WO2004035043A1

WO2004035043A1 - Clofarabine and platinum chemotherapy combination

Info

Publication number: WO2004035043A1
Application number: PCT/US2003/032889
Authority: WO
Inventors: Katherine Stephenson; Sean T. Wilson; Steven D. Weitman
Original assignee: Ilex Products, Inc.
Priority date: 2002-10-16
Filing date: 2003-10-14
Publication date: 2004-04-29
Also published as: AU2003277416A1

Abstract

The present invention provides for the treatment of cancers by a combination of clofarabine and a platinum cancer therapeutic agent.

Description

DESCRIPTION

CLOFARABINE AND PLATINUM CHEMOTHERAPY COMBINATION

FIELD OF THE INVENTION

This invention relates to the use of clofarabine in cancer therapy. More particularly, it relates to the use of a combination of clofarabine and a platinum cancer therapeutic agent in the treatment of cancer.

BACKGROUND OF THE INVENTION

Cancer remains a major world-wide health problem. Although many advances have been made in cancer detection and therapy, no universally successful method for treatment or prevention is currently available. Cancer therapy currently relies on a combination of early diagnosis and treatment, which may include radiotherapy, chemotherapy or hormone therapy. The toxicity of such treatments often imposes limits on the use of presently available anticancer agents. The high mortality rate for many cancers indicates that improvements are needed in cancer prevention and treatment. Clofarabine (2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine) is a synthetic nucleoside analog that incorporates the favorable properties of fludarabine and cladrabine. Thus, clofarabine has a chlorine atom at the purine C-2 position that confers resistance to deamination, and a fluorine at the C-2' of the arbinofuranosyl moiety that decreases the susceptibility to phosphorolytic cleavage. Clofarabine has shown potent cytotoxicity in human cell lines (Secrist et al., 1988; Carson et al., 1992) and therapeutic activity in murine tumor models (Montgomery et al., 1992). Preclinical screening also suggests that, in contrast to fludarabine and cladrabine, clofarabine has potential activity against solid tumors (Waud et al, 2000). Phase I and phase II clinical studies reported a marked decrease in leukemic cell counts in patients with acute myelogenous leukemia (Kantarjian et al, 2001). The dose-limiting toxicity for clofarabine is myelosuppression in solid tumors and hepatic and skin toxicity in leukemias, the maximum tolerated dose being reported as 2-4 mg/kg for solid tumors when given daily for five days (Kozuch et al., 1999), while the maximum tolerated doses for leukemias are at least an order of magnitude higher (Gandi et al., 2002; Jeha et al., 2002). Use of clofarabine in combination regimens with other chemotherapeutic agents may enhance the benefits of both clofarabine and the combined chemotherapeutic agent, thereby facilitating the treatment of a variety of tumor types while maintaining an acceptable toxicological profile.

SUMMARY OF THE INVENTION

This invention provides for the use of clofarabine in combination with platinum cancer therapeutic agents, wherein such combinations enhances the efficacy relative to either agent, thereby potentially reducing the amount of clofarabine and/or platinum cancer therapeutic agent required to elicit an anticancer effect when used in combination. One aspect of the present invention is a method for inhibiting the growth of a tumor cell, comprising contacting the tumor cell with clofarabine and a platinum cancer therapeutic agent, wherein the dose of clofarabine, when combined with the dose of the platinum cancer therapeutic agent, is effective to inhibit tumor cell growth. In various embodiments, the platinum cancer therapeutic agent is selected from the group consisting of cisplatin, oxaliplatin and carboplatin, or on one embodiment, the platinum cancer therapeutic agent is oxaliplatin. In various embodiments, the tumor cell is selected from the group consisting of a skin cancer cell, a prostate cancer cell, a lung cancer cell, a brain cancer cell, a breast cancer cell, an ovarian cancer cell, a cervical cancer cell, a liver cancer cell, a pancreatic cancer cell, a colon cancer cell, a stomach cancer cell, a leukemia cell, and a lymphoma cell. In another aspect, the present invention provides for a method of killing tumor cells, comprising contacting the tumor cell with clofarabine and a therapeutic platinum cancer therapeutic agent, wherein the dose of clofarabine, when combined with the dose of the platinum cancer therapeutic agent, is effective to kill said tumor cell.

A further aspect of the present invention provides for a method for treating cancer in a human patient comprising administering clofarabine and a platinum cancer therapeutic agent, wherein the dose of clofarabine, when combined with the dose of the platinum cancer therapeutic agent, is effective to treat the cancer. In various embodiments, the platinum cancer therapeutic agent is selected from the group consisting of cisplatin, oxaliplatin and carboplatin, or on one embodiment, the platinum cancer therapeutic agent is oxaliplatin. In various embodiments the cancer is selected from the group consisting of skin cancer, prostate cancer, lung cancer, brain cancer, breast cancer, ovarian cancer, cervical cancer, liver cancer, pancreatic cancer, colon cancer, stomach cancer, leukemia and lymphoma. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical depiction of the response of subcutaneous HT29 human colon tumors to Oxaliplatin. • = control group; __ = Oxaliplatin 7.5 mg/kg/dose Q7Dx3; Δ =

Oxaliplatin 3.75 mg kg/dose Q7Dx3; V= Oxaliplatin 1.88 mg kg dose Q7Dx3.

FIG. 2 is a graphical depiction of the response of subcutaneous HT29 human colon tumors to chlofarabine. • = control group; __ = Clofarabine 4 mg/kg/dose Q4Hx3, QlDxlO; Δ =

Clofarabine 2 mg/kg/dose Q4Hx3, QlDxlO; V = Clofarabine 1 mg/kg/dose Q4Hx3, QlDxlO.

FIG. 3 is a graphical depiction of the response of subcutaneous HT29 human colon tumors to a combination treatment of 4 mg/kg/dose clofarabine and 7.5 mg/kg/dose taxotere. • = control group; __ = Clofarabine 4 mg/kg/dose single agent; Δ = Oxaliplatin 7.5 mg/kg/dose single agent; V = Clofarabine 4 mg/kg/dose and Oxaliplatin 7.5 mg/kg/dose combination.

FIG. 4 is a graphical depiction of the response of subcutaneous HT29 human colon tumors to a combination treatment of 2 mg/kg/dose clofarabine and 3.75 mg/kg/dose taxotere. • = control group; __ = Clofarabine 2 mg/kg/dose single agent; Δ = Oxaliplatin 3.75 mg/kg/dose single agent; V = Clofarabine 2 mg/kg/dose and Oxaliplatin 3.75 mg/kg/dose combination.

FIG. 5 is a graphical depiction of the response of subcutaneous HT29 human colon tumors to a combination treatment of 1 mg/kg/dose clofarabine and 1.88 mg/kg/dose taxotere. • = control group; □ = Clofarabine 2 mg kg/dose single agent; Δ = Oxaliplatin 1.88 mg/kg/dose single agent; V = Clofarabine 1 mg/kg/dose and Oxaliplatin 1.88 mg/kg/dose combination.

DETAILED DESCRIPTION OF THE INVENTION

A. Clofarabine Clofarabine is disclosed and claimed as a composition in U.S. Patent 5,384,310 and disclosed and claimed as a method of killing cancer cells in U.S. Patent 5,661,136, both herein incorporated by reference.

B. Platinum Cancer Therapeutic Agents Platinum cancer therapeutic agent is defined generally as any platinum coordination complex that has an anti-neoplastic effect and includes: cisplatin and analogs including oxaliplatin, carboplatin, iproplatin (CHIP); ormaplatin (tetraplatin) and (R,R-1,2- diaminocyclohexane)PtCl₂trans(acetato)₂; platinum (IN) compounds including JM216 (bis(acetato)aminedicholoro(cyclohexylamine)platinum (IN)) and JM335 (trα«5-amine (cyclohexylamine)dichlorodihydroxo platinum(lN)); and multinuclear platinum complexes including BBR3436 (two trα»-?-PtCl(ΝH₃)₂ bridged by (tr «5-Pt(NH₃)₂(NH₂(CH₂)₆NH₂)₂)²⁺), BBR3005 ((trαn-?-PtCl(NH₃))₂(NH₂(CH₂)6NH₂)²⁺), and BBR3171 ((cis-

PtCl(NH₃))₂(NH₂(CH₂)₆NH₂)²⁺).

The preparation, physical properties, and beneficial pharmacological properties of oxaliplatin are described in U.S. Patents 4,169,846, 5,290,961, 5,298,642, 5,338,874, 5,420,319 and 5,716,988, all herein incorporated by reference. Cisplatin, carboplatin and (R,R-1,2- diaminocyclohexane)PtCl₂trans(acetato)₂ are disclosed by U.S. Patents 5,562,925, 4,657,927 and 5,434,256 respectively, all herein incorporated by reference. Various multinuclear platinum compounds are disclosed in U.S. Patents 4,225,529, 4,250,189, 4,533,502, 4,565,884, 4,571,335, 4,797,393, 5,380,897, 5,744,497 and 6,313,333, all herein incorporated by reference. Various platinum (TV) complexes are disclosed by U.S. Patents 5,072,011, 5,244,919 and 5,665,771, all herein incorporated by reference.

C. Formulations and Administration

The therapeutic agents of the present invention can be formulated in a variety of conventional pharmaceutical formulations and administered to cancer patients, in need of treatment, by any one of the drug administration routes conventionally employed including oral, intravenous, parental or intrapenitoneal. In this invention, the preferred routes of administration include intravenous (IV), intraperitoneal (IP) and oral (PO).

For oral administration the therapeutic agents of the present invention may be formulated, for example, with an inert diluent or with an assimiable edible carrier, or enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain the following: a binder, a gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit for is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Of course, any material used in preparing a dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, other chemotherapeutic compounds may be incorporated into sustained-release preparation and formulations.

Pharmaceutical formulations of the therapeutic agents of the present invention that are suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that each syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and anti-fungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the therapeutic agent in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and anti-fungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the composition.

Platinum cancer therapeutic agents are dosed clinically at levels as known in the art, e.g., oxaliplatin is commonly given in combination therapeutic regimens at single doses of 85 mg/m² every two weeks or 130 mg/m every three weeks, such doses being administered by a two hour intravenous infusion (Johnson et al., 2001; Nam et al., 2002; Zelek et al., 2002; Faivre et al., 2002). Cisplatin is commonly administered intravenously over 0.5 to 2 hours. Patients are prehydrated with at least 500 ml of a salt solution to reduce the risk nephrotoxicity (Johnson et al., 2001). Regional administration of cisplatin may be used to increase local drug concentrations while reducing side effects (Ozols et al., 1984; Howell et al., 1983). Carboplatin is commonly dosed in combination therapy regimens at area under the concentration-time curve 5-7 mg/ml/min by a rapid 30 minute intravenous infusion once in a 3 or 4 week treatment cycle (e.g., Belani, 2002; Sederholm, 2002; Chen et al., 2002; Masotti et al., 2002). The clinical dosage of clofarabine may be optimized for the tumor type as may be determined by one of skill in the art by routine experimentation. Administration regimens include single weekly intravenous administration of 4 to 50 mg/m , given in cycles of three weeks of dosing with one week of no administration. Other administration regimens include daily intravenous dosing about 15 to about 50 mg/m , wherein such dosing may be given in cycles of 5 consecutive days.

The treatment with clofarabine may precede or follow treatment with platinum cancer therapeutic agents by intervals ranging from seconds to weeks and/or be administered concurrently with such treatments. In embodiments where clofarabine and platinum cancer therapeutic agents are administered separately, steps should be taken to ensure that a period of time does not expire between the time of each delivery, such that the combination of the treatments would not be able to exert an advantageously combined therapeutic effect.

Tumors that can be suitably treated with the methods of the present invention include; but are not limited to, tumors of the brain (glioblastomas, medulloblastoma, astrocytoma, oligodendroglioma, ependymomas), lung, liver, spleen, kidney, lymph node, small intestine, pancreas, blood cells, colon, stomach, breast, endometrium, prostate, testicle, ovary, skin, head and neck, esophagus, bone marrow, blood and other tissue. The tumor may be distinguished as metastatic and non-metastatic.

EXAMPLES OF THE INVENTION

A. HT29 Human Colorectal Adenocarcinoma Model

The study was designed to evaluate the antitumor efficacy of combined Clofarabine and Oxaliplatin compared to each drug given alone. The HT29 humor colon tumor was implanted subcutaneously (SC) in female nude mice as 30 to 40 mg tumor fragments. The treatment study design is summarized in Table 1. There were 20 animals in the control group and 10 animals in each treatment group. The implants grew to median tumor sizes of 135-153 mg (individual tumor ranging from 100-198 mg) before treatment began on day 10. The treatment regimen for Oxaliplatin was by intraperitoneal (IP) injection given every seven days for three injections (Q7D X 3) at dosages of 7.5, 3.75, 1.88 mg/kg/dose. The treatment regimen for Clofarabine was by IP injection, given three times daily, every four hours for ten consecutive days (Q4H X 3, Q1D X 10) at dosages of 4, 2, and 1 mg/kg/dose. In the combined regimens, the corresponding high, medium, and low dosages of each compound were paired together. The time to reach the evaluation size (three tumor doublings) for the tumor of each animal was used to calculate the overall delay in the growth of the tumor (T-C).

Results are summarized in Table 2 and FIGS. 1-5. Control tumors grew well in all mice with a median time of 16.8 days to three tumor doublings. Oxaliplatin treatment was well tolerated with no observed body weight loss at any dosage. Treatment with Oxaliplatin did not show antitumor activity against HT29 human colon tumor xenografts at any dosage (FIG. 1) with T-C values of -0.9, -0.5, and -1/4 days, respectively.

Clofarabine treatment at all dosages was well tolerated with a maximum weight loss of 5% (1 g) observed. Treatment with Clofarabine showed strong antitumor activity at the two highest dosages tested against HT29 human colon tumor xenografts with a slight effect at the lowest dosage (FIG. 2). A dose-dependence for Clofarabine was shown with T-C values of 24.0, 21.4, 5.1 days, respectively, although a difference at the highest dosages was not obvious (FIG.

2).

Combined treatment with Clofarabine and Oxaliplatin was well tolerated at all combinations with a maximum weight loss of 9% (2 g) for the highest single dosage of each compound. The combined highest dosage of each compound was more effective against HT29 human colon tumor xenografts than Clofarabine alone (FIG. 3) with T-C values of 30.7, vs. 24.0 days respectively. The increased efficacy of the combined treatment demonstrates an apparent interaction between the two drugs under these experimental conditions, since no effect was observed with Oxaliplatin alone. An interaction of these compounds was not apparent at the intermediate combined dosages (FIG. 4) although the T-C value was slightly increased for the combined treatment compared to Clofarabine treatment alone (24.8 vs. 21.4 days). The combination of both compounds at he lowest dosages showed an apparent interaction (FIG. 5) with a T-C values 2.5 times greater for the combined treatment compared to Clofarabine alone (13.0 vs. 5.1 days).

In summary, Oxaliplatin as a sole agent did not show any efficacy against HT29 human colon tumor xenografts, while Clofarabine was effective. Combined treatment with Clofarabine and Oxaliplatin at the highest and lowest dosage combinations was more effective than Clofarabine alone.

Group Compound Dose Route Schedule No. of

No. (mg/kg/dose) Mice

1 Vehicle Control — — — 20

2 Oxaliplatin 7.5 IP Q7x3 10

3 Oxaliplatin 3.75 IP Q7x3 10

4 Oxaliplatin 1.88 IP Q7x3 10

5 Clofarabine 4 IP Q4Hx3, QlDxlO 10

6 Clofarabine 2 IP Q4Hx3, QlDxlO 10

7 Clofarabine 1 IP Q4Hx3, QlDxlO 10

8 Clofarabine 4 IP Q4Hx3, QlDxlO 10

Oxaliplatin 7.5 IP Q7x3

9 Clofarabine 2 IP Q4Hx3, QlDxlO 10

Oxaliplatin 3.75 IP Q7x3

10 Clofarabine 1 IP Q4Hx3, QlDxlO 10

Oxaliplatin 1.88 IP Q7x3

Q4Hx3, QlDxlO = Administered three times daily for ten consecutive days. Q7Dx3 = administered every seven days for three doses (i.e., 3 cycles).

REFERENCES

The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference:

Belini, "Docetaxel in combination with platinums (cisplatin or carboplatin) in advanced and metastatic non-small cell lung cancer," Semin. Oncol., 29:4-9, 2002. Carson et al., "Oral antilymphocytic activity and induction of apoptosis by 2-chloro-2'-arabino- fluror-2'-deoxyadenosine," Proc. Nat'l. Acad. Sci. USA, 89:2970-2974, 1992. Chen et al, "Paclitaxel plus carboplatin, compared with paclitaxel plus gemcitabine, shows similar efficacy while more cost-effective: a randomized phase II study of combination chemotherapy against inoperable non-small-cell lung cancer previously untreated," Ann.

Oncol., 13:108-115, 2002. Faivre et al, "Phase I-II and pharmacokinetics study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma," Ann.

Oncol., 13:1479-1489, 2002. Ghandi et al, "Cellular pharmacokinetics and pharmacodynamics of clofarabine (2-chloro-2'- fluoro-arabinosyladenine) in acute leukemia blasts during a phase I clinical trial," Proc.

Am. Assoc. Cancer Res., 77 Suppl. 77-78, 2002. Howell et al, "Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection," Cancer Res., 43:1426-1431, 1983. Jeha et al., "Clofarabine (CLOFAREX™) is an active agent in pediatric leukemias," Proc.

ASCO, 21: 397a, 2002. Johnson et al, "Cisplatin and its analogues," in Cancer Principles and Practice (Da Vita et al eds, 6^th ed) Vol. 1, pp 376-387, Lippincott, Williams & Wilkins, 2001.

Kantarjian et al, "Phase I clinical and pharmacological study of clofarabine," Blood, 94:127,

2001. Kozuch et al, "Phase I clinical and pharmacological study of clofarabine," Blood, 94, Suppl. 1,

127a, 1999. Masotti et al, "Activity of gemcitabine and carboplatin in advanced non-small cell lung cancer: a phase II trial," Lung Cancer, 36:99-103, 2002. Montgomery et al, "III. Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-β-D arabinofuranosyladenine," J. Med. Chem., 35:397-401, 1992. Nan et al, "Oxaliplatin and UFT combination chemotherapy in patients with metastatic colorectal cancer," Am. J. Clin. Oncol., 25:354-357, 2002. Ozols et al, "High dose cisplatin in hypertonic saline," Ann. Intern, med., 100: 19-24, 1984). Secrist et al, "Synthesis and biological evaluation of certain 2-halo-2'-substituted derivatives of 9-β-D arabinofuranosyladenine," J. Med. Chem., 31 :405-410, 1988.

Sederholm, "Gemcitabine versus gemcitabine/carboplatin in advanced non-small cell lung cancer: preliminary findings in a phase II trial of Swedish Lung cancer Study Group,"

Semin. Oncol., 29:50-54, 2002. Waud et al, "Preclinical antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-β-D- arabinofuranosyl)adenine (Cl-F-ARA-A)," Nucleosides Nucleotides Nucleic Acids,

19:447-460, 2000. Zelek et al, "Phase II study of oxaliplatin and fluorouracil in taxane- and anthracycline- pretreated breast cancer patients," J. Clin. Oncol., 20:2551-2558, 2002.

Claims

1. A method for inhibiting the growth of a tumor cell comprising contacting said tumor cell with clofarabine and a platinum cancer therapeutic agent, wherein the combined doses of clofarabine and said platinum cancer therapeutic agent are effective to inhibit the growth of said tumor cell.

2. The method of claim 1, wherein said platinum cancer therapeutic agent is selected from the group consisting of cisplatin, oxaliplatin and carboplatin.

The method of claim 1, wherein said platinum cancer therapeutic agent is oxaliplatin.

4. The method of claim 1, wherein said tumor cell is selected from the group consisting of a skin cancer cell, a prostate cancer cell, a lung cancer cell, a brain cancer cell, a breast cancer cell, an ovarian cancer cell, a cervical cancer cell, a liver cancer cell, a pancreatic cancer cell, a colon cancer cell, a stomach cancer cell, a leukemia cell and a lymphoma cell.

5. A method for killing a tumor cell comprising contacting said tumor cell with clofarabine and a platinum cancer therapeutic agent, wherein the combined doses of clofarabine and said platinum cancer therapeutic agent are effective to kill said tumor cell.

6. The method of claim 5, wherein said platinum cancer therapeutic agent is selected from the group consisting of cisplatin, oxaliplatin and carboplatin.

7. The method of claim 5, wherein said platinum cancer therapeutic agent is oxaliplatin.

8. The method of claim 5, wherein said tumor cell is selected from the group consisting of a skin cancer cell, a prostate cancer cell, a lung cancer cell, a brain cancer cell, a breast cancer cell, an ovarian cancer cell, a cervical cancer cell, a liver cancer cell, a pancreatic cancer cell, a colon cancer cell, a stomach cancer cell, a leukemia cell, and a lymphoma cell.

9. A method for treating cancer in a human patient comprising administering clofarabine as a first treatment modality and administering a platinum cancer therapeutic agent as a second treatment modality, wherein the dose of said clofarabine when combined with the dose of said platinum cancer therapeutic agent, is effective to treat said cancer.

10. The method of claim 9, wherein said platinum cancer therapeutic agent is selected from the group consisting of cisplatin, oxaliplatin and carboplatin.

11. The method of claim 9, wherein said platinum cancer therapeutic agent is oxaliplatin.

12. The method of claim 9, wherein said cancer is selected from the group consisting of skin cancer, prostate cancer, lung cancer, brain cancer, breast cancer, ovarian cancer, cervical cancer, liver cancer, pancreatic cancer, colon cancer, stomach cancer, leukemia and lymphoma.