Combination methods of treating cancer

• US 20070190022A1
• Filed: 08/12/2004
• Published: 08/16/2007
• Est. Priority Date: 08/29/2003
• Status: Abandoned Application

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center), Merck HDAC Research LLC (Merck & Co., Inc.)
• Original Assignee: Merck HDAC Research LLC (Merck & Co., Inc.)
• Inventors: Miller, Thomas, Marks, Paul, Chiao, Judy, Rifkind, Richard, Richon, Victoria, Paradise, Carolyn, Bacopoulos, Nicholas
• Application Number:
  US10/567,953
• Publication Number:
  US 20070190022A1
• Time in Patent Office: Days
• US Class Current: 424/85.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, in a first treatment procedure, and a second amount of an anti-cancer agent in a second treatment procedure. The first and second amounts together comprise a therapeutically effective amount. The effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.

Claims

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of suberoylanilide hydroxamic acid (SAHA) represented by the structure:

or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of an anti-cancer agent, thereby treating the cancer.

2. The method of claim 1, wherein said anti-cancer agent is a histone deacetylase (HDAC) inhibitor, an alkylating agent, an antibiotic agent, an antimetabolic agent, a hormonal agent, a plant-derived agent, an anti-angiogenic agent, a differentiation inducing agent, a cell growth arrest inducing agent, an apoptosis inducing agent, a cytotoxic agent, a biologic agent, a gene therapy agent, or any combination thereof.

15. The method of claim 1, wherein the anti-cancer agent is an alkylating agent selected from the group consisting of bischloroethylamines, aziridines, alkyl alkone sulfonates, nitrosoureas, nonclassic alkylating agents, platinum compounds, and carboplatin.

16. The method of claim 1, wherein the anti-cancer agent is an antibiotic agent selected from the group consisting of irenotecan, doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione, mitomycin C, bleomycin, dactinomycin, and plicatomycin.

17. The method of claim 1, wherein the anti-cancer agent is an antimetabolic agent selected from the group consisting of floxuridine, fluorouracil, methotrexate, leucovorin, hydroxyurea, thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine phosphate, cladribine, asparaginase, capecitabine, and gemcitabine.

18. The method of claim 17, wherein said antimetabolic agent is gemcitabine.

19. The method of claim 1, wherein the anti-cancer agent is an hormonal agent selected from the group consisting of an estrogen, a progestogen, an antiesterogen, an androgen, an antiandrogen, an LHRH analogue, an aromatase inhibitor, diethylstibestrol, tamoxifen, toremifene, fluoxymesterol, raloxifene, bicalutamide, nilutamide, flutamide, aminoglutethimide, tetrazole, ketoconazole, goserelin acetate, leuprolide, megestrol acetate, and mifepristone.

20. The method of claim 1, wherein the anti-cancer agent is a plant-derived agent selected from the group consisting of vincristine, vinblastine, vindesine, vinzolidine, vinorelbine, etoposide teniposide, paclitaxel and docetaxel.

21. The method of claim 1, wherein the anti-cancer agent is a biologic agent selected from the group consisting of immuno-modulating proteins, monoclonal antibodies against tumor antigens, tumor suppressor genes, and cancer vaccines.

22. The method of claim 21, wherein the biologic agent is selected from the group consisting of trastuzumab, interleukin 2, interleukin 4, interleukin 12, interferon El interferon D, interferon alpha, erythropoietin, granulocyte-CSF, granulocyte, macrophage-CSF, bacillus Cahnette-Guerin, levamisole, and octreotide.

23. The method of claim 21, wherein the tumor suppressor gene is selected from the group consisting of DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA, and BRCA2.

33. The method of claim 1, wherein said anti-cancer agent is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.

34. The method of claim 1, wherein SAHA is administered orally in a pharmaceutical composition comprising SAHA and a pharmaceutically acceptable carrier or diluent.

50. The method of claim 1, wherein the cancer is selected from the group consisting of a leukemia, a lymphoma, a myeloma, a sarcoma, a carcinoma, a solid tumor or any combination thereof.

51. The method of claim 1, wherein the cancer is selected from the group consisting of cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides, acute leukemia, chronic leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma, multiple myeloma, mesothelioma, childhood solid tumors, pediatric brain neuroblastoma, pediatric retinoblastoma, rhabdomyosarcoma, Wilms'"'"' tumor, bone cancer and soft-tissue sarcomas, common solid tumors of adults, head and neck cancers, lung tumors, breast tumors, colon tumors, prostate tumors, bladder tumors, rectal tumors, brain tumors, endometrial tumors, oral cancer, laryngeal cancer, esophageal cancer, genito urinary cancers, prostate cancer, bladder cancer, renal cancer, uterine cancer, endometrial cancer, ovarian cancer, testicular cancer, rectal cancer, colon cancer, lung cancer, non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, malignant melanoma, skin cancers, gastric cancer, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, cancers with leukocyte infiltration of the skin or organs, breast carcinoma, cervical carcinoma, ovarian carcinoma, testicular carcinoma, lung carcinoma, bladder carcinoma, renal carcinoma, colon carcinoma, rectal carcinoma, colorectal carcinoma, stomach carcinoma, liver carcinoma, pancreatic carcinoma, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, medullary carcinoma, osteo sarcoma, Ewing'"'"'s sarcoma, veticulum cell sarcoma, Kaposi'"'"'s sarcoma, meningioma, neuroblastoma, glioblastoma, and retinoblastoma.

3. -14. (canceled)

24. -32. (canceled)

35. -49. (canceled)

52. -105. (canceled)

106. A method of selectively inducing terminal differentiation of neoplastic cells in a subject and thereby inhibiting proliferation of said cells in said subject, said method comprising administering to said subject a first amount of suberoylanilide hydroxamic acid (SAHA) represented by the structure:

or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of an anti-cancer agent, thereby inducing terminal differentiation of said cells.

107. -108. (canceled)

109. An in-vitro method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of said cells, said method comprising contacting the cells with a first amount of suberoylanilide hydroxamic acid (SAHA) represented by the structure:

or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of an anti-cancer agent, thereby inducing terminal differentiation of said cells.

110. -111. (canceled)

112. A pharmaceutical composition comprising a first amount of suberoylanilide hydroxamic acid (SAHA) represented by the structure:

or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of an anti-cancer agent.