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  Use of a nitroxide or a prodrug thereof in the prophylactic and therapeutic treatment of cancerUSPTO Application #: 20070021323Title: Use of a nitroxide or a prodrug thereof in the prophylactic and therapeutic treatment of cancer Abstract: in an amount sufficient to prevent or treat said cancer, wherein said cancer is susceptible to prevention or treatment by said nitroxide or prodrug thereof. Also provided is a composition for use in the method. The present invention provides a method for the prophylactic and therapeutic treatment of cancer. The method comprises administering to an animal, preferably a mammal, more preferably a human, at risk for developing a cancer or having a cancer a nitroxide or a prodrug thereof, wherein the nitroxide or prodrug thereof preferably is alicyclic or heterocyclic and more preferably is a compound of Formula I or Formula II: (end of abstract) Agent: Leydig, Voit & Mayer, Ltd. - Chicago, IL, US Inventors: James B. Mitchell, Angelo Russo, Murali Krishna Cherukuri, Anne Marie DeLuca USPTO Applicaton #: 20070021323 - Class: 514002000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai The Patent Description & Claims data below is from USPTO Patent Application 20070021323. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This patent application is a continuation of copending U.S. patent application Ser. No. 09/424,519, which is the national phase of PCT/US98/10685, filed May 27, 1998, claiming the benefit of U.S. Provisional Patent Application No. 60/047,724, filed May 27, 1997. FIELD OF THE INVENTION [0002] The present invention relates to nitroxides and prodrugs thereof and their use in the prophylactic and therapeutic treatment of cancer. BACKGROUND OF THE INVENTION [0003] Cancer is a major world-wide health problem. Given that the vast majority of human tumors are difficult to treat effectively, those afflicted suffer physically, emotionally and financially and inevitably die an early death. There is also a tremendous burden on the families and friends of those afflicted as well as on society at large. Accordingly, the ability to prevent cancer, delay its onset and/or slow its progression would benefit everyone. [0004] Although extensive research around the world has led to advances in cancer treatment, progress has been slow and there is no known cure. However, modern molecular biological techniques have contributed to our understanding of the genetic aspects of cancer development. For example, the tumor suppressor gene p53, which is representative of a general class of genes that code for products that regulate cellular function by thwarting the cascade of events that causes a normally functioning cell to either die or become immortal, i.e., cancerous, has been shown to encode a transcription factor that suppresses tumor development. Mutations in the p53 tumor suppressor gene have been shown to affect the production of the oncogene-suppressing transcription factor. For example, either no transcription factor is produced or a transcription factor that is ineffectual or partially effective is produced. In fact, the p53 tumor suppressor gene is the most common site of genetic lesions in human cancers (Levine et al., Nature 351: 453-456 (1991); and Hollstein et al., Science 253: 49-53 (1991)), with more than half of all human tumors exhibiting p53 point mutations or deletions (Chang et al., Am. J. Gastroenterol. 88: 174-186 (1993)). Mutations in the p53 gene also have been associated with Li-Fraumeni syndrome, a familial autosomal dominant disease associated with an increased risk of tumorigenesis (Srivastava et al., Nature 348: 747-749 (1990)). The p53 protein also plays a role in the cellular response to DNA-damaging agents by facilitating a block in the G1 phase of the cell cycle following DNA damage, thereby providing time for repair of the DNA damage (Pietenpol et al., Nature 365: 17-18 (1993); and Kuerbitz et al., PNAS USA 89: 7491-7495 (1992)) or by causing apoptosis (Yonish-Rouach et al., Nature 352: 345-347 (1991)). [0005] In order to enable the further study of the p53 gene, recombinant DNA techniques have been used to develop rodent models. In one model, the rodents are homozygous for mutant p53 alleles (p53-/-), such that the p53 gene is disrupted or "knocked-out" (p53-/-) and does not function, and the rodents are highly susceptible at an early age to a variety of tumors (Donehower et al., Nature 356: 251-221 (1992)). In another model, the rodents are heterozygous for wild-type and mutant p53 alleles (p53+/-) and, although they develop tumors 10-20 months after birth, they live considerably longer than the homozygous mutant p53 rodents (Harvey et al., Nature/Genetics 5: 225-229 (1993)). Exposure of these rodents to carcinogens, such as dimethylnitrosamine, or whole body irradiation accelerates tumor formation (Harvey et al. (1993), supra; and Lee et al., Oncogene 12: 3731-3736 (1994)). [0006] Nitroxides are stable compounds, which are low in molecular weight, metal-independent, nontoxic and nonallergenic, and are characterized by low reactivity with oxygen, high solubility in aqueous solutions, and the ability to cross cellular membranes. The lipophilicity of nitroxides can be controlled by the addition of various organic substituents, in order to facilitate the targeting of the nitroxides to specific organs or organelles. [0007] Nitroxides have been shown to protect cells and animals against the untoward acute effects, such as cytotoxicity, of short-term exposure to lethal doses of free radicals and oxidative species, such as superoxide, hydrogen peroxide, hydroxyl radicals, and hydroperoxides, i.e., by functioning as antioxidants (U.S. Pat. No. 5,462,946). In cell culture, nitroxides have been shown to sensitize hypoxic cells to ionizing radiation and, paradoxically, protect aerobic cells from ionizing radiation. Also in cell culture, nitroxides have been shown to protect cells against the acute cytotoxic affects of paraquat and anti-neoplastic agents. In animals, nitroxides have been shown to protect against radiation-induced alopecia and to induce weight loss. It has been reported that nitroxides can be used to protect against pulmonary adult respiratory distress syndrome, lenticular degeneration and hyaline membrane disease in infants, cataracts, oxidative stress, such as that associated with oxygen therapy or hyperbaric oxygen treatment, reperfusion injury, such as that associated with myocardial infarction, stroke, pancreatitis, intestinal ulceration, and organ transplantation. [0008] It has now been surprisingly and unexpectedly discovered that nitroxides and prodrugs thereof are useful in the prophylactic and therapeutic treatment of cancer (i.e., prevention, delay of onset, and slowing of progression of cancer). Accordingly, it is an object of the present invention to provide a method for the prophylactic and therapeutic treatment of cancer. It is another object of the present invention to provide a composition for use in the method. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein. BRIEF SUMMARY OF THE INVENTION [0009] The present invention provides a method for the prophylactic and therapeutic treatment of cancer. The method comprises administering to an animal, preferably a mammal, more preferably a human, at risk for developing a cancer or having a cancer, a nitroxide or a prodrug thereof in an amount sufficient to prevent or treat the cancer, respectively, wherein said cancer is susceptible to prevention or treatment with said nitroxide or said prodrug thereof. Preferably, the nitroxide or prodrug thereof is alicyclic or heterocyclic. More preferably, the nitroxide or prodrug thereof is a compound of Formula I or Formula II: wherein R.sub.1 is selected from the group consisting of H, OH, OZ, O., .dbd.O and Y, wherein Y is a leaving group, which can be converted to H, OH, O. or .dbd.O by reaction with a nucleophilic agent, and Z is selected from the group consisting of a C.sub.1-20 aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, a C.sub.1-20 alicyclic group, a noncarbon/nonoxygen moiety, a carbohydrate, a lipid, a nucleic acid and a protein. Preferably, the aromatic group comprises a 5- or 6-membered structure in which each member is independently selected from the group consisting of carbon and a heteroatom. Preferred heteroatoms in the aromatic group include nitrogen, oxygen, sulfur, phosphorus and boron. The noncarbon/nonoxygen moiety preferably comprises a member selected from the group consisting of boron, sulfur, phosphorus and nitrogen. R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently selected from the group consisting of a C.sub.1-20 alkyl group, a C.sub.2-20 alkenyl group, a C.sub.2-20 alkynyl group, and --CH.sub.2--[CR'R''].sub.m--CH.sub.3, wherein R' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, and a multicyclic aromatic group as described above, and R'' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, and a multicyclic aromatic group as described above, a C.sub.1-20 alicyclic group, a noncarbon/nonoxygen moiety as described above, a carbohydrate, a lipid, a nucleic acid, and a protein, and m.ltoreq.30. R.sub.2 and R.sub.3 or R.sub.4 and R.sub.5 can be connected through one or more members, each of which is independently selected from the group consisting of carbon and a heteroatom. R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently selected from the group consisting of hydrogen, a hydroxyl group, a C.sub.1-20 aldehydic group, a C.sub.1-20 keto group, a primary amino group, a secondary amino group, a tertiary amino group, a sulfido group, a disulfido group, a sulfato group, a sulfito group, a sulfonato group, a sulfinato group, a sulfenato group, a sulfamato group, a metal-containing group, wherein the metal is preferably selected from the group consisting of a transition metal and a lanthanide, a silicone group, a halide, a C.sub.1-20 ester-containing group, a carboxyl group, a phosphato group, a phosphino group, a phosphinato group, a phosphonato group, a C.sub.1-20 alkyl group, a C.sub.2-20 alkenyl group, a C.sub.2-20 alkynyl group, and --CH.sub.2--[CR'R''].sub.m--CH.sub.3, wherein R' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, and a multicyclic aromatic group as described above, and R'' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, a multicyclic aromatic group as described above, a C.sub.1-20 alicyclic group, a noncarbon/nonoxygen moiety as described above, a carbohydrate, a lipid, a nucleic acid and a protein, and m.ltoreq.30. Any one of R.sub.6, R.sub.7, R.sub.8 and R.sub.9 can be attached covalently or noncovalently to a polymer of synthetic or natural origin. In Formula I, one of R.sub.6 and R.sub.7 and one of R.sub.8 and R.sub.9 can be absent such that a double bond joins the two carbon atoms to which the remaining R groups are attached. In Formula I, n=0-20, and in Formula II, n=1-20. X is a heteroatom, and R.sub.10 and R.sub.11 are independently selected from the group consisting of a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, a multicyclic aromatic group as described above, each as defined above, a C.sub.1-20 aliphatic/aromatic group, a heteroatomic group, a C.sub.1-20 ether-containing group, a C.sub.1-20 keto group, a C.sub.1-20 aldehydic group, a carboxamido group, a cyano group, an amino group, a carboxyl group, a selenium-containing group, a sulfato group, a sulfito group, a sulfenato group, a sulfinato group, and a sulfonato group. R.sub.10 and R.sub.11 can be connected through an aliphatic group and/or an aromatic group, or R.sub.10 and/or R.sub.11 can comprise a member selected from the group consisting of a carbohydrate, a lipid, a nucleic acid and a protein. Also provided by the present invention is a composition comprising a nitroxide or a prodrug thereof for use in the above-described method. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG. 1 is a graph of tumor-free survival (%) vs. time (days), wherein open circles represent the control animals and closed circles represent the nitroxide treated animals. [0011] FIG. 2 is a graph of total number of tumors/group (n=20) versus control-1, control-2, Tempol/1 year, and Tempol/entire life span groups. DETAILED DESCRIPTION OF THE INVENTION [0012] The present invention provides a method for the prophylactic and therapeutic treatment of cancer in an animal, preferably a mammal, more preferably a human. The cancer can be due to a genetic defect, such as a point mutation, an insertion or a deletion, which can be either homozygous or heterozygous, in (i) a tumor suppressor gene, such that the tumor suppressor gene no longer suppresses tumor formation or does so with reduced efficacy, or (ii) a protooncogene, such that the protooncogene is converted to an oncogene, which causes cancer. Examples of inherited genetic defects that predispose humans to developing cancer include, but are not limited to, ataxia telangiectasia, Cowden's disease, Torre's syndrome, Gardner's syndrome, Wiskott-Aldrich syndrome, Peutz-Jeghers syndrome, Bloom's syndrome, Fanconi's syndrome, Wemers syndrome, Chediak-Higashi syndrome, retinoblastoma, Beckwith-Wiedeman syndrome, and neuroblastoma. In addition to cancers arising from such inherited genetic defects, genetic defects can be induced by a variety of agents that damage DNA. For example, a number of studies have shown that oxidizing agents (e.g., ionizing radiation and/or oxygen derived free radicals) increase DNA mutations, leading to cancer induction in mammals (see, e.g., Helbock et al., PNAS USA 95: 288-293 (1998); Kreutzer et al., PNAS USA 95: 3578-3582 (1998); Valentine et al., Biochemistry 37: 7030-7038 (1998); McBride et al., Biochemistry 30: 207-213 (1991); Reid et al., Princess Takamatsu Symp. 22: 221-229 (1991); and Klaunig et al., Environ. Health Perspect. 106 (Suppl.): 289-95 (1998)). [0013] Genetic "knock-out" models can be developed for genetic defects in accordance with methods known in the art (Joyner et al., Nature 338: 153-156 (1989); see also Donehower et al. (1992), supra, and Harvey et al. (1993), supra) so as to determine whether or not a cancer caused by such a defect can be prevented, its onset delayed, and/or its progression slowed by a nitroxide or prodrug thereof in accordance with the present invention. Such models then can be used further to determine which nitroxides or prodrugs thereof are particularly effective in the prophylactic and therapeutic treatment of a given cancer, and in what amounts. A genetic "knock-out" model has been developed for ataxia telangiectasia (Barlow et al., Cell 86: 159-171 (1996)). [0014] The method of the present invention comprises administering to an animal, preferably a mammal, more preferably a human, at risk for developing a cancer or having a cancer (e.g., a genetic defect or a proclivity for a genetic defect, such as an induced or inherited genetic defect, that promotes or causes cancer), a nitroxide or a prodrug thereof in an amount sufficient to prevent or treat said cancer, respectively, wherein said cancer is susceptible to prevention or treatment with said nitroxide or said prodrug thereof. By "nitroxide" is meant a compound that contains one or more nitroxide groups (i.e., N--O. groups). By "prodrug" is meant a compound that contains at least one functional group that can be converted into a nitroxide group, thereby transforming the prodrug into a nitroxide. [0015] If the cancer is caused by a genetic defect, preferably the genetic defect affects a cancer regulatory gene or a tumor suppressor gene. A cancer regulatory gene is a gene that up-regulates or down-regulates a gene that causes cancer. Examples of such a gene include abl and bcl2. A tumor suppressor gene is a gene that suppresses tumor formation, such as the p53 gene, which is preferred. [0016] The nitroxide or prodrug thereof to be administered preferably is alicyclic or heterocyclic. More preferably, the alicyclic or heterocyclic nitroxide or prodrug thereof is a compound of Formula I or Formula II: wherein R.sub.1 is selected from the group consisting of H, OH, OZ, O., .dbd.O and Y, wherein Y is a leaving group, which can be converted to H, OH, O or .dbd.O by reaction with a nucleophilic agent, and Z is selected from the group consisting of a C.sub.1-20 aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, a C.sub.1-20 alicyclic group, a noncarbon/nonoxygen moiety, a carbohydrate, a lipid, a nucleic acid and a protein. Preferably, the aromatic group comprises a 5- or 6-membered structure in which each member is independently selected from the group consisting of carbon and a heteroatom. Preferred heteroatoms in the aromatic group include nitrogen, oxygen, sulfur, phosphorus and boron. The noncarbon/nonoxygen moiety preferably comprises a member selected from the group consisting of boron, sulfur, phosphorus and nitrogen. R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently selected from the group consisting of a C.sub.1-20 alkyl group, a C.sub.2-20 alkenyl group, a C.sub.2-20 alkynyl group, and --CH.sub.2--[CR'R''].sub.m--CH.sub.3, wherein R' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, and a multicyclic aromatic group as described above, and R'' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, a multicyclic aromatic group as described above, a C.sub.1-20 alicyclic group, a noncarbon/nonoxygen moiety as described above, a carbohydrate, a lipid, a nucleic acid, and a protein, and m.ltoreq.30. R.sub.2 and R.sub.3 or R.sub.4 and R.sub.5 can be connected through one or more members, each of which is independently selected from the group consisting of carbon and a heteroatom. R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently selected from the group consisting of hydrogen, a hydroxyl group, a C.sub.1-20 aldehydic group, a C.sub.1-20 keto group, a primary amino group, a secondary amino group, a tertiary amino group, a sulfido group, a disulfido group, a sulfato group, a sulfito group, a sulfonato group, a sulfinato group, a sulfenato group, a sulfamato group, a metal-containing group, wherein the metal is preferably selected from the group consisting of a transition metal and a lanthanide, a silicone group, a halide, a C.sub.1-20 ester-containing group, a carboxyl group, a phosphato group, a phosphino group, a phosphinato group, a phosphonato group, a C.sub.1-20 alkyl group, a C.sub.2-20 alkenyl group, a C.sub.2-20 alkynyl group, and --CH.sub.2--[CR'R''].sub.m--CH.sub.3, wherein R' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, and a multicyclic aromatic group as described above, and R'' is selected from the group consisting of hydrogen, a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, a multicyclic aromatic group as described above, a C.sub.1-20 alicyclic group, a noncarbon/nonoxygen moiety as described above, a carbohydrate, a lipid, a nucleic acid and a protein, and m.ltoreq.30. Any one of R.sub.6, R.sub.7, R.sub.8 and R.sub.9 can be attached covalently or noncovalently to a polymer of synthetic or natural origin. In Formula I, one of R.sub.6 and R.sub.7 and one of R.sub.8 and R.sub.9 can be absent such that a double bond joins the two carbon atoms to which the remaining R groups are attached. In Formula I, n=0-20, and in Formula II, n=1-20. X is a heteroatom, and R.sub.10 and R.sub.11 are independently selected from the group consisting of a C.sub.1-20 aliphatic group, a monocyclic aromatic group as described above, a bicyclic aromatic group as described above, a multicyclic aromatic group as described above, a C.sub.1-20 aliphatic/aromatic group, a heteroatomic group, a C.sub.1-20 ether-containing group, a C.sub.1-20 keto group, a C.sub.1-20 aldehydic group, a carboxamido group, a cyano group, an amino group, a carboxyl group, a selenium-containing group, a sulfato group, a sulfito group, a sulfenato group, a sulfinato group, and a sulfonato group. R.sub.10 and R.sub.11 can be connected through an aliphatic group and/or an aromatic group, or R.sub.10 and/or R.sub.11 can comprise a member selected from the group consisting of a carbohydrate, a lipid, a nucleic acid and a protein. The aliphatic group can be branched, substituted and/or unsaturated. If the aliphatic group is substituted, preferably it is substituted with a heteroatom, which is preferably selected from the group consisting of oxygen, phosphorus, selenium, sulfur and nitrogen. The aromatic group can be substituted. If the aromatic group is substituted, preferably it is substituted with a heteroatom, which is preferably selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus and boron. The alicyclic group can be substituted and/or unsaturated. If the alicyclic group is substituted, preferably it is substituted with a heteroatom. The amino group also can be substituted. If the amino group is substituted, preferably it is substituted with up to three substituents selected from the group consisting of a C.sub.1-20 aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, and a C.sub.1-20 alicyclic group, all of which are as described above. Although carbon ranges have been specified for a number of the substituents recited above, such carbon ranges are only preferred, as substituents comprising carbon atoms outside the specified ranges can be effective in the context of the present inventive method. [0017] The above-described method can be adapted for in vitro utilization for scientific and research purposes, including the determination of which types of cancers can be treated by administration of a nitroxide or a prodrug thereof in accordance with the present inventive method. However, the above-described method has particular usefulness in in vivo applications, e.g., in the prevention, delay of onset, and/or slowing of the progression of cancer. [0018] One skilled in the art will appreciate that many suitable methods of administering a nitroxide or a prodrug thereof to an animal, preferably a mammal, more preferably a human, are available, that more than one route can be used to administer a particular compound, and that a particular route can provide a more immediate and more effective treatment than another route. Accordingly, the above-described method is merely exemplary and is in no way limiting. Continue reading... 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