WO2002028270A2 - The treatment of cancer utilizing a cox-2 inhibitor and a hmg-coa reductase inhibitor - Google Patents
The treatment of cancer utilizing a cox-2 inhibitor and a hmg-coa reductase inhibitor Download PDFInfo
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- WO2002028270A2 WO2002028270A2 PCT/US2001/031328 US0131328W WO0228270A2 WO 2002028270 A2 WO2002028270 A2 WO 2002028270A2 US 0131328 W US0131328 W US 0131328W WO 0228270 A2 WO0228270 A2 WO 0228270A2
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- Prior art keywords
- dose
- cancer
- therapeutic window
- lovastatin
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Definitions
- the inventors propose a combination of an HMG-CoA reductase inhibitor (also referred to as "HMG-CoA inhibitor(s)”), and COX-2 inhibitor for the treatment of cancer especially prostate cancer and a method of treatment of cancer by that combination, especially prostate cancer.
- HMG-CoA inhibitor(s) also referred to as "HMG-CoA inhibitor(s)”
- COX-2 inhibitor for the treatment of cancer especially prostate cancer and a method of treatment of cancer by that combination, especially prostate cancer.
- Methods of manufacturing are also claimed.
- the invention is applicable to cancers generally in mammals and the reference to human biochemistry is not intended to be limiting, but illustrative.
- the term patient or body or reference to humans is utilized for convenience, but includes all mammalian patients or bodies.
- the first premise is to recognize the highly adaptable characteristics and durable biochemistry of the cancer cell from a biochemical and genetic viewpoint. Many cancer cells are body cells gone awry. The literature solidly suggests that cancer cells in a patient's body have a capability to readapt their functions to adjust to ambient conditions. A patient's body also has an impressive capability to adapt to changing macro-environmental conditions, as well as the micro-environmental conditions in biological chemistry internal to the cell.
- Cancer cells in a genetic or evolutionary sense, are not "bad" cells. Rather, they are efficient cells; in fact, they are highly efficient cells in a certain way. They use relatively less oxygen for the total amount of activity they undertake, and they divide rapidly, enabling them by normal processes of mutation and evolution to adapt their genetic material more quickly. Were the systems and cells in the rest of our bodies equally efficient, we would be greater evolutionary giants than we stand today. For any attack on cancer cells to be successful, unless they can be physically cut out of the body by surgery, the attack cannot be "too successful.” Cancer cells are us, and in a much slower evolutionary way, we are cancer cells. Too much success in damaging cancer cells pharmacologically in the prior art has often been destructive of the host body.
- the blood vessels biochemically "transport" substances either to cells or from cells.
- biochemicals travel by osmosis affected and influenced by biochemical cycles.
- cells are short of glucose, the basic fuel product of food, cells have a lower concentration of a substance they need, and if there is a higher concentration of glucose in an adjacent capillary which has a blood cell, some of that glucose flows across the membrane in a complicated biochemical transport mechanism to restore the concentration of glucose in the cell, naturally depleting the concentration in the blood stream.
- not all membranes allow all substances to pass. Some are only semi-permeable, allowing only compounds in certain shapes or sizes to pass.
- cancer cells need energy in order to do what they do the most and best, which is to divide or replicate. Energy in a cell is provided by the Krebs cycle. Cancer cells, because they divide frequently, are very sensitive to interference with their energy processes. Second, when any cell divides, including cancer cells, the bag around the cell which is the membrane has to split into two bags.
- cancer cell needs relatively more cholesterol in order to replicate successfully than a normal cell needs for its normal activities.
- the membrane is necessarily weakened somewhat as the dividing process occurs and the cell transforms from one cell into two cells like a sandwich being pulled apart into two halves.
- the human body is not completely helpless against cancers.
- cancer cells are relatively good at deceiving or confusing the immune system of our body into believing that the cancer cells are not as bad as they really are, or alternatively, because of rapid replication and evolution, developing defenses against the immune system. Further, as cancer progresses, it damages the body's immune system, including by triggering long-term inflammatory mechanisms .
- this invention proposes to use a novel combination to inhibit key biochemical cycles in a way that causes more damage to the cancer cell than to other cells, to decrease long-term inflammation, and to improve and sustain the body's immune system so it can better attack the weakened cancer cells and support the body's remaining essential functions.
- the inventors propose to selectively modify several biochemical pathways so as not to destroy overall body function, but disproportionately harm cancer cells, to enhance the body' s immune system in order that the immune system may attack the cancer cells, and by stressing the cancer cell, to inhibit the cancer cell's normal resistance to immune system function, and to protect the body's normal cells.
- the inventors propose a method of treatment of cancer, particularly prostate cancer and pancreatic cancer, by a particular combination of drugs for that purpose which has not been previously proposed for that purpose.
- the inventors propose a method of treatment of cancer involving a novel combination of drugs which simultaneously slows the cancer but also enables the body's immune system to better attack or fend off the cancer.
- the first object of this invention proposes to selectively interfere with the production of cholesterol in two places in a way that impairs the energy cycle of all cells but which normal cells can overcome because they need less energy to survive because they are not dividing, but in a way that has a disproportionate and damaging effect on cancer cells which must replicate, or the cancer will not spread.
- a second object is to selectively modify a biochemical cycle that targets inflammatory mechanisms in the body.
- One of the most damaging aspects of cancer cells is that they trigger an extended inflammatory response in the body. Further, as cancer progresses, it damages the body's immune system by a number of mechanisms, including the triggering of an extended inflammatory response in the body, which is less efficient in the removal of cancers.
- Prostaglandins are some of the most important signals to cause inflammatory responses.
- the biochemical cycle that we propose to selectively inhibit is an important cycle that converts arachidonic acid to several forms of prostaglandins.
- That cycle is the cyclooxygenase or COX cycle.
- Biochemical cycles have many intermediate steps in them and the intermediate compounds are known as "intermediates.”
- One of those intermediates in the cyclooxygenase cycle is prostaglandin H2 synthase, which has two forms: COX-1 and COX-2.
- COX-1 is known as a housekeeping substance which helps generate substances that protect the stomach. Ding et al, "Blockade of Cyclooxygenase-2 Inhibits Proliferation and Induces Apoptosis in Human Pancreatic Cancer Cells, vol. 20 AntiCancer Research, 2625-2632 (2000).
- Aspirin inhibits COX-1 and therefore, because it inhibits a substance that protects the stomach, often has gastrointestinal side effects.
- COX-2 enzymes regulate pain, inflammation and fever, i.e. inflammatory mechanisms.
- the COX-2 inhibitors in this invention interfere with the transformation of a substance called squalene to cholesterol.
- squalene There are numerous intermediates from squalene to cholesterol.
- Acetyl-CoA enzyme Earlier in the biochemical cycle that produces cholesterol is a substance called Acetyl-CoA enzyme. It is converted to an intermediate called mevalonate by an enzyme called 3-hydroxy-3-methylgmtamate-CoA reductase ("HMG-CoA").
- HMG-CoA 3-hydroxy-3-methylgmtamate-CoA reductase
- Recent pharmaceutical advances have produced a number of substances that inhibit the activity of HMG-CoA and slow the production of cholesterol.
- a third object of this invention is to utilize the more optimal function of cystine in the pH balance of a normal cell than in the lower pH of a cancer cell.
- the administration of cystine enhances the body's immune system benefitting the total body disproportionately to any benefit cystine administration may have for a cancer cell.
- the premise of this invention is that the cancer cells divide rapidly, that they have significant anaerobic glycolytic processes, and that the body is one large biochemical machine in which we can play to the strength of our body to the detriment of the cancer cell.
- COX-2 inhibitors may have efficacy toward certain cancers.
- Fosslien Biochemistry of Cyclooxygenase (COX)-2 Inhibitors and Molecular Pathology of COX- 2 in Neoplasia," Crit. Rev. in Clin. Lab. Sci. 37(5): 431-502 (2000).
- COX-2 inhibitors were reported to be inhibiting certain cancers, particularly familial adenomatous polyposis. See, 319 (7218) British Medical Journal 1155 (Oct. 30, 1999).
- COX-2 inhibitors in that instance, celecoxib, a COX-2 inhibitor manufactured by G.D.Searle, and sold under the brand name Celebrex, had caused a reduction in adenomatous polyps which are a virtual guarantor of cancer of the colon if left untreated. Cyclooxygenase-2 had been implicated in colorectal cancer and colonic tumorigenesis. See, "The Relationship Between Cyclooxygenase-2 Expressions and Colorectal Cancer", 282(13) J. Amer. Med.
- simvastatin functions in a similar way to lovastatin, another drug marketed by Merck under the registered trademark of MENACOR, the pharmaceutical product description for which is adopted herein and attached for reference. Both are derived from aspergillus terreus. Certain literature has suggested that HMG-CoA inhibitors may have efficacy toward certain cancers.
- lipid lowering/modifying drugs such as lovastatin were suggested to be more cancer-free than those using bile acid- binding resins. See, 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors and the Risk of Cancer: A Nested Case-Control Study, 160(5) Archives of Internal Med: 2363-2368 (2000). "Therapeutic Approaches to Bone Diseases [Bone Remodeling and Repair: Review]," Science, 289(5484), Sept. 1, 2000:1508-1514. No patent or literature suggests that the substances be combined to treat cancer nor is the synergistic effect set forth in this specification suggested or described.
- a COX-2 inhibitor be combined with an HMG-CoA inhibitor to retard cancer and be further combined with .
- a glutathione-cycle enhancing compound such as cystine, cysteine, or N-acetyl-cysteine, also called NAC, to improve immune system competency to further retard cancer.
- NAC N-acetyl-cysteine
- No literature suggests another preferred embodiment: using a COX-2 inhibitor and HMG-CoA inhibitor set forth in this invention to retard cancer.
- Reduction to practice The combination of a selective COX-2 inhibitor and an HMG-CoA reductase inhibitor exhibits the unexpected property of enabling management of cancer. This has been demonstrated in two specific instances. Both patients were diagnosed with Stage 4 metastatic cancer and were refractory to other treatments.
- the first patient had prostate cancer and showed a PSA (prostate specific antigen-a widely accepted marker of prostate cancer activity) of 71 according to the patient.
- the patient was placed on a regimen of NIOXX and MENACOR, and has survived with good quality of life such as mowing his lawn, steady weight, and the like while the patient's PSA fell from tests conducted by one of the inventors to less than 2.5 with scan-documented lack of progression.
- a second patient diagnosed with pancreatic cancer which was also refractory to other treatment was placed on a regimen of VIOXX and MENACOR with a whey supplement containing cystine and survived approximately four months and initially gained some weight since first presenting while sustaining a reasonable quality of life until death.
- Pancreatic cancer is one of the most intractable cancers known and any success with pancreatic cancer is surprising in light of existing literature and art.
- Pharmacological compounds in this invention The science behind the combination is based on a triad of attacks in the biochemical cycles contributing to cancer cell replication. Cancer cells must necessarily replicate for a "cancer" to thrive. Attacks on biochemical cycles at points where replication are involved are a favored approach. Cancer cells are particularly vulnerable to interference with lipid cell membrane status and ATP synthesis.
- This invention proposes not only attack with a COX-2 inhibitor to interfere with the cyclooxygenase pathway, but by combination with an HMG-CoA reductase inhibitor, a statin, including simvastatin or lovastatin, focuses on another cycle, the formation of polyisoprenoids, particularly cholesterol.
- the invention claims the use of selective COX-2 inhibitor, including rofecoxib or celecoxib, but the principles stated are generally applicable to all selective COX-2 inhibitors.
- Cyclooxygenase-2 inhibitor or "selective COX-2 inhibitor” in this invention shall include the following in this paragraph: all of the compounds and substances beginning on page 8 of Winokur WO99/20110 as members of three distinct structural classes of selective COX-2 inhibitor compounds, and the compounds and substances which are selective COX-2 inhibitors in Morrisberger, U.S. Pat.
- COX-2 inhibitor in this invention shall include the compounds and substances referenced and incorporated into Winokur WO99/20110 by reference to art therein, the compounds and substances referenced and incorporated into Morrisberger, U.S.
- COX-2 inhibitors referenced and incorporated into Isakson et al, PCT application WO/09641645 published 27 December 1996, filed as PCT/US 9509905 on 12 June 1995, entitled "Combination of a Cyclooxygenase-2 Inhibitor and a Leukotriene B4 Receptor Antagonist for the Treatment of Inflammations.”
- the meaning of COX-2 inhibitor in this invention also includes rofecoxib, and celecoxib, marketed as VIOXX and CELEBREX by Merck and Searle/Pfizer respectively.
- COX-2 inhibitor in this invention also includes valdecoxib, See, "4-[5-Methyl-3-phenylisoxazol-l- yljbenzenesulfonamide, Valdecoxib: A Potent and Selective Inhibitor of COX-2", J. Med. Chem. 2000, Vol. 43: 775-777, and parecoxib, sodium salt or parecoxib sodium, See, N-[[(5-methyl-3-phenylixoxazol-4yl)- ⁇ henyl]sulfonyl]propanimide, Sodium Salt, Parecoxib Sodium: A Potent and Selective Inhibitor of COX-2 for Parenteral Administration", J. Med. Chem.
- COX-2 inhibitor in this invention also includes the substitution of the sulfonamide moiety as a suitable replacement for the methylsulfonyl moiety. See, J. Carter et al, Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors", Bioorg. Med. Chem. Lett 1999 Apr. 19: Vol. 9(8): 1171-74, and compounds referenced in the article "Design and synthesis of sulfonyl-substituted 4,5-diarylthiazoles as selective cyclooxygenase-2 inhibitors", Bioorg. Med. Chem.
- COX-2 inhibitor in this invention includes the cyclo-oxygenase-2 selective compounds referenced in Mitchell et al, "Cyclo-oxygenase- 2: pharmacology, physiology, biochemistry and relevance to NSAID therapy", Brit. J. of Pharmacology (1999) vol.128: 1121-1132, see especially p. 1126.
- the meaning of COX- 2 inhibitor in this invention includes so-called NO-NS ALOs or nitric oxide-releasing- NSAlDs referred to in L. Jackson et al, "COX-2 Selective Nonsteriodal Anti- Inflammatory Drugs: Do They Really Offer Any Advantages?", Drugs, June, 2000 vol.
- COX-2 inhibitor in this invention includes any substance that selectively inhibits the COX-2 isoenzyme over the COX-1 isoenzyme in a ratio of greater than 10 to 1 and preferably in ratio of at least 40 to 1 as referenced in Winokur WO 99/20110, and has one substituent having both atoms with free elections under traditional valence-shell-electron- pair-repulsion theory located on a cyclic ring (as in the sulfylamine portion of celecoxib), and a second substituent located on a different ring sufficiently far from said first substituent to have no significant election interaction with the first substituent.
- the second substituent should have an electronegativity within such substituent greater than 0.5, or the second substituent should be an atom located on the periphery of the compound selected from the group of a halogen F, CI, Br or I, or A group VI element S or O.
- a COX-2 inhibitor one portion of the COX-2 inhibitor should be hydrophilic and the other portion lipophilic.
- COX-2 inhibitor is to comprehensively include all selective COX-2 inhibitors, selective in the sense of inhibiting COX-2 over COX-1.
- the package inserts for rofecoxib and celecoxib are attached and adopted herein by reference.
- the inventors add to the class of COX-2 inhibitors useful in the invention the drug bearing the name etoricoxib referenced in the Wall Street Journal, December 13, 2000 manufactured by Merck. See, also, Chauret et al, "In vitro metabolism considerations, including activity testing of metabolites, in the discovery and selection of the COX-2 inhibitor etoricoxib (MK-0663)," Bioorg. Med. Chem.
- Another selective COX-2 inhibitor is DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone] referenced in Yergey et al, Drug Metab. Dispos. 29(5):638-44 (May 2001).
- the inventors also include as a selective COX-2 inhibitor flavolignanes which have selective COX-2 inhibitory activity over COX-1 inhibitory activity, including the flavonoid antioxidant silymarin itself, and an active ingredient in silymarin, silybinin, which demonstrated significant COX-2 inhibition relative to COX-1 inhibition.
- the silymarin also showed protection against depletion of glutathione peroxidase. Zhao et al, "Significant Inhibition by the Flavonoid Antioxidant Silymarin against 12-O- tetracecanoylphorbol 13 -acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1 alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion," Mol. Carcinog. Dec. 1999, Vol 26(4):321-33 PMID 10569809. Silymarin has been used to treat liver diseases in Europe.
- COX-2 inhibitor includes all pharmaceutically acceptable salts for the selective COX-2 inhibiting compound selected.
- salt forms of COX-2 inhibitors include but are not limited to salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamide, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glutamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, troethamine, and the like.
- basic ion exchange resins such as arginine
- HMG-CoA reductase inhibitor claimed in this invention is lovastatin or simvastatin or cholestin which are compounds related to aspergillus terreus.
- the principles of this invention are generally applicable to all statins.
- the meaning and definition of a 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase inhibitor ("HMG- Co A inhibitor") in this invention is any selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA into mevalonate, generally referred to as cholesterol-lowering statins, and includes 1) lovastatin, marketed under the tiademark MEVACOR by Merck, and described, among other places in U.S. Pat.
- HMG-CoA inhibitor (used as shorthand for and also referred to as "HMG-CoA reductase inhibitor") further includes all HMG-CoA reductase inhibitors described in Winokur, PCT Appl. US98/21901, filed 16 Oct. 1998, published as WO99/20110 entitled Combination Therapy for Reducing the Risks Associated with Cardio and Cerebrovascular Disease," and the compounds and substances which are HMG-CoA inhibitors in brinberger, U.S. Pat.
- HMG-CoA inhibitor in this invention shall include the compounds and substances referenced and incorporated into Winokur WO99/20110 by reference to art therein, and the compounds and substances referenced and incorporated into Morrisberger, U.S. Pat. 6,136,804, October 24, 2000, by reference to art therein.
- Compactin is also described as a fungi derived competitive inhibitor of HMG-CoA reductase. Lehninger, Principles of Biochemistry (3 rd ed. 2000) at 811.
- An HMG-CoA reductase inhibitor with the natural structure of lovastatin identical to the synthetic structure of lovastatin, can also be isolated from red rice yeast or the rice in sufficient quantity and is an HMG-CoA reductase inhibitor.
- the red rice yeast is found as cholestin or cholestol and is available on the Internet from a variety places including China Beijing Jingxin Biochemical Products Factor, Linxiao Rd. S., Daxing Count, Beijing, PRC or its U.S. agent PHC Resources, Inc., 77 Milltown Rd., East Brunswick, NJ 08816.
- the red rice yeast is referred to in an FDA warning letter of May 8, 2001 to Maypro Industries available at www, fda.
- simvastatin functions in a similar way to lovastatin, another drug marketed by Merck under the registered trademark of MEVACOR, the pharmaceutical product description for which is adopted herein and attached for reference. Both are derived from aspergillus terreus.
- HMG-CoA inhibitor encompasses the pharmaceutically acceptable salts of HMG-CoA inhibitor selected.
- the invention includes pharmaceutically active salts of an HMG-CoA inhibitor, which may include non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base.
- salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, citrate, dihydrochloride, edentate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laureate, malate, maleate, mandelate, mesylate, methylbromide, methylnitiate, methylsulfate, mutate, napsylate, initiate, oleate, oxalate, pamao
- HMG-CoA inhibitors may act as prodrugs which, when absorbed into the bloodstream of a warm- blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
- Cystine is (3,3'-dithiobis [2-aminopropanoic acid]). Cystine is readily reduced to cysteine. Cystine is present in most mammalian hair and keratin. Cysteine is 2-amino-3-mercapto propanoic acid. It is readily converted by oxioreduction to cystine. It is a constituent of glutathione and abundantly present in the metallothioneines. Cystine in the body-useful form as L-cystine is available from Spectrum Chemical Mfg. Corp. 14422 S. San Pedro St., Gardena, California 90248.
- cystine Cystine, cysteine, and N-Acetyl cysteine and pharmaceutically acceptable salts, including the pharmaceutically active forms described in Kozhemyakin et al, published by WTPO as WO 00/031120, PCT/RU99/00453, filed internationally on 19 Nov. 1999, "Hexapeptide with the Stabilized Disulfide Bond and Derivatives Thereof Regulating Metabolism, Proliferation, Differentiation and Apoptosis," will all collectively be referred to as cystine in this invention. Included in the term cystine is also any therapeutically beneficial sulfur donating compound, including ebselen, which interacts with the glutathione pathway.
- the invention contemplates in the term cystine undenatured whey protein products designed to have enhanced cystine concentration as well as protein products which contain cysteine and cystine. They can be in the form of food products. Immunocal® whey protein diet supplement by Immunotek Research Ltd. of Montreal Quebec is a useful product with cystine. The addition of cystine, cysteine, N-acetyl cysteine, or the pharmaceutically acceptable salt of those substances yields another effect in this invention not facially evident from the independent properties of the basic components of the invention.
- a glutathione pathway enhancing and detoxifying compound preferably cystine, which has the best and most rapid upload into the glutathione pathway and better storage capability by the body, or N-acetyl cysteine, enhances the immune system competency of the patient.
- Lipoic acid can be an adjunct to the cystine. All of these cystine and cystine-like compounds function as a glutathione pathway enhancing and detoxifying compound. They have the additional benefit of ameliorating the negative renal, hepatic and gastric effects of COX-2 inhibitors and HMG-CoA inhibitors, both as a combination and individually.
- the enhancement of the glutathione level and pathway has a second important and unexpected effect. The avoidance of a glutathione deficiency steers the patient to have a higher Th-1 response to Th-2 response ratio than the patient would have with any glutathione deficiency
- the preferred mode of invention without limiting its use or use of pharmaceutical equivalents to those described herein is to administer a therapeutic dose of a cyclooxygenase-2 inhibitor, namely VIOXX (a registered trademark of Merck Co. for a drug formally known as rofecoxib) or CELEBREX (a registered tiademark of Searle and Pfizer for a drug formally known as celecoxib) (both referred to as a "COX-2 inhibitor”), in combination with a therapeutic dose of a 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase inhibitor, namely with Mevacor (a registered tiademark of Merck Co.
- VIOXX a registered trademark of Merck Co. for a drug formally known as rofecoxib
- CELEBREX a registered tiademark of Searle and Pfizer for a drug formally known as celecoxib
- COX-2 inhibitor a registered tiade
- HMG-CoA inhibitor for a drug formally known as lovastatin), or ZOCOR (a registered trademark of Merck Co. for a drug formally known as lovastatin) or cholestin (all referred to as "HMG-CoA inhibitor") starting with the minimum initial recommended doses of each drug on the package inserts attached to provisional application 60/245,592.
- This mode is therefore a COX-2 inhibitor beginning with an HMG-CoA inhibitor in the minimum doses for each.
- the dosage should be increased in step wise fashion to the maximum dose in the therapeutic window. The preferred mode of so doing is to monitor the patient each six weeks.
- a person of ordinary skill in the medical arts can apply the regimen described in this specification.
- the inventors suggest measuring at least cholesterol level and isoprostane level. If a patient's cholesterol level is decreasing, then the HMG Co A inhibitor is affecting cholesterol synthesis. If isoprostane levels are rising, then the COX-2 inhibitor should be having an effect. The lack of change in one or the other suggests that the medication to achieve the desired metabolic pathway effect should be adjusted. Another way to test for effectiveness and enable dosage adjustment is to test cytokine levels. Once at least two inflammatory response markers show therapeutic change then the combination should be having an effect.
- the preferred markers include upregulation of IX- 12 and downregulation of IL-10. "Specific inhibition of cyclooxygenase restores anti-tumor reactivity by altering balance of IL-10 and IL-12 synthesis", J.
- Advanced prostate cancer particularly refers to prostate cancer that has not been successfully tieated by surgery, chemotherapy, radiation and/or androgen suppressant(s).
- VIOXX a registered tiademark of Merck Co. for a drug formally known as rofecoxib
- CELEBREX a registered tiademark of Searle and Pfizer for a drug formally known as celecoxib
- COX-2 inhibitor a registered tiademark of Searle and Pfizer for a drug formally known as celecoxib
- Mevacor a registered trademark of Merck Co. for a drug formally known as lovastatin
- ZOCOR a registered trademark of Merck Co.
- lovastatin a drug formally known as lovastatin
- cholestin all referred to as "HMG-CoA inhibitor”
- the invention retards or drives prostate cancer into remission, best illustrated by lowering the Prostate Specific Antigen, the standard measure of prostate cancer activity in the human body.
- the method of the invention is the step of administering the combination of COX- 2 inhibitor and HMG-CoA inhibitor, including lovastatin or simvastatin and rofecoxib or celecoxib, or the combined sequence of steps of sequentially administering the COX-2 inhibitor and HMG-CoA inhibitor, including lovastatin and rofecoxib.
- An alternative of this method of the invention is the combined sequence of steps of sequentially administering the COX-2 inhibitor and HMG-CoA inhibitor, including lovastatin or simvastatin and rofecoxib or celecoxib.
- Celecoxib may be used in lieu of rofecoxib, and simvastatin in lieu of lovastatin.
- Another preferred method is the step of administering the combination of COX-2 inhibitor, HMG-CoA inhibitor, particularly lovastatin or simvastatin and rofecoxib or celecoxib, along with cystine as a glutathione pathway enhancing and detoxifying compound.
- An alternative of this method of the invention is the combined sequence of steps of sequentially administering the COX-2 inhibitor and HMG-CoA inhibitor, particularly including lovastatin or simvastatin, and rofecoxib or celecoxib, along with cystine as a glutathione pathway enhancing and detoxifying compound.
- Also part of the invention is the method of manufacturing a combination of a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase inhibitor, that is manufacturing a combination of an HMG-CoA inhibitor, including lovastatin or simvastatin, and a COX-2 inhibitor, including rofecoxib or celecoxib.
- Also part of the invention is the method of manufacturing a combination of a COX-2 inhibitor, a 3- hydroxy-3-methylglutaryl-Coenzyme-A reductase inhibitor, namely manufacturing a combination of lovastatin or simvastatin, and rofecoxib o celecoxib, along with cystine as a glutathione pathway enhancing and detoxifying compound.
- a COX-2 inhibitor and an HMG-CoA inhibitor is another preferred mode of the invention.
- Another mode of the invention includes a COX-2 inhibitor and an HMG-CoA inhibitor, including rofecoxib or celecoxib and lovastatin or simvastatin and cystine or another glutathione pathway enhancing compound.
- cystine is being used to enhance the immune system competency and assist normal cells, through the glutathione pathway, in maintaining their stability.
- the combination of a COX-2 inhibitor and an HMG-CoA inhibitor could also be used as an aborfacient.
- the invention also can utilize one or more of certain additional active agents in combination with the HMG-CoA inhibitor and COX-2 inhibitor, or in combination with the HMG-CoA inhibitor, COX-2 inhibitor, and cystine.
- the additional active agents can be in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration.
- additional active agents examples include squalene epoxidase inhibitors, squalene synthase inhibitors, probucal, glycoprotein Ilb/IIIa fibrinogen receptor antagonists, and pharmaceutically acceptable salts of those additional active agents which do not interfere with the HMG-CoA inhibitor and COX-2 inhibitor combination and method or with the HMG-CoA inhibitor, COX-2 inhibitor, and cystine.
- additional active agents include squalene epoxidase inhibitors, squalene synthase inhibitors, probucal, glycoprotein Ilb/IIIa fibrinogen receptor antagonists, and pharmaceutically acceptable salts of those additional active agents which do not interfere with the HMG-CoA inhibitor and COX-2 inhibitor combination and method or with the HMG-CoA inhibitor, COX-2 inhibitor, and cystine.
- the therapeutically effective amount to use for these additional active agents is referred to in the just-cited art, can be seen in the Physician Desk Reference (PDR) 2001 , and may be seen on the package inserts.
- the instant pharmaceutical combination comprising an HMG-CoA inhibitor in combination with a COX-2 inhibitor and cystine includes admimstiation of a single pharmaceutical dosage formulation which contains both the HMG-CoA inhibitor and the COX-2 inhibitor and cystine, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
- a cystine supplement taken at a different time of day may be a separate dose without the HMG-CoA inhibitor or the COX-2 inhibitor.
- Cystine is the suggested glutathione pathway enhancing and detoxifying compound.
- the amount of cystine to be included in an oral dosage combination is a therapeutically effective amount to reach normal glutathione levels. Such therapeutically effective amount should preferably and initially be 140mg/70 Kg man twice per day.
- the HMG-CoA inhibitor and the COX-2 inhibitor can be administered at essentially the same time, i.e., concurrently, or at staggered intervals, i.e., sequentially.
- the instant pharmaceutical combination comprising an HMG-CoA inhibitor in combination with a COX-2 inhibitor includes administiation of a single pharmaceutical dosage formulation which contains both the HMG-CoA inhibitor and the COX-2 inhibitor, as well as administiation of each active agent in its own separate pharmaceutical dosage formulation.
- the instant pharmaceutical combinations are understood to include all these regimens.
- Administiation in these various ways is suitable for the present invention as long as the beneficial pharmaceutical effect of the HMG-CoA inhibitor and the COX-2 inhibitor are realized by the patient at substantially the same time.
- Such beneficial effect is preferably achieved when the target blood level concentrations of each active drug are maintained at substantially the same time.
- the HMG-CoA inhibitor and the COX-2 inhibitor be co-administered concurrently on a once-a-day dosing schedule; however, varying dosing schedules, such as the HMG-CoA once per day and the COX-2 inhibitor once, twice or more times per day, is also encompassed herein.
- a single oral dosage formulation is preferred.
- a single dosage formulation will provide convenience for the patient, which is an important consideration especially for patients who may be in need of multiple medications.
- Administiation of the HMG-CoA inhibitor or COX-2 inhibitor can be by tablet, liquid suspension, or many other pharmaceutically acceptable carriers known by or used by reasonably skilled practitioners in the art of pharmacology or pharmacological manufacturing including by the combinations and methods in the cited Winokur art, PCT Appl. US98/21901, filed 16 Oct.
- the active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- the active drugs may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. They may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl- methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
- the active drugs may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. All of these are described in Morrisberger, U.S. Pat. 6,136,804, Oct. 24, 2000.
- therapeutically effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
- a therapeutic change is a change in a measured biochemical characteristic in a direction expected to alleviate the disease or condition being addressed.
- prophylactically effective amount is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
- therapeutic window is intended to mean the range of dose between the minimal amount to achieve any therapeutic change, and the maximum amount which results in a response that is the response immediately before toxicity to the patient.
- minimum recommended dose is that amount either recommended in the package insert for the selected FDA approved drug, or for other substances and compounds, the minimum therapeutically effective amount for a typical patient of the size and weight being treated.
- Minimum recommended dose in the context of commencing treatment is also referred as the minimum initial recommended dose and is that amount recommended for patients as the starting dose. Adjustment of dose upward by 10% or "dose being adjusted upward by at least 10% of the previous dose” means increasing the dose by that approximate amount.
- the pharmaceutical carrier, or pill may have to be divided, but generally an increase to the next highest dose is acceptable within the therapeutic window.
- the references in the claims to specific dosages of specific FDA approved drugs are to tablets having those dosages as referenced in the package inserts adopted herein by reference from Prov. Appl. 60/249,592 dated November 17, 2000.
- the dosage regimen utilizing an HMG-CoA inhibitor in combination with COX-2 inhibitor is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the cardiac, renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. Dosages in all events should be limited to the therapeutic window.
- an interesting and surprising aspect of the invention which suggests many of the pharmakinetics, is that quality of life is not substantially affected by the treatment; the patient is alive, the patient does not die; at the same time, at least in the short term, the cancer is also present albeit repressed in its activity.
- the consideration of pharmakinetics attempts to comprehend these combined phenomena.
- An important aspect of the pharmakinetics is the selectivity to cancer cells and essentially microadministiation of cancer therapy. For instance, this invention proposes to affect ubiquinones in important ways.
- the inventors propose that one of the dilemmas of cancer therapy is to deliver the needed dose to the right place and minimize harm when the therapy is not in the right place.
- the inventors believe that the most optimal treatments involve the utilization of the biochemical physiologic machine of the body, and preferably of the individual cell, to construct, manufacture and adjust the individual cell chemistry to achieve the desired object: in the case of the cancer cell or other afflicted and undesired cell, to disrupt its mechanisms of replication, primarily by focusing on the energy mechanism of the cell with the corollary result of interfering with membrane synthesis and cell replication, and in many instances, as the cell struggles to reach homeostasis, inducing apoptosis.
- the invention renders cancer cells vulnerable to poor replication and subject to bodily defenses, thus slowing the cancer activity, and in the instance of prostate cancer, lowering the PSA of the patient while destroying cancer cells.
- the COX-2 inhibitor and the cyclox genase-prostaglandin pathway interferes with the operation of the cyclooxygenase cycle from which are generated prostaglandins critical in cell division chemistry. Direct inhibition occurs of the synthesis of COX-2, a precursor of prostaglandins. Biochemistry, Geigy Scientific Tables, Book 4, ed. by C. Lemtner, published by Ciba-Geigy (1986) ISBN -0-91-4168-53-3, Lib. Cong. Cat. No. 81-70045 pp. 25-27 attached to Prov. Appl. 60/245,592, the text of which attachment is adopted by reference herein). This effect has been discussed in the literature.
- COX-2 inhibitors were reported to be inhibiting certain cancers, particularly familial adenomatous polyposis. See, 319 (7218) British Medical Journal 1155 (Oct. 30, 1999).
- COX-2 inhibitors in that instance, celecoxib, a COX-2 inhibitor manufactured by G.D.Searle, and sold under the brand name Celebrex, had caused a reduction in adenomatous polyps which are a virtual guarantor of cancer of the colon if left untreated.
- Cyclooxygenase-2 had been implicated in colorectal cancer and colonic tumorigenesis. See, "The Relationship Between Cyclooxygenase-2 Expressions and Colorectal Cancer", 282(13) J. Amer. Med. Ass'n: 1254-1257 (Oct. 6, 1999). Both celecoxib and rofecoxib are suggested to have similar effects. See Vol. 56(2) Amer. J. of Health-System Pharmacy: 106-107 (Jan. 15, 1999).
- One of the clear benefits of the selective COX-2 inhibitor is that COX-1 isoenzymes have what has been characterized as having general housekeeping functions generally ameliorative to bodily health. .
- COX-2 inhibitor and angiogenesis In mice, a COX-2 inhibitor, NS398, was reported to inhibit angiogenesis of a prostate cancer specimen in vivo. Liu et al, "Inhibition of Cyclooxygenase-2 suppresses Angiogenesis and the Growth of Prostate Cancer in Vivo," 164 J. of Urology 820-825 (September 2000) at 820. Inhibition of cholesterol synthesis by COX-2 inhibitor and HMG-CoA inhibitor: In viewing the biochemical cycle through which the formation of polyisoprenoids occurs, there are a series of intermediates. See, Biochemistry, Geigy Scientific Tables, Book 4, ed. by C.
- a key end product of the biochemical cycle of formation of polyisoprenoids is cholesterol.
- the entire cholesterol cycle must be functioning properly and cholesterol is especially critical to membrane stabilization, a necessary ingredient for successful cancer cell replication.
- the "early" cholesterol pathway Acetyl CoA to mevalonate Examining the intermediates in the polyisoprenoid formation cycle carefully, beginning with Acetyl-CoA, the next intermediate is 3-Hydr ⁇ xy-3-methylglutaryl-CoA ("HMG-CoA"). There is a feed back regulation mechanism immediately after this intermediate before transition occurs to the next intermediate: Mevalonate. Salway, Metabolism at a Glance, 88-89 (Blackwell Science 2 nd ed. Oxford 1999). The invention proposes to use lovastatin as an HMG-CoA reductase inhibitor.
- An HMG-CoA reductase inhibitor interferes in the polyisoprenoid formation cycle, and particularly interferes with cell wall synthesis, thereby interfering with a necessary construct of cancer replication.
- ATP cycle intermediaries are juxtaposed to the HMG-CoA feedback mechanism,' and ATP and ATP cycle intermediaries are apparent in transition steps of biosynthesis of cholesterol subsequent to the Mevalonate intermediate, the effect of a cancer cell starved of necessary cholesterol is to biochemically invite increased production of intermediaries in the transition from mevalonate to cholesterol, and to biochemically invite increased production of HMG-CoA, whose biosynthesis is being inhibited. Such increased production draws on the ATP and ATP cycle intermediaries in the cancer cell.
- the later cycle squalene to cholesterol synthesis
- the cycle continues with the formation of isopentenyl diphosphate, and then farnesyl diphosphate.
- Salway Metabolism at a Glance at 88-89, (Blackwell Science 2nd ed Oxford 1999).
- a second effect cooperates with the HMG-CoA inhibitor to exacerbate the energy drain on a cancer cell. This collateral effect is additional to the effect of a COX-2 inhibitor on the cyclooxygenase cycle.
- the COX-2 inhibitor because of the active electron field substituents, also interferes in a way not discussed in the literature with the normal biochemistry of squalene to cholesterol synthesis. Squalene transitions through a complex series of intermediates to cholesterol. This interference in the biosynthesis pathway subsequent to squalene synthesis further disables the cell division chemistry of a cancer cell and leaves it vulnerable to apoptosis. Notably, the transition states from squalene to cholesterol between intermediaries depend on critical inputs of ATP cycle chemicals, including NADP and NADPH.
- a COX-2 inhibitor interferes with, but does not appear to stop, synthesis of certain of these intermediaries. This either results in insufficient cholesterol for cancer cell replication or results in introduction of further drain on the ATP cycle chemicals to produce the desired cholesterol critical for cell replication. This drain on the ATP cycle is beyond the sitessses already imposed by the HMG-CoA inhibitor. As the replicating cell has further need for cholesterol, further energy is diverted from the cell.
- the "middle" of the cholesterol synthesis cycle Farnesyl Pyrophosphate and ubiquinones
- a corollary effect of the partial inhibition of the production of cholesterol from squalene and the triggering of increased production of farnesyl pyrophosphate is that relatively more ubiquinones are produced which are not being inhibited in the same manner as the squalene to cholesterol synthesis is inhibited.
- Ubiquinones are key participants in the Q cycle in mitochondrial respiration. With the relative overproduction of ubiquinone that occurs in order to attempt to produce the requisite cholesterol for cell replication, one of two effects, or both effects, occur on mitochrondrial respiration.
- the replicating cancer cell either comes under osmotic pressure to decrease the concentration of ubiquinone, or the increased ubiquinone concentration changes the electron transport mechanism in the inner membrane of the mitochondria. If the cell admits fluid to stabilize the ubiquinone concentration, the cell must normally change size or shape to do so.
- Ellerby et al Measurement of Cellular Oxidation, Reactive Oxygen Species, and Antioxidant Enzymes during Apoptosis, 322 Method in Enzym. 413 (Academic Press 2000), Bortner, Volume Regulation and Ion Transport during Apoptosis, 322 Method in Enzym. 421 (Academic Press 2000).
- the predicted effect is that there is a change in election transfer from Complex 1 toward Complex 3. See Metabolism at a Glance, J.G. Salway, p. 12-15 (Blackwell Science Ltd., Oxford and London, 2 nd ed. 1999). Simultaneous to the ubiquinone effect, giving attention to both the COX-2 inhibitor with the hydrophilic and lipophilic substituents referred to earlier in this specification and the chemical potential of the unpaired elections on the first and second substituents, the electrochemical potential and gradient between the matrix side of the membrane and the opposite side membrane is changed, which affects the proton pump and migration of ⁇ ions and in turn interferes with ATP synthesis.
- the likely reason is one of several, or a combination of several reasons.
- the novel combination for retarding cancer does so in part by producing osmotic stress selectively in cancer cells, and in part by interfering with membrane synthesis in cancer cells. Movement of any osmotically obligated fluid has a corollary effect of also speeding into replicating cells potentially detrimental biochemicals from the body' s own immune system. Another corollary of any change in electrochemistry in the area of the matrix or the size of the cell is damage to ion transport channels, the blockage or overexpansion of which ion transport channel is often fatal to the cell. Ellerby, 322 Methods in Enzym. 413-421, Bortner, 322 Methods in Enzym.
- the invention takes advantage of the increased ratio of anaerobic to aerobic functionality of a cancer cell compared to that ration in a normal cell.
- the growth rates of cancers parallel their level of differentiation and the relative number of their cells in mitosis. Mitoses are more abundant in the anaplastic rapidly dividing variants, meaning in the cancer cells that are creating "clones" of each other by cell division and replication.
- the increased glycolytic processes particularly the anaerobic processes, generate relative more waste product such as CO2 and lactic acid.
- the COX-2 inhibitor shifts the reaction equilibrium to promote a higher concentration of arachidonic acid. Biochemistry, Geigy Scientific Tables, Book 4, ed. by C. Lemtner, publ. by Ciba-Geigy (1986), p. 25-27; .
- the glutathione functionality is important in reducing reactive oxygen species to relieve subsequent oxidative stress which is deleterious to any cell.
- the effect in the cancer cell of the relatively reduced glutathione functionality and generation of increased wastes from increased and unregulated glycolysis is to either cause a slowing of the processes leading to waste production, thereby slowing replication, or to cause a change in osmolarity of the cell which is normally offset by increased water and a corresponding change in cell size.
- an enhancement in relief of oxidative stress occurs, as well as maintenance of full functionality, thereby strengthening the immune system competency and total body system.
- cystine Another accomplishment of the invention not suggested by the literature is to utilize cystine to ameliorate the negative renal, hepatic and gastric effects of COX-2 inhibitors and HMG-CoA inhibitors, both as a combination and individually.
- NSAlDs non-steroidal anti-inflammatory
- the COX-2 inhibitors are felt to cause a range of gastrointestinal problems.
- This amelioration by the invention of negative renal, gastric and hepatic effects is accomplished by cystine, especially in a glutathione deficient patient.
- the avoidance of a glutathione deficiency steers the patient to have a higher Th-1 response to Th-2 response ratio than the patient would have with any glutathione deficiency.
- Fosslien suggests that antioxidants such as TROLOX also inhibit COX-2 induction: "Inhibitors of COX-2 induction are tumor suppressor protein p53, estrogen, and antioxidants such as Trolox (N-acetylcysteine, 6-hydroxy-2,5,7,8-tetiamethylchroman-2- carboxylic acid), PDTC, and U75006" Fosslien, "Biochemistry of Cyclooxygenase (COX)-2 Inhibitors and Molecular Pathology of COX-2 in Neoplasia," Crit. Rev. in Clin. Lab. Sci. 37(5): 431, 433 (November 2000). TROLOX is not practical for combating cancer in mammals because it is an extremely powerful anti-oxidant and potentially toxic.
- Lovastatin its interaction with a selective COX-2 inhibitor and isoprostanes and the lipoxygenase pathway.
- lipid lowering/modifying drugs such as lovastatin were suggested to be more cancer-free than those using bile acid-binding resins. See, 3- Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors and the Risk of Cancer: A Nested Case-Control Study, 160(5) Archives of Internal Med: 2363-2368 (2000).
- Lovastatin can be predicted to have another cooperative effect with rofecoxib with respect to cancer, especially prostate cancer. There is stiong evidence that oxidative stress and subsequent free radical damage is very important in prostate cancer. Chung et al, Prostate Cancer: Biology, Genetics and the New Therapeutics, "Chemoprevention of Prostate Cancer" by Brooks and Nelson p.
- COX-2 inhibitor and the lipooxygenase pathway In examining the cyclooxygenase pathway, see Biochemistry, Geigy Scientific Tables, Book 4, ed. by C. Lemtner, publ by Ciba-Geigy (1986), p. 25, by application of Le Chatelier's principle, an inhibition of the cyclooxygenase pathway will cause the concentration of arachidonic acid to increase. Such increased concentration will cause an increase in products produced in the lipooxygenase pathway. One of those products is Leukotriene B4. Leukotriene B4 is implicated in lipoperoxidative stress to cells.
- the lipooxygenase pathway and isoprostanes As a cancer cell signals for increased COX-2 expression which is being inhibited, the signal is directed to creation of further arachidonic acid ("AA"). The differentiation from normal cells is that a normal cell is not signaling for more AA to delivery more COX-2 expression. From both COX-2 inhibition and saturation from products of AA in the lipooxygenase (“LPO") pathway, a significant buildup of AA occurs which can be most easily relieved from a redox viewpoint by creation of isoprostanes. Such excess production has implications for the lipooxygenase metabolic pathway.
- isoprostanes which are prostaglandin-like compounds which are formed by free radical catalysed peroxidation of arachidonic acid esterified in membrane phospholipids (Neurochem Res 2000 Oct;25(9-10):1357-64).
- isoprostanes are indicators of damage to membrane phospolipids.
- Arachidonic acid (AA) is sterified in the membrane phospholipids, and when oxidized, isoprostanes are the end-product. The peroxidation products are monitored by measuring the isoprostanes and lipid peroxides.
- Lipid peroxidation is best characterized as a series of chain breaking reactions in the lipid bi-layer at the membrane which inhibits the proper growth of proteins.
- the membrane is rendered more porous and susceptible to degeneration, or to penetration by other molecules in the body's immune system.
- lipid peroxidation by heat occurs in an egg white when heated. In the body, and as is desired in cancer cells, such lipid peroxidation occurs chemically.
- the HMG-CoA reductase inhibitor simvastatin has been shown to produce positive effects in the endothelial lining of blood vessels even independent of its lipid lowering effects.
- simvastatin is an analog of lovastatin, which are both statins produced from aspergillus terreus.
- the presence of the HMG-CoA reductase inhibitor may contribute to moderating the effects of lipid peroxidation produced in the normal cells moderating production of isoprostanes.
- cancer cells While a protective effective may not seem facially desirable, consideration needs to be made of the selectivity which occurs.
- cancer cells In order to obtain COX-2, cancer cells have a signaling system to stimulate the precursor of COX-2, which is arachidonic acid. Normal cells which do not have a similar need for COX-2 apparently do not have such a signaling system.
- statin for a cancer cell which under normal replication conditions will experience a more rapid genesis of lipid peroxidation products from membrane synthesis, the inventors surmise that the partial protective effect of a statin to slow the rise in isoprostane levels is selectively insufficient to protect the cancer cell from excess arachidonic acid, while acting protectively in normal cells.
- statin may have against the lipooxygenase pathway products is not sufficient to overcome either the toxic effects of excess arachidonic acid, nor to offset the cholesterol synthesis inhibition occurring in the cholesterol synthesis pathway with respect to production of mevalonate and occurring with respect to excess geraniol as a result of interference with squalene conversion to cholesterol.
- 5-HETE Another product that can result from increased arachidonic acid is 5-HETE which has been implicated in prostate cancer. Miller et al, "5-HETE Congeners as Modulators of Cell Proliferation," Bioorg. Med. Chem. Ltr. 10(17): 913-916 (Sep. 4, 2000). It is poorly disposed of. However once saturated, it will cause increased arachidonic acid buildup if arachidonic acid buildup is being artificially stimulated such as by a COX-2 inhibitor.
- the addition of CLA to the diet of people undergoing metabolic cancer therapy with a Hmg-CoA and a COX-2 inhibitor would result in an enhanced effect by increasing the lipid oxidation effect of the isoprostanes, and shows the creation of excess arachidonic acid has antitumorigenic effect as predicted by the inventors.
- the treatment dose of the COX-2 inhibitor can be maximized to give the maximum tolerated dose for use in cancer therapy without creating excessive systemic toxicity. More lipid oxidation activity indicates increased oxidative stress, usually a characteristic of cancer activity. A long-term falling level of isoprostanes will mean for COX-2 expressing cancers that there is relatively less cancer risk.
- statin can ameliorate the tendency to lipid peroxidation, which is why a lower dose is preferred, it need only be sufficient to impair cholesterol synthesis, and there remain sufficient lipid peroxidants to damage cancer cells while normal cells are slightly protected.
- the presence of ubiquinones in normal cells with adequate glutathione does not materially change their characteristics; however in cancer cells, the excess ubiquinones in combination with the already nascent tendency to express lipid peroxidation sufficiently the weakens the cells to expose them to immune system attack, a tendency not overcome by the presence of glutathione which is less active in the more anaerobic environment of a cancer cell.
- Lovastatin and its inhibition of farnesyl pyrophosphate and generaylgeranylpyrophosphate Lovastatin has another inhibitory effect which has implications for both cholesterol synthesis, ubiquinone concentration, and farnesyl pryrophosphate concentration.
- Lovastatin an HMG-CoA reductase inhibitor that inhibits the biosynthesis of farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GPP) is used routinely as a positive control for inhibition of processing of both geranylgeranylated and farnesylated proteins [citations omitted].
- GPP inhibition likely has the same effect as post-lanosterol cholesterol cycle inhibition in that additional energy must be used to overcome inhibitory effects.
- the Vogt article also notes that cysteine is important in ras oncogene activation. This teaches away from the benefits of glutathione pathway protection, but the inventors suggest that the combination of diversion of glutathione pathway resources to stabilize other adversely affected metabolic pathways of a cancer cell is likely sufficient in combination with FPP and GPP inhibition to interfere with cell replication. What FPP is generated will be diverted to enhance cholesterol synthesis making it less available for ras oncogene activation in conjunction with cysteine.
- Nitric oxide though being a free radical shows a long range of action and rather low toxicity. It inhibits lipid peroxidation and caspases. Interaction of nitric oxide with superoxide anions causes the formation of peroxynitrite, a potent lipid peroxidant and apoptosis inducer.” Id. at 4116. There are a series of reactions, several of which involve glutathione. The positive empirical results from the patients on which this invention was tested indicate that peroxynitrite acts as a strong oxidant when increased there is cytokine production.
- cancer cells having complete angiogenesis will be less affected by these reactions, the inclination to apoptosis and the degeneration of angiogenic species either as a result of the death of a cell, or the waste of energy in the tumor to generate unutilized angiogenesis both inhibit the cancer cell's growth.
- H 2 O 2 has a potential rescuing effect for cells to blunt NO mediated apoptosis at high cell density.
- a primary generator of H 2 O 2 is glutathione reactions which in a normal cell environment remove hydroxyl radicals, and nitric oxide radicals.
- metal ions particularly copper, zinc and magnesium
- glutathione competent cells the H O 2 breaks down into water.
- cells are in a sense rescued from apoptosis in that situation. In cells not so equipped, which would include a number of cancer cells in a tumor, more hydroxyl radicals are generated, and there is not a rescue from apoptosis.
- H 2 O 2 is a far-ranging species that can intercept NO species far from a cell membrane
- intercellular range is less of an issue
- the relatively toxicity and tumorogenicity of those cancers where the range of operation is less of a factor in what self-protective mechanisms the body has to battle the cancer.
- the presence of HOCl cannot be ignored which Bauer believes interacts with H 2 O 2 to generate non reactive molecules such as oxygen, water, chloride anions and protons.
- Bauer 20 AntiCancer Research 4115-4140, generally.
- Glutathione Glutathione
- Glutathione a critical element in immune system function, unquestionably has some positive effects for the cancer cell because it can scavenge free radicals. Yet this is needed in all cells. Glutathione does have a favorable effect on cancer cells through its protection of the disulfide bridges. Protection of disulfide bridges inhibits lipid peroxidation therefore protecting protein structure, particularly tertiary and quaternary structures. "Glutathione probably helps maintain the sulfhydryl groups of proteins in the reduced state and the iron of heme in the ferrous (Fe2+) state, and it serves as a reducing agent for glutaredoxin in deoxyribonucleotide synthesis (see Fig. 2-37 [in source]).
- Glutathione is gamma-Glu-Cys-Gly.
- the COO- ion on the end of the chain will be more present and a more favored species in a less acidic environment.
- the more acidic environment of anaerobic glycolysis in cancer cells causes a shift to moderately lower relative glutathione concentrations, and consequently less protection from apoptotic free radical reactions.
- the competitive consumption of energy to overcome cholesterol synthesis, to overcome interference with mitochrondrial respiration, and the competitive consumption of GSH to thwart lipid peroxidation, and to rescue cancer cells from reactive oxygen and nitrogen species either weakens existing cells, weakens newly generated cells (which may then undergo self-apoptosis) or inhibits membrane and DNA synthesis or all of these.
- the inherent characteristics of replicating cancer cells and the necessary anaerobic enhancement to their energy processes enable the invention to selectively attack cancer cells while normal cells and their homeostatic processes can protect the mammalian organism which the inventors desire to preserve.
- the administiation of the compounds in the invention enable the organism to achieve the senescence which cancer cells have attempted to elude through a variety of mechanisms that the body in many instances is helpless to resist.
- the use of HOCl, and the application of NO «- and OH «- is the usual means to achieve senescence, and the invention enables proper operation of that mechanism.
- NADPH concentration, COX-2 inhibitors and apoptosis A corollary effect of the inhibition of creation of cholesterol relates to the shifting of equilibrium toward to squalene and a higher concentration of NADPH+H+ as a result of the action of the COX-2 inhibitor.
- NADPH +H+ has a series of contradictory effects. Exterior to the mitochrondria, increased levels of NADPH can be seen to slow reactions in the pentose phosphate pathway, namely in the transition from glucose 6-phosphate to ribulose 5-phosphate. Selective shifts in this pathway affect glucose-6-phosphate, though perhaps only mildly. NADPH concentration shifts also slow the conversion of malate to pyruvate, a precursor to acetyl CoA, a precursor to cholesterol, a possible positive in inhibiting cancer cell membrane synthesis.
- Salway Metabolism at a Glance (Blackwell Science Oxford 1999) at p. 60.
- homeostasis is such that an Acetyl CoA imbalance is not toxic on refeeding after starvation because the Acetyl CoA /CoA precursor ratio is not affected.
- Metal complex interactions The interaction of nitrous oxide and reactive oxygen species is one of the most important apoptotic triggers in anti-tumor activity.
- COX-2 has two interactions with mitochrondrial respiration and ATP utilization, one direct and one indirect.
- the direct interaction is the lipophilic/hydrophilic orientation which can inhibit the F0/F1 channel in complex IV. Salway, Metabolism at a Glance at 14-15 (Blackwell Science 2 nd ed. 1999).
- the indirect interaction is the increased relative production of ubiquinone as a result of the inhibition of cholesterol demethylation.
- Metal ions have the capacity to catalyze, in conjunction with superoxide dismutase (SOD), generation of compounds influential in apoptotic process.
- SOD superoxide dismutase
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AU2002213050A AU2002213050A1 (en) | 2000-10-06 | 2001-10-06 | A combination and method of treatment of cancer utilizing a cox-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (hmg-coa) reductase inhibitor |
US09/997,490 US20020132781A1 (en) | 2000-10-06 | 2001-11-17 | Combination and method of treatment of cancer utilizing a COX-2 inhibitor and A 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor |
PCT/US2002/002477 WO2002094021A1 (en) | 2000-10-06 | 2002-01-26 | A combination and method of treatment of cancer utilizing a cox-2 inhibitor and an hmg-coa inhibitor and cystine to enhance glutathione |
US10/057,511 US20020169195A1 (en) | 2001-01-26 | 2002-01-26 | Combination and method of treatment of cancer utilizing a COX-2 inhibitor and an HMG-CoA inhibitor and cystine to enhance glutathione |
PCT/US2002/002480 WO2002067853A2 (en) | 2000-10-06 | 2002-01-26 | A combination and method of treatment of hiv and viral diseases, vascular disease and cancer utilizing a cox-2 inhibitor and cystine |
AU2002251833A AU2002251833A1 (en) | 2001-01-26 | 2002-01-26 | A combination and method of treatment of hiv and viral diseases, vascular disease and cancer utilizing a cox-2 inhibitor and cystine |
PCT/US2002/002478 WO2002083124A1 (en) | 2000-10-06 | 2002-01-26 | A composition and method of sustaining chemotherapeutic effect while reducing dose of chemotherapeutic agent using cox-2 inhibitor and statin |
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US60/238,506 | 2000-10-06 | ||
US24390200P | 2000-10-27 | 2000-10-27 | |
US24390100P | 2000-10-27 | 2000-10-27 | |
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US60/243,902 | 2000-10-27 | ||
US24559200P | 2000-11-03 | 2000-11-03 | |
US60/245,592 | 2000-11-17 | ||
US26451101P | 2001-01-26 | 2001-01-26 | |
US60/264,511 | 2001-01-26 | ||
US30768901P | 2001-07-25 | 2001-07-25 | |
US09/912,703 US6534540B2 (en) | 2000-10-06 | 2001-07-25 | Combination and method of treatment of cancer utilizing a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (HMG-CoA) reductase inhibitor |
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WO2004024165A1 (en) * | 2002-09-09 | 2004-03-25 | Novartis Ag | Combination therapy comprising a bisphosphonate and a hmg-coa reductase inhibitor |
WO2004062659A1 (en) * | 2003-01-13 | 2004-07-29 | Mayne Pharma Pty Ltd | Methods and compositions for preventing/reducing the severity of side effects of chemotherapy and/or radiotherapy |
WO2007005941A2 (en) | 2005-07-05 | 2007-01-11 | President And Fellows Of Harvard College | Liver targeted conjugates |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999020110A1 (en) * | 1997-10-22 | 1999-04-29 | Merck & Co., Inc. | Combination therapy for reducing the risks associated with cardio- and cerebrovascular disease |
US5972986A (en) * | 1997-10-14 | 1999-10-26 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia |
US6025353A (en) * | 1997-11-19 | 2000-02-15 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents |
US6203820B1 (en) * | 1998-05-28 | 2001-03-20 | Brice E. Vickery | Compositions and methods for enhancing protein anabolism and detoxification |
-
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---|---|---|---|---|
US5972986A (en) * | 1997-10-14 | 1999-10-26 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia |
WO1999020110A1 (en) * | 1997-10-22 | 1999-04-29 | Merck & Co., Inc. | Combination therapy for reducing the risks associated with cardio- and cerebrovascular disease |
US6025353A (en) * | 1997-11-19 | 2000-02-15 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents |
US6203820B1 (en) * | 1998-05-28 | 2001-03-20 | Brice E. Vickery | Compositions and methods for enhancing protein anabolism and detoxification |
Non-Patent Citations (3)
Title |
---|
AGARWAL B. ET AL.: 'Lovastatin augments sulindac-induced aoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac' GASTROENTEROLOGY vol. 117, no. 4, 1999, pages 838 - 847, XP002930774 * |
VITALE M. ET AL.: 'Prenyltransferase inhibitors induce apoptosis in proliferating thyroid cells trough a p53-independent, CrmA-sensitive and caspace-3-like protease-dependent mechanism' ENDOCRINOLOGY vol. 140, no. 2, 1999, pages 698 - 704, XP000997985 * |
WOJCIK C. ET AL.: 'Lovastatin and simvastatin are modulators of the proteasome' INT. J. BIOCHEM. CELL BIOL. vol. 32, no. 9, 01 September 2000, pages 957 - 965, XP002908434 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2004024165A1 (en) * | 2002-09-09 | 2004-03-25 | Novartis Ag | Combination therapy comprising a bisphosphonate and a hmg-coa reductase inhibitor |
CN1327844C (en) * | 2002-09-09 | 2007-07-25 | 诺瓦提斯公司 | Combination therapy comprising a bisphosphonate and a HMG-COA reductase inhibitor |
WO2004062659A1 (en) * | 2003-01-13 | 2004-07-29 | Mayne Pharma Pty Ltd | Methods and compositions for preventing/reducing the severity of side effects of chemotherapy and/or radiotherapy |
WO2007005941A2 (en) | 2005-07-05 | 2007-01-11 | President And Fellows Of Harvard College | Liver targeted conjugates |
EP1948600A2 (en) * | 2005-07-05 | 2008-07-30 | THE PRESIDENT & FELLOWS OF HARVARD COLLEGE | Liver targeted conjugates |
EP1948600A4 (en) * | 2005-07-05 | 2011-09-07 | Harvard College | Liver targeted conjugates |
US9585964B2 (en) | 2005-07-05 | 2017-03-07 | President And Fellows Of Harvard College | Liver targeted conjugates |
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