonin, hydroxyurea, BTG ICRF-187, ilmofosin, irinotecan, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, ketocona ?: ol, Otsuask K-76COONa, Kireha Chemical K-AM, MECT Corp Kl-8110, American Cynamid L-623, leucovorin, levamisole, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, Maternal, NCI (US) MAP, maricine, Merrel Dow MDL-27048, Medco MEDR-340, megestrol, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Generics MGI-136 , minactivine, mitonafide, mitochidone, Monocal, mopidamol, motretinide, Zenyaku Kogyo MST-16, Mylanta, N- (retinoyl) amino acids, Nilandron; Nisshin Flour Milling N-021, N-acylate-dehydroalanines, nafazatrom, Taisho NCU-190, Nefo-Calci tablets, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361 56, NCI NSC-604782, NCI NSC- 95580, octreotide, Ono ONO-112, oquizanocin, Akzo Org-10172, paclitaxel, pancratistatin, paxeliptin, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, peptide D of ICRT, piroxantrone, polyhematoporphyrin, polyprotein acid, Efamol porphyrin, probiota, procarbazine, proglumide, protease nexin I from Invitron, Tobishi RA-700, razoxane, Encoré Pharmaceutics R-flurbiprofen, Sandostatin; Sapporo Breweries RBS, restrictin-P, reteliptina, retinoic acid, Rhone Poulenc RP-49532, Rhone Poulenc RP-56976, Scherring-Plow SC-57050, Scherring-Plow SC-57068, selenium (selenite and selenomethionine), SmithKine SK &F -104864, Sumitomo SM- 108, Kuraray SMANCS, SeaPharm SP-10094, espatol, spirocyclopropane derivatives, Spirogermanium, Unimed, SS Pharmaceutical SS-554, Strypoldinone, Stipendione, Suntory SUN 0237, Suntory SUN 2071, Sugen SU-101, Sugen SU-5416, Sugen SU -6668, sulindac, sulindac sulfone, superoxide dismutes a, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, taliblastin, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ucraine, Eastman Kodak USB-006, vinbalstin sulfate, vincristine, vindesine, vinestramide, vinorrelbine, vintriptol, vinzolidine, witanolides, Yamanouchi YM-534, Zileuton, ursodeoxycholic acid and Zanosar. Preferred varied agents that can be used in the present invention include, but are not limited to, those identified below in Table No. 8.

Table No. 8. Varied agents Some preferred additional antineoplastic agents include those described in the individual patents listed below in Table No. 9, and are individually incorporated herein by reference Table No. 9. Antineoplastic agents Table No. 10 provides illustrative examples of average dose for selected anti-cancer agents that can be used in combination with an anti-angiogenic agent. It should be noted that the specific dose regimen for chemotherapeutic agents below depends on dosing considerations based on a variety of factors including the type of neoplasia; the stage of the neoplasm; Age, weight, sex and condition medical of the patient; the administration route; kidney and liver function and the particular combination used. TABLE No. 10 Average dose for selected anticancer agents NAME OF AGENT QUMIOTERAPEUTICO DOSAGE AVERAGE Asparaginase 10,000 units Bleomycin sulfate 15 units Carboplatin 50-450 mg Carmuslina 100 mg Cisplatin 10-50 mg Cladribine 10 mg Cyclophosphamide (lyophilized) 100 mg-2 gm Cyclophosphamide (without lyophilization) 100 mg-2 gm Cyclarabine (lyophilized powder) 100 mg-2 gm Dacarbazine 100 mg-200 mg Dactinomycin 0.5 mg Daunorubicin 20 mg Diethylstilbestrol 250 mg Doxorubicin 10-150 mg Etidronate 300 mg Etoposide 100 mg Floxuridine 500 mg Fludarabine phosphate 50 mg Fluorouracil 500 mg-5 gm TABLE No. 10 (with t.) Goserelin 3.6 mg Granisetron hydrochloride 1 mg Idarubicira 5-10 mg Ifosfamide 1-3 mg Leucovorin Calcic 50-350 mg Leuprolide 3.75-7.5 mg Mechlorethamine 10 mg Medroxyprogesterone 1 gm Melfalan 50 gm Methotrexate 20 mg-1 gm Mitomycin 5-40 mg Mitoxantrone 20-30 mg Ondansetron Hydrochloride 40 mg Paclitaxel 30 mg Disodium Pamidronate 30-90 mg Pegaspargase 750 units Plicamycin 2,500 mcgm Streptozocin 1 gm Tiotepa 15 mg Teniposide 50 mg Vinblastine 10 mg Vincristine 1-5 mg Aldesleucin 22 million units Epoetin alfa 2,000-10,000 units Filgrastim 300-480 mcgm Immunoglobulin 500 mg-10 gm Interferon alfa-2a 3-36 million units Interferon alfa-2b 3-50 million units Levamisole 50 mg Octreolide 1, 000-5,000 mcgm Sargramostim 250-500 mcgm The anastrozole used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,935,437. The capecitabine used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 5,472, 949. The carboplatin used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the US patent. No. 5,455,270. The cisplatin used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,140,704. The cyclophosphamide used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,537,883. The eflornithine (DFMO) used in combinations Therapeutics of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,413,141. The docetaxel used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,814,470. The doxorubicin used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent € i E.U.A. No. 3, 590,028. The etoposide used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,564,675. The fluorouracil used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,336,381. The gemcitabine used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the US patent. No. 4,526,988. The goserelin used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4, 100.274. The irinotecan used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,604,463. The ketoconazole used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,144,346. The letrozole used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,749,713. The leucovorin used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,148,999. The levamisole used in the therapeutic combinations of the present invention can be prepared in the manner indicated in GB 11 / 20,406. The megestrol used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,696,949. The mitoxantrone used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,310,666. The paclitaxel used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 5, 641, 803. The retinoic acid used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,843,096. The tamoxifen used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 4,418,068. The topotecan used in the therapeutic combinations of the present invention can be prepared in the manner disclosed in the US patent. No. 5,004,758. The toremifene used in the therapeutic combinations of the present invention can be prepared in the manner indicated in EP 00 / 095,875. The vinorelbine used in the therapeutic combinations of the present invention can be prepared in the manner indicated in EP 00 / 010,458. The sulindane sulfone used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the patent E.U.A. No. 5,858,694. The selenium (selenomethionine) used in the therapeutic combinations of the present invention can be prepared in the manner indicated in EP 08 / 04,927. The ursodeoxycholic acid used in the therapeutic combinations of the present invention can be prepared in the manner indicated in the document WO 97/34608. The ursodeoxycholic acid can also be prepared according to the manner indicated in EP 05 / 99,282. Finally, the ursodeoxycholic acid can be prepared according to the manner indicated in the patent E.U.A. No. 5,843,929. Preferred antineoplastic agents include: anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461 compound, cyclophosphamide, docetaxel, doxorubicin, etoposide Exisulind®, fluorouracil (5-FU), fluoximestrin, gemcitabine , goserelinei, irinotecan, ketoconazole, letrozole, leucovorin, levamisole, megestrol, mitoxantrcna, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, (selenomethionine) selenium, ursodeoxycholic acid, sulfone sulindac and eflornithine (DFMO). The phrase "taxano" includes a family of diterpenic alkaloids of which all contain a particular "taxano" ring structure of eight (8) links. Taxanes such as paclitaxel prevent the normal disintegration of microtubules, subsequent to division, which are formed to pull and separate the newly duplicated pairs of chromosomes towards the opposite poles of the cell before cell division. In cancer cells, which divide rapidly, the taxane therapy causes the microtubules to accumulate, which ultimately prevents further division of the cancer cells. Taxane therapy also has effects on other cellular processes that depend on microtubules such as cell motility, the shape of the cell and intracellular transport. The main 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) 8 (5), incorporated in the present invention for reference). Specific adverse side effects include neutropenia, alopecia, bradycardia, cardiac conduction defects, acute hypersensitivity reactions, neuropathy, mucosal inflammation, dermatitis, extravascular fluid accumulation, arthralgia and myalgias. Various treatment regimens have been developed in an effort to minimize the side effects of taxane therapy, but adverse effects remain the limiting factor in taxane therapy. It has recently been discovered in vitro that the expression of COX-2 is elevated in cells treated with taxanes. Elevated levels of COX-2 expression are associated with inflammation and the generation of other side effects of prostaglandin derived from COX-2. Accordingly, when a patient is provided with taxane therapy, administration of a COX-2 inhibitor is contemplated to reduce the side effects of inflammation and other side effects of prostaglandin derived from COX-2 associated with taxane therapy. It has been found that taxane derivatives are useful for treating refractory ovarian carcinoma, urothelial cancer, breast cancer, melanoma, non-small cell-type lung carcinoma, gastric and colon carcinomas, squamous cell carcinoma of the head and neck, lymphoblastic leukemia , myeloblastic leukemia and carcinoma of the esophagus. Paclitaxel is typically administered in a dose of 15-420 mg / m2 by infusion for 6 to 24 hours. For renal cell carcinoma, squamous cell carcinoma of the head and neck, esophageal carcinoma, non-small cell-type lung cancer and breast cancer, paclitaxel is typically administered as an infusion of 250 mg / m2 for 24 hours. hours every 3 weeks. For refractory ovarian cancer, paclitaxel is typically administered in a scaled dose starting at 110 mg / m2. Docetaxel is typically administered in a dose of 60-100 mg / m2 intravenously for one hour, every three weeks. However, it should be mentioned that the specific dose regimen depends on dosing considerations based on 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 liver and kidney function of the patient; and of the agents and particular combination used. In one embodiment, paclitaxel is used in the present invention in combination with a cyclooxygenase-2 inhibitor and with cisplatin, cyclophosphamide, or doxorubicin the treatment of breast cancer. In another embodiment, paclitaxel is used in combination with an inhibitor of cyclo-oxygenase-2, cisplatin or carboplatin and ifosfamide the treatment of ovarian cancer. In another embodiment, docetaxal is used in the present invention in combination with an inhibitor of cyclo-oxygenase-2 and in combination with cisplatin, cyclophosphamide or doxorubicin for the treatment of ovarian 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. 11 below, which are incorporated individually for reference in the present invention, describe various taxanes and taxane derivatives suitable for use in the present invention and methods for their manufacture.

TABLE No. 11 Taxanes and taxane derivatives TABLE No. 11 (cont.) 15 20 TABLE No. 11 (cont.) The patent E.U.A. No. 5,019,504 describes the isolation of paclitaxel and related alkaloids from Taxus brevifolia cells grown in culture medium. The patent E.U.A. No. 5,675,025 describes methods for synthesizing Taxol®, analogs and intermediates of Taxol® from baccatin III. The patent E.U.A. No. 5,688,977 describes the synthesis of Docetaxel from 10-desacetyl baccatin III. The patent E.U.A. No. 5,202,488 describes the conversion of a partially purified taxane mixture to baccatin III. The patent E.U.A. No. 5,869,680 describes the procedure for the preparation of taxaNo derivatives. The patent E.U.A. No. 5,856,532 describes the production process of Taxol®. The patent E.U.A. No. 5,750,737 describes the method for synthesizing paclitaxel. The patent E.U.A. No. 6,688,977 describes methods for the synthesis of docetaxel. The patent E.U.A. No. 5,677,462 describes the process for the preparation of taxaNo derivatives. The patent E.U.A. No. 5,594,157 describes the process for making Taxol® derivatives. Some preferred taxanes and taxane derivatives are disclosed in the patents listed in Table No. 12 below, and therefore such patents are incorporated individually for reference in the present invention.

TABLE No. 12 Some preferred taxanes and taxane derivatives The phrase "retinoid" includes compounds which are synthetic and natural analogs of retinol (vitamin A). Retinoids bind to one or more of the retinoic acid receptors to initiate diverse processes such as reproduction, development, bone tissue formation, cell proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision. Retinoids are necessto maintain the normal proliferation and differentiation of almost all cells and have been shown to reverse / suppress carcinogenesis in a variety of experimental cancer models in vitro and in vivo, [see Moon et al., Chap. 14"Retinoids and Cancer" (retinoids and cancer) in The Retinoids (Los Retinoids), vol. 2, Academic Press, Inc. 1984. See also Roberts et al., "Cellular biology and biochemistry of the retinoids" (Cell biology and biochemistry of retinoids) in The Retinoids, vol. 2, Academic Press, Inc. 1984, incorporated herein by reference], which also demonstrates that the vesanoid (trans-retinoic tretinoid acid) is indicated to induce remission in patients with acute promyelocytic leukemia (APL).

English). A synthetic description of retinoid-type compounds is described in: Dawson Ml and Hobbs PD, The synthetic chemistry of retinoids: in The Retinoids, 2nd edition. MB Sporn, AB Roberts and DS Goodman (editors), New York: Raven Press, 1994, pp 5-178. Lingen et al., Describe the use of retinoic acid and interferon alpha against squamous cell carcinoma of the head and neck [Lingen, MW et al., "Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma (Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against squamous cell carcinoma of the head and neck), Cancer Research 58 (23) 5551-5558 (1998) incorporated in the present invention for reference]. Luriaro et al., describe the use of beta interferon and 13-cis-retinoic acid to inhibit angiogenesis. [luriaro, M et al., Beta interferon inhibits HIV-1Tat-induced angiogenesis: synergism with 13-cis-retinoic acid (beta interferon inhibits Tat-induced angiogenesis of HIV-1: synergism with 13-cis-retinoic acid ), European Journal of Cancer 34 (4) 570-576 (1998), incorporated in the present invention for reference]. Majewski et al., Describe vitamin D3 and retinoids in the inhibition of angiogenesis induced by tumor cells. [Majewski, S et al., Vitamin D3 is a potent inhibitor of tumor cell-induced angiogenesis (Vitamin D3 is a potent inhibitor of tumor cell-induced angiogenesis), J. Invest.

Dermatology Symposium Proceedings, 1 (1), 97-101 (1996), incorporated in the present invention for 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 (Role of cytokines, retinoids and other factors in tumor angiogenesis), Central-European Journal of Immunalogy 21 (4) 281-289 ( 1996), incorporated in the present invention for reference). Bollag describes retinoids and alpha-interferon in the prevention and treatment of neoplastic diseases. [Bollag W., Retinoids and alpha-interferon in the prevention and treatment of preneoplastic and neoplastic diseases (Retinoids and alpha-interferon in the prevention and treatment of pre-neoplastic and neoplastic diseases), Chemotherapie Journal, (Suppl) 5 (10) 55-64 (1996), incorporated in the present invention for reference]. Bigg, HF et al., Describe all trans retinoic acid with basic factor of fibroblast growth and epidermal growth factor to stimulate the tissue inhibitor of metalloproteinases from fibroblasts. [Bigg, HF et al., All-trans-retinoic acid interactions synergystically with basicfibroblast growth factor and epidermal growth factor to stimulate the production of tissue inhibitor oF metal loproteinases from fibroblasts (All-trans retinoic acid interacts synergistically with the basic factor of fibroblast growth and with epidermal growth factor to stimulate the production of inhibitor: isolate of metalloproteinases from fibroblasts), Arch.

Biochem. Biophys. 319 (1) 74-83 (1995), incorporated in the present invention for reference]. In the following Table No. 13, non-limiting examples of retinoids that could be used in the present invention are identified.

TABLE 1 No. 13 Retinoids TABLE No.13 (copt.) The following individual patent references listed in Table No. 14, incorporated for reference in the present invention, describe various rotatinoids and retinoid derivatives suitable for use in the present invention described therein and methods for their manufacture.

TABLE No. 14 Retinoids Some preferred retinoids include Accutane; Adapalene; AGN-193174 do Allergan; AGN-193676 from Allergan; AGN-193836 from Allergan; AGN-193109 of Allergan; AR-623 from Aronex; BMS-181162; CD-437 by Galderma; ER-34617 of Eisai; Etrinato; Fenretinide; LGD-1550 of Ligand; lexacalcitol; MX-781 from Maxia Pharmaceuticals; mofarotene; MDI-101 by Molecular Design; MDI-301 from Molecular Design; MDI-403 from Molecular Design; Motretinide; 4- (2- [5- (4-methyl-7-et!! benzofuran-2-yl) pyrrolyl]) benzoic acid from Eisai; N- [4- [2-tyl-1- (1H-imidazol-1-yl) butyl] phenyl] -2-benzothiazolamine from Johnson & Johnson; Soriano; SR-11262 from Roche; Tocoretinato; trans-retinoic acid from Advanced Polymer Systems; UAB-8 of the UAB Foundation for research; Tazorac; TopiCare; TAC-101 of Taiho and Veisanoide. The cGMP phosphodiesterase inhibitors, including the sulphone of Sulindac (Exisulind®) and CP-461 for example, are inducers of apoptosis and do not inhibit the »routes of the cyclo-oxygenase. The cGMP phosphodiesterase inhibitors increase apoptosis in tumor cells without stopping the normal cycle of cell division or altering the expression in the cell of the p53 gene. Ornithine decarboxylase is a key enzyme in the pathway of synthesis of polyamine that is found in high levels in most tumors and of lesions prior to the formation of malignant tumors. The induction of cell growth and proliferation is associated with dramatic increases in the activity of ornithine decarboxylase and the subsequent synthesis of polyamine. In addition, blocking the formation of the polyamines reduces or stops growth in the transformed cells. Therefore, it is believed that polyamines play a role in tumor growth. Difluoromethylornithine (DMFO) is a potent inhibitor of ornithine decarboxylase that has been shown to inhibit the development of cancer induced by carcinogen in a variety of rodent models [Meyskens et al., Development of Difluoromethylornithine (DMFO) as a chemoprevention agent (Development Difluoromethylornithine (DMFO) as a chemoprevention agent), Clin. Cancer Res. 1999 May, 5 (5): 945-951, incorporated in the present invention for reference). DMFO is also known as 2-difluoromethyl-2,5-diaminopantanoic acid or 2-difluoromethyl-2,5-diaminovaleric acid or a- (difluoromethyl) ornithine.; DMFO is sold under the trade name Elfomithine®. Therefore, the use of DMFO in combination with COX-2 inhibitors to treat or prevent cancer is contemplated, including but not limited to colon cancer or colon polyps. It has been reported that populations with high levels of calcium in the diet are protected from colon cancer. Calcium carbonate has been shown in vivo to inhibit colon cancer by a mechanism of independent action of COX-2 inhibition. In addition, 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 colon polyps. Several studies have focused attention on bile acids as a potential mediator of the influence of diet on the risk of colorectal cancer. Bile acids are important detergents for the solubilization and digestion of fats in the proximal intestine. The specific transport processes in the apical domain of the entero ileum of the terminal ileum and the basolateral domain of the hepatocyte explain efficient conservation in the enterohepatic circulation. Only a small fraction of the bile acids enter the colon; However, disturbances in the cycling rate of bile acids caused by diet (eg, fats) or surgery could increase the bile load in the stool and perhaps explain the increased risk associated with colon cancer. (Hill MJ, Bile flow and colon cancer (Bile flow and colon cancer), 233 Mutation Review, 313 (1990). The ursodeoxycholate (URSO), the 7-beta hydrophilic epimer of chenodeoxycholate, is non-toxic in a variety of systems. of animal models including colon epithelium.The URSO is also virtually free of side effects.The URSO, at a dose of 15 mg / kg / day used mainly in clinical trials of biliary cirrhosis, was extremely well tolerated and without toxicity. [Pourpon et al. al., A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis (A controlled clinical trial of ursodiol, in multiple centers, for the treatment of cirrhosis biliary primary), 324 New Engl. J. Med. 1548 (1991)]. Although the precise mechanism of action of URSO is unknown, the beneficial effects of URSO therapy are related to the enrichment of the hepatic bile acid pool with this hydrophilic bile acid. Therefore, it has been hypothesized that the: more hydrophilic bile acids than the URSO will have beneficial effects even greater than those of URSO. For example, tauroursodesoxycholate (TURSO for its acronym in English), the taurine conjugate of URSO. Nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit neoplastic transformation of the colorectal epithelium. The probable mechanism to explain this chemopreventive effect is the inhibition of prostaglandin synthesis. NSAIDs inhibit cyclo-oxygenase, the enzyme that converts arachidonic acid to prostaglandins and thromboxanes. However, the potential chemoprotective benefits of NSAIDs such as sulindac or mesalamine are dominated by their well-known toxic effects and by the moderately high risk of intolerance. Abdominal pain, dyspepsia, nausea, diarrhea, constipation, rash, dizziness or headaches have been reported in up to 9% of patients. Older adults appear to be particularly vulnerable as the incidence of gastroduodenal ulcer disease induced by NSAIDs, including gastrointestinal bleeding, is higher in those over 60 years of age; This age group is also more likely to develop colon cancer and therefore is the group that will likely benefit from chemoprevention. The gastrointestinal side effects associated with the Use of NSAIDs results from the inhibition of cyclo-oxygenase-1, an enzyme responsible for the maintenance of the gastrointestinal 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 colon polyps; it is contemplated that this treatment will result in reduced gastrointestinal side effects than the combination of standard NSAIDs and URSO. An additional class of antineoplastic agents that could be used in the present invention include nonsteroidal anti-inflammatory drugs (NSAIDs). It has been found that NSAIDs prevent the production of prostaglandins by inhibiting enzymes in the arachidonic acid / prostaglandin pathway in humans, including the enzyme cyclo-oxygenase (COX). However, for the purposes of the present invention, the definition of an NSAID does not include the "cyclooxygenase-2 inhibitors" described in the present invention. Therefore, the phrase "non-steroidal anti-inflammatory drug" or "NSAID" includes agents that specifically inhibit cyclo-oxygenase-1, without significantly inhibiting cyclo-oxygenase-2.; or which inhibit cyclooxygenase-1 and cyclo-oxygenase-2 with substantially the same potency, or which do not inhibit either cyclooxygenase-1 or cyclo-oxygenase-2. The potency and selectivity towards the enzyme cyclo-oxygenase-1 and cyclo-oxygenase-2 can be determined by tests 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 combinations of the present invention include sulindaco, indomethacin, naproxep, diclofenac, tolectin, fenoprofen, phenylbutazone, piroxicam, ibuprofen, ketofen, mefenamic acid, tolmetin, flufenamic acid, nimesulide, niflumic acid, piroxicam , tenoxicam, phenylbutazone, fenclofenac, flurbiprofen, ketoprofemo, fenoprofen, acetaminophen, salicylate and aspirin. The term "clinical tumor" includes neoplasms that can be identified by clinical evaluation or by diagnostic procedures including, but not limited to, palpation, biopsy, cell proliferation index, endoscopy, mammography, digital mammography, ultrasonography, computed tomography (CT by its acronyms in English), magnetic resonance imaging (MRI), positron emission tomography (PET), radiography, radionuclide evaluation, cytology by CT guided aspiration or by MRI , and needle biopsy guided by image formation, among others. Such diagnostic techniques are well known to those skilled in the art and are described in Cancer Medicine (Medicine for Cancer) 4th edition, volume one, J.F. Holland, R.C. Bast, D.L Morton, E. Frei III, D.W. Kufe and R.R. Weichseloaum (editors), Williams & Wilkins, Baltimore (1997). The term "tumor marker" or "tumor biomarker" encompasses a wide variety of molecules with divergent characteristics that are present in body fluids or tissues in association with a clinical tumor and also includes chromosomal changes associated with the tumor. The markers of tumor are classified mainly into three categories: molecular or cell markers, chromosomal markers and serological or serum markers. Molecular and chromosomal markers complement the standard parameters used to describe a tumor (ie, histopathology, grade, tumor size) and are used mainly in the refinement of diagnosis and prognosis; of the disease after the clinical manifestation. Serum markers can often be measured many months before clinical tumor detection and are therefore useful as an early diagnostic test, during patient monitoring and in the evaluation of therapy.

Molecular tumor markers Molecular cancer markers are products of cancer cells or molecular changes that occur in cells due to the activation of cell division or the inhibition of apoptosis. The expression of these markers can predict a malignant potential of the cell. Because cell markers are not secreted, tumor tissue samples are usually required for detection. Non-limiting examples of tumor cell markers that can be used in the present invention are listed in Table No. 1 below.

TABLE No. 1 Non-limiting examples of tumor molecular markers Tumor chromosomal 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 large effort has been made to identify chromosomal alterations induced by tumor. Cancer chromosome markers, in the same way as cell markers, 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 germline mutations can be used to predict the likelihood that a particular person will develop a particular type of tumor. Non-limiting examples of chromosomal markers of tumor that can be used in the present invention are listed in Table No. 2 below.

TABLE No. 2 Non-limiting examples of tumor chromosomal markers Serological markers of tumor Serum markers including soluble antigens, enzymes and hormones comprise a third category of tumor markers. Monitoring of serum tumor marker concentrations during therapy provides an early indication of tumor recurrence and the effectiveness of therapy. Serum markers are convenient for monitoring the patient compared to molecular markers and chromosomal markers because serum samples can be obtained more easily than tissue samples, and because serum tests can be performed in serial form and more quickly. Serum tumor markers can be used to determine the appropriate therapeutic doses within individual patients. For example, the efficacy of a combination regimen consisting of chemotherapeutic agents and anti-angiogenic agents can be measured by monitoring the relevant serum cancer marker levels. In addition, an effective therapeutic dose can be obtained by modulating the therapeutic dose such that the concentration of the particular tumor serum marker or within the reference range is stable, which can vary depending on the indication. Accordingly, the amount of therapy for each patient can be modulated in a specific manner such that side effects are minimized and stable levels in the reference range of the tumor marker are maintained at the same time. Table No. 3 provides non-limiting examples of serum tumor markers that can be used in the present invention.

TABLE No. 3 Non-limiting examples of serum tumor markers EXAMPLES 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 α-fetoprotein (AFP), human chorionic gonadotropin (hCG its abbreviations in English) and its beta subunit (hCGb), lactate dehydrogenase (LDH for its acronyms in English and placental alkaline phosphatase (PLAP).) The AFP has a reference limit higher than approximately - kU / L after the first year of life and could be elevated in germ cell tumors, in hepatocellular carcinoma and also in gastric, colon, biliary, pancreatic and lung cancers. The serum half-life of AFP is approximately 5 days after orchidectomy. In accordance with EGTM recommendations, serum AFP levels of less than 1,000 kU / L correlate with an adequate prognosis, AFP levels between 1,000 and 10,000, inclusive, correlate with an intermediate prognosis. and AFP levels greater than 10,000 U / L correlate with a low prognosis. HCG is synthesized in the placenta and is also produced by malignant tumors. Serum hCG concentrations may be increased in pancreatic adenocarcinomas, in islet cell tumors, in tumors of the large and small intestine, in the hepatoma, and in tumors of the stomach, lung, ovaries, breast, and kidney. Because some tumors only produce iCGb, it is recommended to measure both hCG and hCGb. Normally, hCG levels in pre-menopausal men and women are as high as -5 U / L while post-menopausal women have levels up to -10 U / L. The serum half-life of hCG varies from 16 to 24 hours. In accordance with the recommendations of EGTM, hCG serum levels below 5,000 kU / L correlate with an adequate prognosis, levels between 5,000 and 50,000 U / L, inclusive, correlate with an intermediate prognosis and hCG levels in serum greater than 50,000 U / L correlate with a low prognosis. In addition, half lives of normal hCG correlate with an adequate prognosis while prolonged half-lives correlate with low prognosis. LDH is an enzyme that is expressed in the heart and skeletal muscle as well as in other organs. The isoenzyme of LDH-1 is found mainly in testicular germ cell tumors but can also occur in a variety of benign conditions such as skeletal muscle disease and myocardial infarction. The total LDH value is used to measure the independent prognostic value in patients with advanced stage germ cell tumors. LDH values less than 1.5 x the reference interval are associated with an adequate prognosis, levels between 1.5 and 10 x the reference interval, inclusive, are associated with an intermediate prognosis and levels greater than 10 x the reference interval are associated with a low prognosis. PLAP is an alkaline phosphatase enzyme expressed normally by the syncytiotrophoblasts of the placenta. Elevated serum PLAP levels 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 the surgical reaction between 0.6 and 2.8 days.

Prostate cancer Prostate-specific antigen (PSA) is a non-limiting example of a tumor marker useful in the present invention to detect cancer of the prostate. prostate. PSA is a glycoprotein that is produced almost exclusively in the prostate. In human serum, un-complexed f-PSA and a complex of f-PSA with a1-antichymotrypsin constitute the total PSA (t-PSA). The t-PSA is useful in determining the prognosis in patients who are not currently undergoing anti-androgen treatment. The elevation of t-PSA levels by serial measurements indicates 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 are not limited to, carcinoembryonic antigen (CEA) and MUC-1 (CA 15.3). Serum CEA and CA15.3 levels are elevated in patients with involvement of the nodules compared to patients without nodule involvement, and in patients with larger tumors compared to patients with smaller tumors. The cutoff points of the normal range (upper limit) are 5-10 mg / liter for CEA and 35-60 u / ml for CA15.3. An additional specificity is obtained (99.3%) confirming the serum levels with two serial increases of more than 15%.

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 / liter; 99% of the post-menopausal women have levels below 20 kU / liter. The concentration of CA125 in serum after chemotherapy is a strong predictor of the result because high levels of CA125 are found in almost 80% of all patients with epithelial ovarian cancer. In addition, the prolonged half-life of CA125 or less than a 7-fold decrease during early treatment is also a predictor of low prognosis of the disease.

Gastrointestinal Cancers A non-limiting example of a tumor marker useful in the present invention for the detection of colon cancer is the carcinoembryonic antigen (CEA). CEA is a glycoprotein produced during embryonic and fetal development and has a high sensitivity to advanced stage carcinomas including those of the colon, breast, stomach and lung. Elevated pre-operative or post-operative concentrations (> 2.5 ng / ml) of CEA are associated with the worst prognosis compared to low concentrations. In addition, some studies in the literature report that slow elevation of CEA levels indicates local recurrence while levels that increase rapidly suggest liver metastasis.

Lung Cancer Examples of serum markers useful in the present invention for monitoring lung cancer therapy include, but are not limited to, CEA, fragments of cytokeratin 19 (CYFRA 21-1) and Neuron Specific Enolase (NSE). The NSE is a glycolytic isoenzyme of enolase that occurs in central and peripheral neurons and in malignant tumors of neuroectodermal origin. During diagnosis, NSE concentrations greater than 25 ng / ml suggest the presence of malignancies and lung cancer while concentrations greater than 100 ng / ml suggest the presence of small cell-type cancer. CYFRA 21-1 is a test for tumor marker that uses two specific monoclonal antibodies against a fragment of cytokeratin 19. During diagnosis, CYFRA 21-1 concentrations greater than 10 ng / ml suggest the presence of malignancies while the concentrations greater than 30 ng / rr I suggest the presence of lung cancer. Accordingly, the dose of the cyclooxygenase-2 inhibitor and the antineoplastic agent can be determined and adjusted based on measurements of tumor markers in body fluids or tissues., based in particular on the serum markers of tumors. For example, a decrease in serum marker level relative to baseline serum marker before administration of the cyclooxygenase-2 inhibitor and antineoplastic agent indicates a decrease in changes associated with cancer and provides a correlation with the inhibition of cancer. Therefore, in one embodiment, the method of the present invention comprises administering the cyclooxygenase-2 inhibitor and the antineoplastic agent at a dose that in combination result in a decrease in one or more of the tumor markers, in particular a decrease in one or more of the serum tumor markers, in the mammal relative to the basal levels of the tumor marker. Similarly, decreasing the concentrations or half-lives of the tumor marker after administration of the combination indicates an adequate prognosis, while tumor marker concentrations that decline slowly and do not reach the normal reference range predict the presence of residual tumor and a low prognosis. In addition, during continuous therapy, increases in tumor marker concentration predict the presence of recurrent disease many months before the clinical manifestation of the disease. In addition to the above examples, the following Table No. 4 lists several references, incorporated individually in the present invention for reference describing tumor markers and their use in the detection and monitoring of tumor growth and progression.

TABLE No. 4 References about tumor markers European n Group on Tumor Markers Publications Committee. Consensus Recommedations (European Group for the Publications Committee on Tumor Markers, Consensus Recommendations). Anticancer Research 19: 2785-2820 (1999). Human Cytogenetic Cancer Markers (Cytogenetic cancer markers of human). Sandra R. Wolman and Stewart Sell (editors). Totowa, New Jersey: Humana Press, 1997. Cellular Markers of Cancer. Carretón Garrett and Stewart Sell (editors). Totowa, New Jersey: Humana Press, 1995.

Also included in the combination of the invention are the isomeric, prodrug and tautomeric forms of the disclosed compounds and the pharmaceutically acceptable salts thereof. Examples of 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 acids , mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamico), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethane sulfonic, sulphanilic, cyclohexylaminosulfonic, algic, b-hydroxybutyric, galactharic and galacturonic.

Suitable pharmaceutically acceptable basic addition salts of the compounds of the present invention include the metal ion salts and the salts of organic ones. More preferred metal ion salts include, but are not limited to, the appropriate alkali metal salts (Group a), alkaline earth metal salts (Group lia) and other physiologically acceptable ions. Such salts can be prepared from the ions of aluminum, 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.

Administration regime Any effective treatment regimen can be used and easily determined and can be repeated as necessary to effect the treatment. In clinical practice, compositions containing a 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 drug based on a COX-2 inhibitor may be used in combination with another antiangiogenic agent or one or more agents against cancer as an immediate initial therapy before surgery, chemotherapy or radiation therapy, and as a continuous therapy after treatment in patients at risk of recurrence or metastasis (for example, in prostate adenocarcinoma, the risk with respect to Metastasis is based on elevated PSA, elongated Gleason score, locally extensive disease and / or evidence of tumor invasion in the surgical specimen. The objective in these patients is to inhibit the growth of potentially metastatic cells from the primary tumor during surgery or radiotherapy and to inhibit the growth of tumor cells from residual primary tumor not detectable. For patients who initially present with advanced or metastatic cancer, a drug based on a COX-2 inhibitor in combination with another anti-angiogenic agent or one or more anti-cancer agents of the present invention is used as a continuous complement for, or as a possible replacement for hormonal elimination. The objective in these patients is to reduce or edit the growth of tumor cells from both the untreated primary tumor and the already existing metastatic lesions. In addition, the invention could be particularly effective during post-surgery recovery, in which the compositions and methods of the present invention could be particularly effective in decreasing the chances of recurrence of a tumor generated by disseminated cells that can not be eliminated by surgical intervention.

Combinations with other treatments The combination of COX-2 inhibitors and ntineoplasic agents may be used in conjunction with other treatment modalities, including but not limited to surgery and radiation, hormone therapy, antiangiogenic therapy, chemotherapy, immunotherapy, and cryotherapy. The present invention could be used in conjunction with any current or future therapy. The following discussion highlights some agents in this regard, which are illustrative, not limiting. A wide variety of other effective agents could also be used.

Surgery and radiation In general, therapies with surgery and radiation are used as potentially curative therapies for patients under 70 years of age who present with clinically localized disease and who are expected to be at least 10 years older. For example, approximately 70% of patients with newly diagnosed prostate cancer fall into this category. Approximately 90% of these patients (65% of all patients) undergo surgery, while approximately 10% of these patients (7% of all patients) undergo radiation therapy. Histopathological evaluation of surgical specimens reveals that approximately 63% of patients who undergo surgery (40% of all patients) have locally extensive tumors or regional metastases (lymph node) that do not were detected in the initial diagnosis. These patients have a significantly higher risk of recurrence. In fact, approximately 40% of these patients will have recurrence within a period of five years after surgery. The results after radiation are even less encouraging. Approximately 80% of patients who have undergone radiation as primary therapy have persistent disease or develop recurrence or metastasis within a period of five years after treatment. Currently, most of these patients undergoing surgery and radiation therapy usually do not receive any immediate follow-up therapy. Instead, for example, these are often monitored for high levels of Prostate-Specific Antigen ("PSA"). , which is the primary indicator of recurrence or metastasis of prostate cancer. Therefore, there is a considerable opportunity to use the present invention in conjunction with the surgical intervention.

Hormone therapy Hormone elimination is the most effective palliative treatment for 10% of patients presenting with prostate cancer at the initial diagnosis. The hormonal elimination by means of medicines and / or extirpation of the testes is used to block the hormones that support the later growth and the metastasis of the cancer of prostate. Over time, both the primary tumors and the metastatic tumors of virtually all these patients become independent of the hormones and become resistant to therapy. Approximately 50% of patients presenting with metastatic disease die within a period of three years after the initial diagnosis, and 75% of such patients die within a period of five years after diagnosis. Continuous supplementation with drugs based on NAALADase inhibitor is used to prevent or reverse this potentially permissive state of metastasis. Among the hormones that could be used in combination with the compounds of the present invention are preferred diethylstilbestrol (DES), leuprolide, flutamide, cyproterone acetate, ketoconazole and aminoglutethimide.

Immunotherapy The cyclooxygenase-2 inhibitors of the present invention could also be used in combination with monoclonal antibodies in the treatment of cancer. For example, monoclonal antibodies could be used in the treatment of prostate cancer. A specific example of one such antibody includes the prostate antibody specific to the cell membrane. The present invention could also be used with immunotherapies based on reagents obtained from polyclonal or monoclonal antibodies, for example. In this regard, reagents based on monoclonal antibodies are most preferred. Such reagents are well known to those skilled in the art. They are also well known by skilled in the art radiolabeled monoclonal antibodies for cancer therapy, such as the recently approved use of monoclonal antibody conjugated with strontium 89.

Antiangiogenic therapy The cyclo-oxygenase inhibitors of the present invention could also be used in combination with other inhibitors of cyclo-oxygenase-2 or with other anti-angiogenic agents in the treatment of cancer. Antiangiogenic agents include, but are not limited to, MMP inhibitors, integrin antagonists, COX-2 inhibitors, angiostatin, endostatin, thrombospondin-1, and interferon alpha. Examples of preferred antiangiogenic agents include, but are not limited to vitaxin, marimastat, Bay-12-9566, AG-3340, metastat, celecoxib, rofecoxib, JTE-522, EMD-121974 and D-2163 (BMS-275291).

Cryotherapy Recently, cryotherapy has been applied to the treatment of some cancers. The methods and compositions of the present invention could also be used in conjunction with an effective therapy of this type. All the various types of cells of the body can be transformed into benign or malignant neoplasms or into tumor cells and are contemplated as objects of the invention. A "benign" tumor cell indicates the non-invasive and non-metastatic state of a neoplasm. In humans, the most frequent site of neoplasia is the lung, followed by the colorectal area, the breast tissue, the prostate, the bladder, the pancreas and then the ovary. Other general types of cancer include leukemia, cancers of the central nervous system, including brain cancer, melanoma, lymphoma, erythroleukemia, cancer of the uterus, and cancer of the head and neck. Examples 1 to 9 are provided to illustrate the contemplated therapeutic combinations and are not intended to limit the scope of the invention.

ILLUSTRATIONS The following non-limiting illustrative examples describe various cancer-type diseases and therapeutic methods that could be used in the present invention, and are for purposes of illustration only. Preferred COX-2 inhibitors of the following non-limiting illustrations include, but are not limited to celecoxib, rofecoxib and JTE-522.

EXAMPLE 1 Lung cancer In many countries including Japan, Europe and the United States, the number of patients with lung cancer is quite large and continues to increase year after year and this is the most frequent cause of cancer death in both men and women. Although there are many causes potential for lung cancer, the use of tobacco, and particularly cigarette smoking, is the most important. In addition, etiological factors such as exposure to asbestos, especially in smokers or radon, are contributing factors. Occupational hazards such as exposure to uranium have also been identified as an important factor. Finally, genetic factors have also been identified as another factor that increases the risk of cancer. Lung cancers can be classified histologically into non-small cell-type lung cancers [e.g., squamous cell carcinoma (epidermoid), adenocarcinoma, large cell (anaplastic large cell) cancer, etc.] and lung cancer of small cell type (oat cell). Non-small cell-type lung cancer (NSCLC) has different biological properties and responses to chemotherapeutic agents than those of small cell-type lung cancer (SCLC). Therefore, chemotherapeutic formulas and radiation therapy are different between these two types of lung cancer.

Non-small cell-type lung cancer When the location of the non-small cell-type lung cancer tumor can be easily removed (stage I and II disease), surgery is the first line of therapy and offers a good opportunity for healing. However, in cases where the disease is in advanced stages (stage Illa and more advanced), in which the tumor has spread to the tissue beyond of bronchopulmonary lymph nodes, surgery may not lead to complete removal of the tumor. In such cases, the possibility of cure for the patient through surgery alone is greatly reduced. In cases in which surgery will not provide complete removal of the NSCLC tumor, other types of therapy should be used. Currently, radiation therapy is the standard treatment for controlling NSCLC tumors that can not be removed or can not be operated on. Improved results have been observed when radiation therapy has been combined with chemotherapy, but achievements have been modest and continuous search for improved methods to combine modalities. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of the reproductive cells in both the tumor and healthy tissue. The radiation dose regimen is usually defined in terms of the dose of radiation absorbed (rad), time and fractionation and must be carefully defined by the oncologist. The amount of radiation the patient receives will depend on several considerations, but the two most important considerations are the location of the tumor relative to other structures or critical organs of the body, and the degree to which the tumor has spread. A preferred course of treatment for a patient undergoing radiation therapy for the NSCLC will be a treatment program for a period of 5 to 6 weeks, with a total dose of 50 to 60 Gy administered to the patient in a single daily fraction of 1.8 up to 2.0 Gy, 5 days a week. A Gy is an abbreviation for Gray and refers to a dose of 100 rads. However, because NSCLC is a systemic disease, and radiation therapy is a local modality, it is unlikely that radiation therapy as an individual line of therapy will provide a cure for NSCLC, at least for those tumors that present metastasis in quite distant areas outside the treatment area. Thus, the use of radiation therapy with other regimens of the modality has important beneficial effects for the treatment of NSCLC. In general, radiation therapy has been combined temporarily with chemotherapy to improve treatment outcomes. There are several terms to describe the temporal relationship of the administration of radiation therapy in combination with COX-2 inhibitors and chemotherapy, and the following examples are the preferred treatment regimens and are provided for illustrative purposes only and are not intended to limit the use of other combinations. "Sequential" therapy refers to the administration of chemotherapy and / or therapy for COX-2 and / or radiation therapy separately in time in order to allow for the separate administration of any chemotherapy, and / or COX-2 inhibitors and / or radiation therapy. "Concomitant" therapy refers to the administration of chemotherapy and / or a COX-2 inhibitor, and / or radiation therapy on the same day. Finally, "alternating" therapy refers to the administration of radiation therapy on the days when the chemotherapy and / or the COX-2 inhibitor has not been administered if administered alone.

It is reported that advanced non-small cell lung cancers do not respond favorably to single-agent chemotherapy and useful therapies for advanced stage cancers that can not be operated on have been limited. (Journal of Clinical Oncology, vol.10, pp. 829-838 (1992)). Japanese patent Kokai 5-163293 refers to some specified 16-link macrolide-type antibiotics as a vehicle for the delivery of drug capable of transporting anthocyclic cancer-like drugs to the lungs for the treatment of lung cancers. , the macrolide-type antibiotics specified in said document are described solely as vehicles for the drug and there is no reference for the use of macrolides against non-small cell-type lung cancers. WO 93/18652 relates to the effectiveness of the specified 16-membered ring macrolides such as bafilomycin, etc. in the treatment of non-small cell-type lung cancers, but these have not yet been clinically practiced. The reference Pharmacology, vol. 41, pp. 177-183 (1990) describes that the long-term use of erythromycin increases the productions of interleukine 1, 2 and 4, all of which contribute to the immune responses of the host, but no reference is made to the effect of this drug on non-small cell-type lung cancers. The reference Teratogenesis, Carcinogenesis and Mutagenesis, vol. , pp. 477-501 (1990) discloses that some of the antimicrobial drugs may be used as an anticancer agent, but does not refer to their application to non-small cell-type lung cancers. In addition, it is known that interleukins have an antitumor effect, but they have not been reported to be effective against non-small cell-type lung cancers. It has not been reported that any of the 14- or 1-link ring macrolides is effective against non-small cell-type lung cancers. However, several chemotherapeutic agents have been shown to be effective 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 therapeutic agents active against NSCLC include cisplatin, ifosfamide, mitomycin C, epirubicin, vinblastine, and vindesine. Other agents that are under investigation for use against NSCLC include: camptothecins, a topoisomerase 1 inhibitor, navelbine (vinorelbine), an inhibitor of microtubule assembly; gemcitabine, a deoxycytidine analogue; fotemustine, a compound of the nitrosourea type; and edatrexate, an antifol. It has been shown that the overall and complete response rates for NSCLC are increased with the use of chemotherapy combination 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 COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) itosfamide, cisplatin , etoposide; 2) cyclophosphamide, doxorubicin, cisplatin; 3) isophamide, carboplatin, etoposide; 4) bleomycin, etoposide, cisplatin; 5) isofamide, mitomycin, cisplatin; 6) cisplatin, vinblastine; 7) cisplatin, vindesine; 8) mitomycin C, vinblastine, ciaplatin; 9) mitomycin C, vindesine, cisplatin; 10) isophamide, etoposide; 11) etoposide, cisplatin; 12) isofamide, mitomycin C; 13) fluorouracil, cisplatin, vinblastine; 14) carboplatin, etoposide; or radiation therapy. Therefore, in addition to the conventional concept of cancer therapy, there is a great need regarding the development of therapies that can be practiced effectively for the treatment of non-small cell-type lung cancers.

Small cell-type lung cancer Approximately 15 to 20 percent of all lung cancer cases reported worldwide are small cell-type lung cancer (SCLC). Ihde DC: Cancer 54: 2722, 1984. Currently, the treatment of SCLC incorporates multimodal therapy, including chemotherapy, radiation therapy and surgery. The response rates of localized or disseminated SCLC remain high towards systemic chemotherapy, however, the persistence of the primary tumor and the 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 COX-2 inhibitors in combination with the following antineoplastic agents: vincristine, cisplatin, carboplatin, cyclophosphamide, epirubicin (high dose), etoposide ( VP-16) intravenous, etoposide (VP-16) oral, isofamide, teniposide (VM-26) and doxorubicin. Other preferred chemotherapeutic agents that are administered alone and which could be used in the present invention include BCNU (carmustine), vindesine, hexamethylmelamine (altretamine), methotrexate, nitrogen mustard and CCNU (lomustine). Other investigational chemotherapy agents that have demonstrated activity against SCLC include iroplatin, gemcitabine, lonidamine, and taxol. Individual chemotherapy agents that have not demonstrated activity against SCLC include mitoguazone, mitomycin C, aclarubicin, diazicuone, bisantrene, cytarabin, idarubicin, mitoxantrone, vinblastine, PCNU and esorubicin. The low reported results from chemotherapy with a single agent has led to the use of combination therapy. A preferred therapy for the treatment of NSCLC is a combination of therapeutically effective amounts of one or more inhibitors. of COX-2 in combination with the following combinations of antineoplastic agents: 1) etoposide (VP-16), cisplatin; 2) cyclophosphamide, adrianmicin [(doxorubicin), vincristine, etoposide (VP-16)]; 3) cyclophosphamide, adrianmicin (doxorubicin), vincristine; 4) etoposide (VP-16), ifosfamide, cisplatin; 5) etoposide (VP-16), carboplatin; 6) cisplatin, vincristine (Oncovin), doxorubicin, etoposide. Additionally, it is contemplated that radiation therapy in conjunction with preferred combinations of COX-2 inhibitors and / or systemic chemotherapy be effective in increasing the response rate for patients with SCLC. The typical dosage regimen for radiation therapy varies from 40 to 55 Gy, in 15 to 30 fractions, 3 to 7 times per week. The volume of tissue that will be irradiated is determined by several factors and generally the hilum and the subcarnial nodules are treated, and the bilateral mediastinal nodes up to the thoracic inlet, as well as the primary tumor at a distance of up to 1.5 to 2.0 cm from the margins.

EXAMPLE 2 Colorectal cancer Survival of colorectal cancer depends on the stage and grade of the tumor, for example adenomas that are precursors to metastatic adenocarcinoma. In general, colorectal cancer can be treated by surgically removing the tumor, but overall survival rates remain between 45 and 50% The morbidity rates for the removal of the colon are quite low and are generally associated with the anastomosis and not with the degree of removal of the tumor and local tissue. In patients with elevated reoccurrence, chemotherapy has been incorporated into the treatment regimen in order to improve survival rates, it is generally believed that metastasis of the tumor before surgery is the cause of failure in the surgical procedure and requires up to one year of chemotherapy to kill the non-excised tumor cells, because the severe toxicity is associated with the chemotherapeutic agents, only patients with high risk of recurrence after surgery are placed on chemotherapy. Therefore, the incorporation of an antiangiogenesis inhibitor in the management of colorectal cancer will play an important role in the treatment of colorectal cancer and leads to improved overall 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 one or more anti-angiogenic agents including an MMP inhibitor, a COX-2 inhibitor, or an integrin antagonist, supplied in cycles over a period of one year. A more preferred combination therapy for the treatment of colorectal cancer is a regimen of one or more COX-2 inhibitors, followed by surgical removal of the colon or rectal tumor and then followed by a regimen of one or more therapeutic agents and one or more COX-2 inhibitors, supplied in cycles for a period of one year. An even more preferred therapy for the treatment of colon cancer is a combination of therapeutically effective amounts of one or more COX-2 inhibitors. A more preferred therapy for the treatment of colon cancer is a combination of therapeutically effective amounts of one or more 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 To date, among the best in the United States, breast cancer is still the cancer diagnosed most frequently. One of 8 women in the United States is at risk of developing breast cancer during their lifetime. Age, family history, diet and genetic factors have been identified as risk factors for breast cancer. Breast cancer is the second cause of death among women. Different chemotherapeutic agents for the treatment of breast cancer are known in the art. The cytotoxic agents used to treat breast cancer include doxorubicin, cyclophosphamide, methotrexate, 5-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 non-inflammatory breast cancer, COX-2 inhibitors may be used to treat the disease in combination with other COX-2 inhibitors or in combination with surgery, radiation therapy or with chemotherapeutic agents or other anti-angiogenic 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, 5-f luorouracil, vincristine, prednisone, mastectomy; 4) cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine, prednisone, radiation therapy; 5) cyclophosphamide, doxorubicin, 5-fluorouracil, premarin, tamoxifen, radiation therapy for the complete pathological response; 6) cyclophosphamide, doxorubicin, 5-fluorouracil, premarin, tamoxifen, mastectomy, radiation therapy for the partial pathological response; 7) mastectomy, radiation therapy, levamisole; 8) mastectomy, radiation therapy; 9) mastectomy, vincristine, doxorubicin, cyclophosphamide, levamisole; 10) mastectomy, vincristine, doxorubicin, cyclophosphamide; 11) mastectomy, cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen, halotestin, radiation therapy; 12) mastectomy, cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen, halotestin. In the treatment of inflammatory breast cancer locally In the advanced stage, COX-2 inhibitors can be used to treat the disease in combination with other anti-angiogenic 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 are not limited to the following combinations: cyclophosphamide, doxorubicin, 5-fluorouracil, radiation therapy; 2) cyclophosphamide, doxorubicin, 5-fluorouracil, mastectomy, radiation therapy; 3) 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine, prednisone, mastectomy, radiation therapy; 4) 5-fluorourac: ilo, doxorubicin, cyclophosphamide, vincristine, mastectomy, radiation therapy; 5) cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine, radiation therapy; 6) cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine, mastectorpia, radiation therapy; 7) doxorubicin, vincristine, methotrexate, radiation therapy, followed by vincristine, cyclophosphamide, 5-fluorouracil; 8) doxorubicin, vincristine, cyclophosphamide, methotrexate, 5-fluorouracil, radiation therapy, followed by vincristine, cyclophosphamide, 5-fluorouracil; 9) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, doxorubicin, vincristine, tamoxifen; 10) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, doxorubicin, vincristine, tamoxifen; 11) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, vincristine, tamoxifen; 12) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, doxorubicin, vincristine; 13) surgery, followed by cyclophosphamide, methotrexate, 5-f luorouracil, prednisone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, doxorubicin, vincristine, tamoxifen; 14) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, doxorubicin, vincristine; 15) surgery, followed by cyclophosphamide, methotrexate, 5-f luorouracil, prednisone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, vincristine; 16) 5-fluorouracil, doxorubicin, cyclophosphamide, followed by mastectomy, followed by 5-f luorouracil, doxorubicin, cyclophosphamide, followed by radiation therapy. In the treatment of metastatic breast cancer, COX-2 inhibitors can be used to treat the disease in combination with other artiangiogenic agents, or in combination with surgery, radiation therapy or with chemotherapeutic agents. Combinations of preferred 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) cyclophosphamide, methotrexate, 5-fluorouracil; 2) cyclophosphamide, adriamycin, 5-fluorouracil; 3) cyclophosphamide, methotrexate, 5- fluorouracil, vincristine, prednisone; 4) adriamycin, vincristine; 5) thiotepa, adriamycin, vinblastine; 6) mitomycin, vinblastine; 7) ciplatin, etoposide.

EXAMPLE 4 Prostate cancer Currently, prostate cancer is the main form of cancer among men and the second most frequent cause of cancer death in men. It is estimated that in 1993 more than 165,000 new cases of prostate cancer were diagnosed, and that more than 35,000 men died of prostate cancer in that same year. In addition, the incidence of prostate cancer has increased by 50% since 1981, and mortality from this disease continues to increase. Previously, most men died from other diseases or conditions before dying from their prostate cancer. Now we are facing an increase in morbidity from prostate cancer because men live longer and the disease has the opportunity to progress. Current therapies for prostate cancer focus exclusively on reducing dihydrotestosterone levels to reduce or prevent the growth of prostate cancer. In addition to the use of digital rectal evaluation and transrectal ultrasonography, the concentration of prostate-specific antigen (PSA) is often 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 COX-2 inhibitors. The patent E.U.A. No. 4,472,382 describes the treatment of benign prostatic hyperplasia (BPH) with an antiandrogen and with certain peptides that act as LH-RH agonists. The patent E.U.A. No. 4,596,797 discloses aromatase inhibitors as a prophylactic and / or treatment method of prostatic hyperplasia. The patent E.U.A. No. 4,760,053 discloses a treatment of certain types of cancer which combines an LHRH agonist with an antiandrogen and / or an antiestrogen and / or at least one inhibitor of sex steroid biosynthesis. The patent E.U.A. No. 4,775,660 discloses a method for treating breast cancer with a combination therapy which could include the surgical or chemical prevention of ovarian secretions and the administration of an anti-androgen compound and an anti-estrogen compound. The patent E.U.A. No. 4, 659,695 discloses a method of treatment for prostate cancer in susceptible male animals including humans whose testicular hormone secretions are blocked by surgical or chemical means, for example using an LHRH agonist, which comprises administering an antiandrogen compound, by example, flutamide, in association with at least one inhibitor of the biosynthesis of the sex hormones, for example aminoglutethimide and / or ketoconazole.

Prostate Specific Antigen A well-known prostate cancer marker is Prostate Specific Antigen (PSA). PSA is a protein produced by prostate cells and is often present at elevated levels in the blood of men suffering from prostate cancer. It has been shown that PSA correlates with the burden of the tumor, serves as an indicator of metastatic involvement and provides a parameter to follow the response to surgery, radiation therapy and androgen replacement therapy in patients They have prostate cancer. It should be noted that the Prostate Specific Antigen (PSA) is a protein completely different from the 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 In 1993, molecular cloning of a prostate-specific membrane antigen (PSMA) was reported as a potential marker of prostate carcinoma and it was hypothesized that it would serve as a target for imaging modalities and cytotoxic treatment for prostate cancer. Antibodies to PSMA have been described and have been clinically examined for the diagnosis and treatment of cancer. prostate. In particular, lndium-111-labeled anti-PSMA antibodies have been described and tested for the diagnosis of prostate cancer, and antibodies against PSA-labeled PSMA have been described and tested for the treatment of prostate cancer.

EXAMPLE 5 The classification of bladder cancer is divided into three main classes: 1) superficial disease, 2) diseases that invade the muscle and 3) metastatic disease. Currently, transurethral resection (TUR), or segment resection, counts as a first-line therapy for superficial bladder cancer, that is, disease confined to the mucosa or lamina propria. However, intravesicular therapies are necessary, for example, for the treatment of high grade tumors, carcinoma in situ, incomplete resections, recurrences and papillary of multiple foci. Recurrence rates vary up to 30 to 80 percent, depending on the stage of the cancer. The therapies that are currently used as intravesicular therapies include chemotherapy, immunotherapy, Bacille-Calmette-Guerin therapy (BCG) and photodynamic therapy. The main objective of intravesicular therapy is a double objective: to avoid recurrence in patients at high risk and to treat the disease that can not be resected. The use of Intravesicular therapies should be balanced with its potentially toxic side effects. In addition, BCG requires an immune system that is not damaged to induce an antitumor effect. Chemotherapeutic agents known to be not active against superficial bladder cancer include cisplatin, actinomycin D, 5-fluorouracil, bleomycin, and cyclophosphamide methotrexate. In the treatment of superficial cancer of the bladder, COX-2 inhibitors can be used to treat the disease in combination with other COX-2 inhibitors or in combination with surgery (TUR), chemotherapy and intravesicular therapies. A preferred therapy for the treatment of superficial bladder cancer is a combination of therapeutically effective amounts of one or more COX-2 inhibitors in combination with: thiotepa (30 to 60 mg / day), mitomycin C (20 to 60 mg / day). day) and doxorubicin (20 to 80 mg / day). A preferred intravesical immunotherapeutic agent that could be used in the present invention is BCG. A preferred daily dose ranges from 60 to 120 mg, depending on the strain of live, attenuated tuberculosis that is used. A preferred photodynamic therapeutic agent that could be used with the present invention is Photofrin I, a photosensitizing agent, administered intravenously. This is captured by the low density lipoprotein receptors of the tumor cells and is activated by means of exposure to visible light. Additionally, YAG laser activation of neodymium generates large amounts of free radicals and oxygen in cytotoxic singlet. In the treatment of muscle-invasive bladder cancer, COX-2 inhibitors can be used to treat the disease in combination with other COX-2 inhibitors, or in combination with surgery (TUR), intravesicular chemotherapy, radiation therapy, and cystectomy. radical with lymph node dissection of the pelvis. A preferred radiation dose for the treatment of vejigg cancer is between 5,000 and 7,000 cGy in fractions of 180 to 200 cGy for the tumor. In addition, a total dose of 3,500 to 4,700 cGy 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 could be considered as a pre-operation therapy. A combination of surgery and preferred chemotherapeutic agents that can be used in combination with the COX-2 inhibitors of the present invention is cystectomy together with five cycles of cisplatin (70 to 100 mg / m2); doxorubicin (50 to 60 mg / m2) and cyclophosphamide (500 to 600 mg / m2). A more preferred therapy for the treatment of superficial cancer of the bladder is a combination of therapeutically effective amounts of one or more COX-2 inhibitors. An even more preferred combination for the treatment of superficial cancer of the bladder is a combination of therapeutically effective amounts of one or more COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubioin, cyclophosphamide, and 2) cisplatin, 5-fluorouracil. An even more preferred combination of chemotherapeutic agents that can be used in combination with radiation therapy and with COX-2 inhibitors is a combination of cisplatin, methotrexate, vinblastine. Currently there is no curative therapy for bladder metastatic cancer. The present invention contemplates an effective treatment of bladder cancer that leads to improved inhibition or regression of the tumor, compared to current therapies. In the treatment of metastatic cancer of the bladder, COX-2 inhibitors can be used to treat the disease in combination with other emtiangiogenic agents, or in combination with surgery, radiation therapy or with chemotherapeutic agents. A preferred therapy for the treatment of metastatic cancer of the bladder is a combination of therapeutically effective amounts of one or more COX-2 inhibitors. A more preferred combination for the treatment of metastatic cancer or of the bladder is a combination of therapeutically effective amounts of one or more COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) cisplatin and methotrexate; 2) doxorubicin, vinblastine, cyclophosphamide and 5-fluorouracil; 3) vinblastine, doxorubicin, cisplatin, methotrexate; 4) vinblastine, cisplatin, methotrexate; 5) cyclophosphamide, doxorubicin, cisplatin; 6) 5-fluorouracil, cisplatin.

EXAMPLE 6 Pancreatic cancer Approximately 2% of diagnoses of new cases of cancer in the United States is pancreatic cancer. Pancreatic cancer is usually classified into two clinical types: 1) adenocarcinoma (metastatic and non-metastatic), and 2) cystic neoplasms (serous cystadenomas, mucinous cystic neoplasms, papillary cystic neoplasms, acinar cell sistadnocarcinoma, cystic choriocarcinoma, teratomas) cystic, angiomatous neoplasms). Preferred combinations of therapy for the treatment of non-metastatic adenocarcinoma that could be used in the present invention include the use of a COX-2 inhibitor in conjunction with decompression of the biliary tract prior to operation (in patients presenting with obstructive jaundice); surgical reaction, including standard resection, extended or radial resection and distal pancreotomy (body and end tumors); auxiliary radiation; anti-angiogenic therapy and chemotherapy. For the treatment of metastatic adenocarcinoma, a preferred combination therapy consists of a COX-2 inhibitor of the present invention in combination with the continuous treatment of 5-fluorouracil, followed by weekly cisplatin therapy. A more preferred combination therapy for the treatment of cystic neoplasms is the use of a COX-2 inhibitor in conjunction with resection.

EXAMPLE 7 Ovarian cancer Coelomic epithelial carcinoma accounts for almost 90% of cases of ovarian cancer. A preferred therapy for the treatment of ovarian cancer is a combination of therapeutically effective amounts of one or more COX-2 inhibitors. Preferred single agents that can be used in combination with a COX-2 inhibitor include, but are not limited to: alkylating agents, ifosfamide, cisplatin, carboplatin, taxol, doxorubicin, 5-fluorouracil, methotrexate, mitomycin, hexamethylmelamine, progestins, antiestrogens, prednimustine, dihydroxyibusulfan, galactitol, interferon alfa and interferon gamma. Preferred combinations for the treatment of coelomic epithelial carcinoma is a combination of therapeutically effective amounts of one or more COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2) hexamethylmelamine, cyclophosphamide, doxorubicin, cisplatin; 3) cyclophosphamide, hexemethylmelamine, 5-fluorouracil, 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; 10) hexamethylmelamine, doxorubicin, carboplatin; 11) cyclophosphamide, hexamethylnelamine, doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide. Germ cell ovarian cancer is responsible for approximately 5% of ovarian cancer cases. Germ cell ovarian carcinomas are classified into two main groups: 1) dysgerminoma and non-dysgerminoma. The non-dysgerminoma is then 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 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 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. Fallopian tube cancer is the least common type of ovarian cancer, accounting for about 400 new cases of cancer per year in the United States. Serous papillary adenocarcinoma is responsible for approximately 90% of all malignant tumors 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 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 COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) alkylating agents, ifosfamide, cisplatin, carboplatin , taxol, doxorubicin, 5-fluorouracil, methotrexate, mitomycin, hexamethylmelamine, progestins, antiestrogens prednimustine, dihydroxibusulfan, galactitol, interferon alpha and interferon gamma. An even more preferred therapy for the treatment of fallopian tube cancer is a combination of therapeutically effective amounts of one or more COX-2 inhibitors in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2) hexamethylmelamine, cyclophosphamide, doxorubicin, cisplatin; 3) cyclophosphamide, hexamethylmelamine, 5-fluorouracil, cisplatin; 4) melphalan, hexamethylrnelamine, cyclophosphamide; 5) melphalan, doxorubicin, cyclophosphamide; 6) cyclophosphamide, cisplatin, carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine, cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylrnelamine, carboplatin; 9) cyclophosphamide, cisplatin; 10) hexamethylmelamine, doxorubicin, carboplatin; 11) cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide.

EXAMPLE 8 Central Nervous System Cancers Central nervous system cancer is responsible for approximately 2% of new cases of cancer in the United States. Common intracranial neoplasms include glioma, meningioma, 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 COX-2 inhibitors. A preferred therapy for the treatment of malignant glioma is a combination of therapeutically effective amounts of one or more COX-2 inhibitors in combination with the following combinations of therapies and antineoplastic agents: 1) radiation therapy, BCNU (carmustine); 2) radiation therapy, methyl UACN (lomustine); 3) radiation therapy, medol; 4) radiation therapy, procarbazine; 5) radiation therapy, BCNU, medrol; 6) therapy with radiation hyperfraction, BCNU; 7) radiation therapy, misopide2: ol, BCNU; 8) radiation therapy, streptozotocin; 9) radiation therapy, BCNU, procarbazine; 10) radiation therapy, BCNU, hydroxyurea, procarba2: ina, VM-26; 11) radiation therapy, BCNU, 5-fluorouracil; 12) radiation therapy, methyl CCNU, dacarbazine; 13) radiation therapy, misonida2: ol, BCNU; 14) diazicuone; 15) radiation therapy, PCNU; 16) procarbazine (matulane), CCNU, vincristine. A preferred dose of therapy with radiation is from about 5,500 to 6,000 cGy. Preferred radiosensitizers include misonidazole, intraarterial Budr and intravenous iododeoxyuridine (lUdR). It is also contemplated that rasio surgery could be used in combinations with antiangiogenesis agents.

EXAMPLE 9 Table 19 lists additional examples of combinations.

TABLE No. 19 Examples of combination therapy COX-2 inhibitor Antineoplastic agents Indication Celecoxib Anastrozole Breast Celecoxib Capecitabine Breast Celecoxib Docetaxel Breast Celecoxib Gemcitabine Breast, pancreas Celecoxib Letrozole Mama Celecoxib Megestrol Mama TABLE No. 19 (cont.) Celecox b Paclitaxel Mama Celecoxib Tamoxifen Mama Celecoxib Toremifene Breast Celecoxib Vinorelbine Breast, lung Celecoxib Topotecan Lung Celecoxib Etoposide Lung Celecoxib Fluorouracil Colon Celecoxib lrinotecan (CPT-11) Colon, bladder Celecoxib Retinoids Colon Celecoxium DFMO Colon Celecoxib Ursodeoxycholic acid Colon Celecoxib Calcium carbonate Colon Celecoxib Selenium Colon Celecoxib Sulfone sulindaco Colon Celecoxib Carboplatin Brain Celßcoxib Goselerin Acetate Prostate Celecoxib Cisplatin Celecoxib ketoconazole Prostate Rofecoxib Anastrozole Mama Rofecoxib Capecitabine Breast TABLE No. 19 (cont.) Rofecoxib Docetaxel Mama Rofecoxib Gemcitabine Breast, pancreas Rofecoxib Letrozole Breast Rofecoxib Megestrol Breast Rofecoxib Paclitaxel Breast Rofecoxib Tamoxifen Breast Rofecoxib Toremifene Breast Rofecoxifc Vinorelbine Breast, lung Rofecoxib Topotecan Lung Rofecoxib Etoposide Lung Rofecoxib Fluorouracil Colon Rofecoxib lrinotecano (CPT-11) Colon, bladder Celecoxib Retinoids Colon Celecoxib DFMO Colon Celecoxib Ursodeoxycholic acid Colon Celeeoxib Calcium carbonate Colon Celecoxib Selenium Colon Celecoxib Sulindac sulfate Colon Rofecoxib Carboplatin Brain Rofecoxib Goselerin acetate Prostate TABLE No. 19 (cont.) Rofecoxib -Cisplattna Rofecoxib Ketoconazole Prostate JTE-522 Anastrozole Breast JTE-522 Capecitabine Breast JTE-522 Docetaxel Breast JTE-522 Gemcitabine Breast, pancreas JTE-522 Breast Letrozole JTE-522 Megestrol Breast JTE-522 Paclitaxel Breast JTE-522 Breast Tamoxifen JTE-522 Breast Toremifene JTE-522 Breast Vinorelbine, Lung JTE-522 Topotecan Lung JTE-522 Etoster Lung JTE-522 Fluorouracil Colon JTE-522 Irinotecan (CPT-11) Colon, bladder Celecoxib Retinoids Colon Celecoxib DFMO Colon Celecoxib Ursodeoxycholic acid Colon Celecoxib Calcium carbonate Colon Celecoxib Selenium Colon Celecoxib Sulfone sulindaco Colon JTE-522 Brain Carboplatin JTE-522 Prostate goserelin acetate JTE-522 Cisplatina JTE-522 Ketoconazole Prostate Table 20 lists additional examples of combinations.

TABLE No. 20 Examples of combination therapy COX-2 inhibitor Antineoplastic agents Indication Celecoxib Doxorubicin and Mama cyclophosphamide Celecoxib Cyclophosphamide, Mama doxorubicin and fluorouracil Celecoxib Cyclophosphamide, Mama fluorouracil and mitoxantrone Celecoxib Mitoxantrone, Fluorouracil Mama and leucovorin TABLE No. 20 (contd) Celecoxib Vinblastine, doxorubicin, Mama tistepa and fluoximestrsna Celecoxrb Cyclophosphamide, Mama methotrexate, Fluorouracil Celecoxib Doxorubicin, Mama cyclophosphamide, Methotrexate, Fluorouracil Celecoxib Vinblastine, Doxorubicin, Mama thiotepa, Fluoximestrone Celecoxib Fluorouracil, Levamisole Colon Celecoxib Leucovorin, fluorouracil Colon Celecoxib Cyclophosphamide, Lung doxorubicin, etoposide Celecoxib Cyclophosphamide, Lung doxorubicin, vipcristin Celecoxib Etoposide, Carboplatin Lung Celecoxib Etoposide, cisplatin Lung Celecoxib Paclitaxel, Carboplatin Lung Celecoxib Gemcitabine, cisplatin Lung- Celepoxib Paclitaxel, cisplatin Lung Rofecoxib Doxorubicin and Mama cyclophosphamide Rofecoxib Cyclophosphamide, Mama doxorubicin and fluorouracil Rofecoxib Cyclophosphamide, Fluorouracil Breast and mitoxantrone rofecoxib Mitoxantrone, Fluorouracil Breast and leucovoruina Rofecoxib Vinblastine, Doxorubicin, Breast Thiotepa and fluoxymestrone Rofecoxib Cyclophosphamide, Breast Methotrexate, Fluorouracil Rofecoxib Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorouracil Rofecoxib Vinblastine, Doxorubicin, Breast Thiotepa, fluoxymestrone epoxy Rof b Fluorouracil, levamisole Colon Rofecoxib Leucovorin, fluorouracil Colon Rofecoxib Cyclophosphamide, Lung doxorubicin, etoposide Rofecoxib Cyclophosphamide, Lung doxorubicin, Vincristine Rofecoxib Etoposide, Carboplatin Lung Rofecoxib Etoposide, cisplatin Lung Rofecoxib Paclitaxel, Carboplatin Lung Rofecoxib Gemcitabine, cisplatin Lung Rofecoxib Paclitaxel, cisplatin lung JTE.522 Doxorubicin and Mama cyclophosphamide JTEr522 Cyclophosphamide, Mama doxorubicin and fluorouracil JTE-522 Cyclophosphamide, Mama fluorouracil and mitoxantrone JTE-522 Mitoxantrone, Fluorouracil Mama and leucovorin JTE-522 Vinblastine, Doxorubicin, Mama thiotepa and fluoximestrone JTE-522 Cyclophosphamide, Mama methotrexate , fluorouracil JTE-522 Doxorubicin, Mama cyclophosphamide, methotrexate, fluorouracil JTE-522 Vinblastine, doxorubicin, Mama thiotepa, fluoximestrone JTE-522 Fluorouracil, Levamisole Colon JTE-522 Leucovorin, fluorouracil Colon JTE-522 Cyclophosphamide, Lung doxorubicin, etoposide JTE-522 Cyclophosphamide, Lung doxorubicrna, Vincristine JTE-522 Etoposide, Carboplatin Lung JTE-5 2 Etoposide, cisplatin Lung JTE-522 Paclitaxel, Carboplatin Lung JTE-522 Gemcitabine, cisplatin Lung JTE-522 Paclitaxel, cisplatin Lung BIOLOGICAL EVALUATION COX-2 inhibitors 1. Lewis lung model Mice were injected subcutaneously into the left paw (1 x 106 tumor cells suspended in 30% Matrigel) and the tumor volume was evaluated using a phletismometer twice a week for a period of 30-60 days. Blood was drawn twice during the experiment in a 24-hour protocol to determine the plasma concentration and total exposure by ABC analysis (area under the curve). The data is expressed as the average +/- SEM. The Student and Mann-Whitney tests were used to evaluate the differences between means using the InStat software package. Celecoxib administered in the diet at doses between 160-3200 ppm delayed the growth of these tumors. The inhibitory effect of celecoxib was dose dependent and ranged from 48% to 85% compared to control tumors. The analysis of lung metastasis was performed in all the animals counting the metastasis in a stereomicroscope and by histochemical analysis: or of consecutive sections of the lung. Celecoxib did not affect the lung metastasis at the lowest dose of 160 ppm, however surface metastasis was reduced by more than 50% when administered at doses between 480-3,200 pprn. In addition, histopathological analysis revealed that celecoxib in a dose-dependent manner reduced the size of metastatic lesions in the lung. 2. Model HT-29 Mice were injected subcutaneously into the left paw (1 x 106 tumor cells suspended in 30% Matrigel) and the tumor volume was evaluated using a phletismometer twice a week for a period of 30-60 days . The implantation of human colon cancer cells (HT-29) in mice without hair produces tumors that will reach 0.6 to 2 ml in a period between 30 and 50 days. Blood was drawn twice during the experiment in a 24-hour protocol to determine the plasma concentration and total exposure by ABC analysis (area under the curve). The data is expressed as the average +/- SEM. The Student and Mann-Whitney tests were used to evaluate the differences between means using the InStat software package. A. Mice injected with HT-29 cancer cells were treated with cytoxine intraperitoneally 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 was determined by measuring the volume of the tumor. Treatment using a COX-2 inhibitor related to celecoxib (SC-58236) reduced tumor volume in a 89% In the same test, indomethacin administered almost at the maximum tolerated dose of 2 mg / kg / day in drinking water inhibited tumor formation by 77%. In addition, the selective inhibitor of COX-2 completely inhibited the formation of lung metastases while the non-selective NSAID indomethacin was not effective. The results from these studies show that celecoxib administered in the diet for mice with tumors can delay the growth and metastasis of the tumors when administered as the only therapy. In addition, a positive benefit was observed when celecoxib was administered in combination with a cytotoxic agent such as cyclophosphamide. B. In a second test, mice injected with cancer HT-29 cells were treated with 5-FU on days 12 to 15. Mice injected with cancer HT-29 cells were treated with 5-FU intraperitoneally to dose of 50 m? i / kg on days 12, 13, 14 and 15 in the presence or absence of celecoxib in the diet. The efficacy of both agents was determined by measuring the volume of the tumor. The treatment using celecoxib reduced the volume of the tumor by 68%. In the same test, 5-FU reduced the volume of the tumor by 61%. In addition, the combination of celecoxib and 5-FU reduced the volume of the tumor by 83%. O In a third test, mice injected with HT-29 colon cancer cells were treated with 5-FU intraperitoneally at a dose of 50 mg / kg on days 14 to 17 in the presence or absence of celecoxib (1, 600 ppm) and valdecoxib (160 ppm) in the diet. The effectiveness of both agents was determined measuring the volume of the tumor. Treatment with 5-FU resulted in a 35% reduction in tumor volume. Treatment with celecoxib and valdecoxib reduced tumor volume by 52% and 69%, respectively. In the same trial, the combination of 5-FU and celecoxib reduced tumor volume by 72% while the combination of 5-FU and valdecoxib reduced tumor volume by 74% (Table 21).

TABLE No. 21 Effect of celecoxib and valdecoxib alone and in combination with 5-fluorouracil on tumor volume TABLE No. 21 (cont.) Volume (ml) D. In a fourth trial, mice injected with HT-29 colon cancer cells were treated with celecoxib (10, 40 or 160 ppm) in the diet starting on day 10. An approximate dose-dependent effect was observed. (Table No. 22).

TABLE No. 22 Celecoxib inhibits human colon HT-29 carcinoma Volume (ml) It is noted that in relation to this date, the best known method known to the applicant to carry out the aforementioned invention, is that which results from the present description of the invention.

Claims (103)

1. CLAIMS Having described the invention as above, the claim contained in the following claims is claimed as property: 1. A method for treating or preventing a neoplasm disorder in a mammal that requires said treatment or prevention, which comprises administering a therapeutically amount to the mammal. effective of a combination of a cyclooxygenase-2 inhibitor and one or more antineoplastic agents, characterized in that the antineoplastic agents are selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cellular Pathways CP-461, docetaxel, doxorubicin, etoposide, fluoximestrin, gemcitabine, goserelin, irinotecan, ketoconazole, letrozole, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, relinotic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorrelbine, vinblastine, vincristine, (selenomethionine) selenium Sulindac sulphone and eflornithine (DFMO).
2. 2. The method according to claim 1, characterized in that the combination is administered in a sequential manner.
3. 3. The method according to claim 1, characterized in that the combination is administered in a substantially simultaneous manner.
4. 4. The method according to claim 1, characterized in that the antineoplastic agent is capecitabine.
5. 5. The method according to claim 1, characterized in that the antineoplastic agent is carboplatin.
6. 6. The method according to claim 1, characterized in that the antineoplastic agent is cisplatin.
7. The method according to claim 1, characterized in that the antineoplastic agent is Cellular Routes CP-461.
8. 8. The method according to claim 1, characterized in that the antineoplastic agent is docetaxel.
9. 9. The method according to claim 1, characterized in that the antineoplastic agent is doxorubicin.
10. 10. The method according to claim 1, characterized in that the antineoplastic agent is etoposide.
11. 11. The method according to claim 1, characterized in that the antineoplastic agent is fluoximestrin.
12. 12. The method according to claim 1, characterized in that the antineoplastic agent is gemcitabine.
13. 13. The method according to claim 1, characterized in that the antineoplastic agent is goserelin.
14. 14. The method according to claim 1, characterized in that the antineoplastic agent is irinotecan.
15. 15. The method according to claim 1, characterized in that the antineoplastic agent is ketoconazole.
16. 16. The method according to claim 1, characterized because the antineoplastic agent is letrozole.
17. 17. The method according to claim 1, characterized in that the antineoplastic agent is leucovorin.
18. 18. The method according to claim 1, characterized in that the antineoplastic agent is levamisole.
19. 19. The method according to claim 1, characterized in that the antineoplastic agent is megestrol.
20. 20. The method according to claim 1, characterized in that the antineoplastic agent is mitoxantrone.
21. 21. The method according to claim 1, characterized in that the antineoplastic agent is paclitaxel.
22. 22. The method according to claim 1, characterized in that the antineoplastic agent is raloxifene.
23. 23. The method according to claim 1, characterized in that the antineoplastic agent is retinoic acid.
24. 24. The method according to claim 1, characterized in that the antineoplastic agent is tamoxifen.
25. 25. The method according to claim 1, characterized in that the antineoplastic agent is thiotepa.
26. 26. The method according to claim 1, characterized in that the antineoplastic agent is topotecan.
27. 27. The method according to claim 1, characterized in that the antineoplastic eigent is toremifene.
28. 28. The method according to claim 1, characterized in that the antineoplastic agent is vinorrelbine.
29. 29. The method according to claim 1, characterized in that the antineoplastic agent is vinblastine.
30. 30. The method according to claim 1, characterized in that the antineoplastic agent is vincristine.
31. 31. The method according to claim 1, characterized in that the antineoplastic agent is selenium (selenomethionine).
32. 32. The method according to claim 1, characterized in that the antineoplastic agent is sulindac sulphone.
33. 33. The method according to claim 1, characterized in that the antineoplastic agent is eflornithine (DFMO).
34. 34. The method according to claim 1, characterized in that the cyclooxygenase 2 inhibitor is selected from compounds, and pharmaceutically acceptable salts thereof, of the group consisting of: D JTE-522, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide; 2) 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine; 3) 2- (3,5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one; 4) 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1-yl] -benzenesulfonamide; 5) rofecoxib, 4- (4- (methylsulfonyl) phenyl) -3-phenyl-2 (5H) furanone 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide; 7) N - [[4- (5-methyl-3-phenylisoxazol-4-yl] phenyl] sulfonyl] propanamide; 4- [5- (4-chlorof in i I) -3- (trifluoromethyl I) -1 H-pyrazol-1-yl] benzenesulfonamide; 9) 10) eleven ) 6 - [[5- (4-chlorobenzoyl) -1,4-dimethyl-1 H -pyrrol-2-yl] methyl] -3 (2 H) -pyridazinone; 12) N- (4-nitro-2-phenoxyphenyl) metasulfonamide; 13) 14) 3- (3,4-difluorophenoxy) -5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone; fifteen) N- [6 - [(2,4-difluorophenyl) thio] -2,3-dihydro-1 -oxo-1 H-inden-5-yl] methanesulfonamide; 16) 3- (4-chlorophenyl) -4- [4- (methylsulfonyl) phenyl] -2 (3H) -oxazolone; 17) - [3- (4-fluorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; 8) - [4- (methylsulfonyl) phenyl] -2-phenyl-2-cyclopenten-1-one; 9) - (2-methyl-4-phenyl-5-oxaxolyl) benzenesulfonamide; 0) - (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (3H) -oxazolone; 1 ) - (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 2) - [5-phenyl] -3- (trifluoromethyl) -1 H -pyrazol-1-yl) benzenesulfonamide;

    2. 3) 4- [1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 24) 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yljbenzenesulfonamide; 25) 2i: N- [2 - (- cyclohexyloxy) -4-nitrophenyl] methanesulfonamide; 26) N- [6- (2,4-difluorophenoxy) -2,3-dihydro-1-oxo-1 H -inden-5-yl] methanesulfonamide; 27) 3- (4-chlorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; 28) 3- (4-fluorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; 29) 3 - [(1-methyl-1 H-imidazol-2-yl) thio] -4 [(methylsulfonyl) amino] -benzenesulfonamide; 30) 5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -3-phenoxy-2 (5H) -furanone; 31) N- [6 - [(4-ethyl-2-thiazolyl) thio] -1,3-dihydro-1-oxo-5-isobenzofuranyl] -methanesulfonamide; 32) 3 - [(2,4-dichlorophenyl) thio] -4 - [(methylsulfonyl) amino] benzenesulfonamide; 33) 1-fluoro-4- [2- [4- (methylsulfonyl) phenyl] cyclopenten-1-yl] benzene; 3. 4) 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 35) 3- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazol-2-yl] pyridine; 36) 4- [2- (3-pyridinyl) -4- (trifluoromethyl) -1 H -imidazol-1-yl] benzenesulfonamide; 37) 4- [5- (hydroxymethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; 38) 4- [3- (4-chlorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; 39) 4- [5- (difluoromethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; 40) [1, 1 ': 2 \ 1"-terphenylH-sulfonamide; 41) 4- (methylsulfonyl) -1, 1 ', 2], 1"-terphenyl; 2) - (2-phenyl-3-pyridinyl) benzenesulfonamide; 43) N- (2,3-dihydro-1,1-dioxide-6-phenoxy-1,2-benzisothiazol-5-yl) methanesulfonamide; Y 44) N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] methanesulfonamide; Four. Five) 46) 47) 10 48)
35. 35. The method according to claim 1, characterized in that the cyclooxygenase 2 inhibitor is 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine.
36. 36. The method according to claim 1, characterized in that the cyclooxygenase 2 inhibitor is 2- (3,5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one.
37. 37. The method according to claim 1, characterized in that the cyclooxygenase 2 inhibitor is 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1-yl] -benzenesulfonamide.
38. 38. The method according to claim 1 characterized in that the cyclooxygenase 2 inhibitor is rofecoxib, 4- (4- (methylsulfonyl) phenyl] -3-phenyl-2- (5H) -furanone
39. 39. The method according to claim 1, characterized in that the cyclooxygenase-2 inhibitor is 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesufonamide.
40. 40. The method according to claim 1, characterized in that the cyclooxygenase 2 inhibitor is N - [[4- (5-methyl-3-phenylisoxazol-4-yl] phenyl] sulfonyl] propanamide
41. 41. The method according to claim 1, characterized in that the cyclooxygenase 2 inhibitor is 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1 H) -pyrazol-1-yl] benzenesulfonamide.
42. 42. The method according to claim 1, characterized in that the neoplasm is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.
43. 43. The method according to claim 1, characterized in that the neoplasm is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cystic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, Bartholin's gland carcinoma , basal cell carcinoma, carcinoma of the bronchial gland, capillary, carcinoid, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, condosarcoma, papilloma / carcinoma of the chorioid plexus, 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,? ilioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo malignant melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal carcinoma, mesothelial carcinoma, mucoepidermoid carcinoma, neuroblastoma, nodular melanoma due to neuroepithelial adenocarcinoma, oat cell cell carcinoma, oligodendroglial osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, carcinoma of renal cell, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin secreting tumor, squamous cell carcinoma, squamous cell carcinoma, submesothelial superficial melanoma, undifferentiated cinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma and Wilm's tumor.
44. 44. A method for treating or preventing a neoplasia disorder in a mammal that requires such treatment or prevention, which comprises administering to the mammal a therapeutically effective amount of a combination of radiation therapy, a cyclooxygenase-2 inhibitor and one or more antineoplastic agents, characterized in that the antineoplastic agents are selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, CP-461 cell lines, docetaxel, doxorubicin, etoposide, fluoximestrin, gemcitabine, goserelin, irinotecan, ketoconeizol, letrozole, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinrelrelbine, vinblastine, vincristine, (selenomethionine) selenium, sulfone sulindac and eflornithine (DFMO).
45. 45. The method according to claim 44, characterized in that the neoplasm is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cystic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, Bartholin's gland carcinoma , basal cell carcinoma, carcinoma of the bronchial gland, capillary, carcinoid, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, condosarcoma, papilloma / carcinoma of the chorioid plexus, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma , endometrioid adenocarcinoma, ependymal, epitheloid, Ewing sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasia, neopla interspithelial squamous cell disease, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo malignant melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal carcinoma, mesothelial carcinoma, mucoepidermoid carcinoma, neuroblastoma, nodular melanoma due to adenocarcinoma neuroepithelial, cell carcinoma in oat grain, 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 secretory tumor, squamous cell carcinoma, squamous cell carcinoma, melanoma of superficial submesodal dissemination, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma and Wilm's tumor.
46. 46. The method according to claim 44, characterized in that the cyclooxygenase 2 inhibitor is selected from compounds, and the pharmaceutically acceptable salts thereof, of the group consisting of: 1) JTE-522, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenz: ensulfonamide; 2) 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine; 3) 2- (3,5-diftuorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one; 4) 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1-yl] -benzenesulionamide; 5) rofecoxib, 4- (4- (methylsulfonyl) phenyl) -3-phenyl-2 (5H) furanone 6) 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide; 7) N - [[4- (5-methyl-3-phenylisoxazol-4-yl] phenyl] sulfonyl] propanamide; 8) 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 9) 10) eleven) 6 - [[5- (4-Chlorobenzoyl) -1,4-dimethyl-1 H -pyrrol-2-yl] methyl] -3 (2 H) -pyridazinora; 12) N- (4-nitro-2-phenoxyphenyl) metasulfonamide; 13) 14) 3- (3,4-difluorophenoxy) -5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone fifteen) N- [6 - [(2,4-difluorophenyl) thio] -2,3-dihydro-1 -oxo-1 H-inden-5-yl] methanesulfonamide; 16) 3- (4-chlorophenyl) -4- [4- (methylsulfonyl) phenyl] -2 (3H) -oxazolone; 17) - [3- (4-fluorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; 8) - [4- (methylsulfonyl) phenyl] -2-phenyl-2-cyclopenten-1-one; 9) - (2-methyl-4-phenyl-5-oxaxolyl) benzenesulfonamide; 0) - (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (3H) -oxazolone; 1 ) - (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 2) - [5-phenyl] -3- (trifluoromethyl) -1 H -pyrazol-1-yl) benzenesulfonamide;

    2. 3) 4- [1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 24) 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 25) N- [2 - (- cyclohexyloxy) -4-nitrophenyl] methanesulfonamide; 26) N- [6- (2,4-difluorophenoxy) -2,3-dihydro-1-oxo-1 H -inden-5-yl] methanesulfonamide; 27) 3- (4-chlorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; 28) 3- (4-fluorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; 29) 3 - [(1-methyl-1 H-imidazol-2-yl) thio] -4 [(methylsulfonyl) amino] -benzenesulfonamide; 30) 5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -3-phenoxy-2 (5H) -furanone; 31) N- [6 - [(4-ethyl-2-thiazolyl) thio] -1,3-dihydro-1-oxo-5-isobenzofuranyl] -methanesulfonamide; 32) 3 - [(2,4-dichlorophenyl) thio] -4 - [(methylsulfonyl) amino] benzenesulfonamide; 33) 1-fluoro-4- [2- [4- (methylsulfonyl) phenyl] cyclopenten-1-yl] benzene; 3. 4) 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1 H -pyrazol-1-yljbenzenesulfonamide; 35) 3- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazol-2-yl] pyridine; 36) 4- [2- (3-pyridinyl) -4- (trifluoromethyl) -1 H -imidazol-1-ylbenzenesulfonamide; 37) 4- [5- (hydroxymethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; 38) 4- [3- (4-chlorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; 39) 4- [5- (difluoromethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; 40) [1, r: 2, 1"-terphenyl] -4-sulfonamide; 41) - (methylsulfonyl) -1, 1 ', 2], 1"-terphenyl; 2) - (2-phenyl-3-pyridinyl) benzenesulfonamide; 43) N- (2,3-dihydro-1,1-dioxido-6-phenoxy-1,2-benzisothiazol-5-yl) methanesulfonamide; Y 44) N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] methanesulfonamide; Four. Five) 46) 47) 10 48)
47. 47. The method according to claim 44, characterized in that the cyclooxygenase 2 inhibitor is 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine.
48. 48. The method according to claim 44, characterized in that the cyclooxygenase 2 inhibitor is 2- (3,5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one.
49. 49. The method according to claim 44, characterized in that the cyclooxygenase 2 inhibitor is 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1-yl] -benzenesulfonamide.
50. 50. The method according to claim 44, characterized in that the cyclooxygenase 2 inhibitor is rofecoxib, 4- (4- (methylsulfonyl) phenyl] -3-phenyl-2- (5H) -furanone
51. 51. The method according to claim 44, characterized in that the cyclooxygenase-2 inhibitor is 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesufonamide.
52. 52. The method according to claim 44, characterized in that the cyclooxygenase-2 inhibitor is N - [[4- (5-methyl-3-phenylisoxazol-4-yl] phenyl] sulfonyl] propanamide
53. 53. The method according to Claim 44, characterized in that the cyclooxygenase 2 inhibitor is 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1 H) -pyrazol-1-IJ-benzenesulfonamide.
54. 54. The method according to claim 44, characterized in that the antineoplastic agent is anastrozole.
55. 55. The method according to claim 44, characterized in that the antineoplastic agent is calcium carbonate.
56. 56. The method according to claim 44, characterized in that the antineoplastic agent is capecitabine.
57. 57. The method according to claim 44, characterized in that the antineoplastic agent is carboplatin.
58. 58. The method according to claim 44, characterized in that the antineoplastic agent is cisplatin.
59. 59. The method according to claim 44, characterized in that the antineoplastic agent is Cellular Routes CP-461.
60. 60. The method according to claim 44, characterized in that the antineoplastic agent is cyclophosphamide.
61. 61. The method according to claim 44, characterized in that the antineoplastic agent is docetaxel.
62. 62. The method according to claim 44, characterized in that the antineoplastic agent is doxorubicin.
63. 63. The method according to claim 44, characterized in that the antineoplastic agent is etoposide.
64. 64. The method according to claim 44, characterized in that the antineoplastic agent is fluorouracil (5-FU).
65. 65. The method according to claim 44, characterized in that the antineoplastic agent is fluoximestrin.
66. 66. The method according to claim 44, characterized in that the antineoplastic agent is gemcitabine.
67. 67. The method according to claim 44, characterized in that the antineoplastic agent is goserelin.
68. 68. The method according to claim 44, characterized in that the antineoplastic agent is irinotecan.
69. 69. The method according to claim 44, characterized in that the antineoplastic agent is ketoconazole.
70. 70. The method according to claim 44, characterized in that the antineoplastic agent is letrozole.
71. 71. The method according to claim 44, characterized in that the antineoplastic agent is leucovorin.
72. 72. The method according to claim 44, characterized in that the antineoplastic agent is levamisole.
73. 73. The method according to claim 44, characterized in that the antineoplastic agent is megestrol.
74. 74. The method according to claim 44, characterized in that the antineoplastic agent is mitoxantrone.
75. 75. The method according to claim 44, characterized in that the antineoplastic agent is paclitaxel.
76. 76. The method according to claim 44, characterized in that the antineoplastic agent is raloxifene.
77. 77. The method according to claim 44, characterized in that the antineoplastic agent is retinoic acid.
78. 78. The method according to claim 44, characterized in that the antineoplastic agent is tamoxifen.
79. 79. The method according to claim 44, characterized in that the antineoplastic agent is thiotepa.
80. 80. The method according to claim 44, characterized in that the antineoplastic agent is topotecan.
81. 81. The method according to claim 44, characterized in that the antineoplastic agent is toremifene.
82. 82. The method according to claim 44, characterized in that the antineoplastic agent is vinorrelbine.
83. 83. The method according to claim 44, characterized in that the antineoplastic agent is vinblastine.
84. 84. The method according to claim 44, characterized in that the antineoplastic agent is vincristine.
85. 85. The method according to claim 44, characterized in that the antineoplastic agent is selenium (selenomethionine).
86. 86. The method according to claim 44, characterized in that the antineoplastic agent is ursodeoxycholic acid.
87. 87. The method according to claim 44, characterized in that the antineoplastic agent is sulindac sulphone.
88. 88. The method according to claim 44, characterized in that the antineoplastic agent is eflornithine (DFMO).
89. 89. The method according to claim 44, characterized in that the neoplasm is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.
90. 90. A combination comprising a cyclooxygenase inhibitor and one or more antineoplastic agents, characterized in that anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, CP-461 cell lines, docetaxel, doxorubicin, etoposide, fluoximestrin, gemcitabine, goserelin, irinotecan, ketoconazole, letrozole, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorrelbine, vinblastine, vincristine, (selenomethionine) selenium, sulfone sulindac and eflornithine (DFMO).
91. 91. The combination according to claim 90, characterized in that the cyclooxygenase 2 inhibitor is selected from compounds, and the pharmaceutically acceptable salts thereof, from the group consisting of: 1) JTE-522, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide; 2) 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine; 3) 2- (3,5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one; 4) 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1 -yl] -benzenesul-1-onamide; 5) rofecoxib, 4- (4- (methylsulfonyl) phenyl) -3-f-enyl-2 (5H) furanone 6) 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide; 7) N - [[4- (5-methyl-3-phenylisoxazol-4-yl] phenyl] sulfonyl] propanamide; 8) 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yl-benzenesulfonamide; 9) 10) eleven) 6 - [[5- (4-chlorobenzoyl) -1,4-dimethyl-1H-pyrrol-2-yl] methyl] -3 (2H) -pyridazinoia; 12) N- (4-nitro-2-phenoxyphenyl) metasulfonamide; 13) 14) 3- (3,4-difluorophenoxy) -5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone; fifteen) N- [6 - [(2,4-difluorophenyl) thio] -2,3-dihydro-1 -oxo-1 H-inden-5-yl] metansjlfonamide; 6) - (4-chlorophenyl) -4- [4- (methylsulfonyl) phenyl] -2 (3H) -oxazolone; 7) - [3- (4-fluorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; 8) - [4- (methylsulfonyl) phenyl] -2-phenyl-2-cyclopenten-1-one; 9) - (2-methyl-4-phenyl-5-oxaxolyl) benzenesulfonamide; 0) - (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (3H) -oxazolone; 1 ) - (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 2) - [5-phenyl] -3- (trifluoromethyl) -1 H -pyrazol-1-yl) benzenesulfonamide; 3) - [1-phenyl-3- (trifluoromethyl) -1 H -pyrazol-5-yl] benzenesulfonamide; 4) 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yl] benzene-sulfonamide; 25) N- [2 - (- cyclohexyloxy) -4-nitrophenyl] methanesulfonamide; 26) N- [6- (2,4-difluorophenoxy) -2,3-dihydro-1-oxo-1 H -inden-5-yl] methanesulfonamide; 27) 3- (4-chlorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; 28) 3- (4-fluorophenoxy) -4 - [(methylsulfonyl) amino] benzenesulfonamide; 29) 3 - [(1-methyl-1 H-imidazol-2-yl) thio] -4 [(methylsulfonyl) amino] -benzenesulfonamide; 30) 5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -3-phenoxy-2 (5H) -furanone; 31) N- [6 - [(4-ethyl-2-thiazolyl) thio] -1,3-dihydro-1-oxo-5-isobenzofuranyl] -methanesulfonamide; 32) 3 - [(2,4-dichlorophenyl) thio] -4 - [(methylsulfonyl) amino] benzenesulfonamide; 33) 1-fluoro-4- [2- [4- (methylsulfonyl) phen] l] cclopenten-1-yl] benzene;

    3. 4) 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1 H -pyrazol-1-yl] benzeneLilphonamide; 35) 3- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazol-2-yl] pyridine; 36) 4- [2- (3-pyridinyl) -4- (trifluoromethyl) -1 H -imidazol-1-yl] benzenesulfonamide; 37) 4- [5- (hydroxymethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; 38) 4- [3- (4-chlorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; 39) 10 4- [5- (difluoromethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; 40) [1, 1 ': 2, 1"-terphenyl] -4-sulfonamide; 41) - (methylsulfonyl) -1, 1 ', 2], 1"-terphenyl; 42) 4- (2-phenyl-3-pyridinyl) benzenesulfonamide; 43) N- (2,3-dihydro-1,1-dioxide-6-phenoxy-1,2-benzisothiazol-5-yl) methanesulfonamide; Y 44) N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-ylmethanesulfonamide; Four. Five) 46) * and Cl: 47) 48)
92. 92. The combination according to claim 90, characterized in that the cyclooxygenase 2 inhibitor is 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine.
93. 93. The combination according to claim 90, characterized in that the cyclooxygenase 2 inhibitor is 2- (3,5-difluorophenyl) -3-4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one.
94. 94. The combination according to claim 90, characterized in that the cyclooxygenase 2 inhibitor is 4- [5- (4-methylphenyl) -3- (trifuloromethyl) -1 H -pyrazol-1 -yl] -benzenes Ifonamide.
95. 95. The combination according to claim 90, characterized in that the cyclooxygenase 2 inhibitor is rofecoxib, 4- (4- (methylsulfonyl) phenyl] -3-phenyl-2- (5H) -furanone
96. 96. The combination according to claim 90, characterized in that the cyclooxygenase-2 inhibitor is 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesufonamide.
97. 97. The method according to claim 1, characterized in that the antineoplastic agent is anastrozole.
98. 98. The method according to claim 1, characterized in that the antineoplastic agent is calcium carbonate.
99. 99. The method according to claim 1, characterized in that the antineoplastic agent is exemestane.
100. 100. The method according to claim 44, characterized in that the antineoplastic agent is exemestane.
101. 101. The method according to claim 90, characterized in that the antineoplastic agent is exemestane.
102. 102. The method according to claim 44, characterized in that the combination is administered in a sequential manner.
103. 103. The method according to claim 44, characterized in that the combination is administered in a substantially simultaneous manner.