Method for enhancing the effectiveness of therapies of hyperproliferative diseases

• US 20040023925A1
• Filed: 04/07/2003
• Published: 02/05/2004
• Est. Priority Date: 06/21/2001
• Status: Abandoned Application

• Current Assignee: Prospect Therapeutics, Inc.
• Original Assignee: Prospect Therapeutics, Inc.
• Inventors: Chang, Yan, Sasak, Vodek
• Application Number:
  US10/408,723
• Publication Number:
  US 20040023925A1
• Time in Patent Office: Days
• US Class Current: 514/54
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/732 Pectin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 33/10 Anthelmintics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The efficacy of conventional cancer therapies such as surgery, chemotherapy and radiation is enhanced by the use of a therapeutic material which binds to and interacts with galectins. The therapeutic material can enhance apoptosis thereby increasing the effectiveness of oncolytic agents. It can also inhibit angiogenesis thereby moderating tumor growth and/or metastasis.

Claims

1. A method for enhancing the efficacy of a therapeutic treatment for cancer and unwanted proliferation of cells in a patient, said therapeutic treatment one which the degree of cytotoxicity is influenced by the status of an anti-apoptotic Bcl-2 protein of the tumor cell, said method further comprising the conjoint administration to said patient of a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone.

28. The method of claim 1, wherein said therapeutic treatment includes ionizing radiation.

31. The method of claim 1, used to inhibit growth of a tumor cell selected from the group consisting of a pancreatic tumor cell, a lung tumor cell, a prostate tumor cell, a breast tumor cell, a colon tumor cell, a liver tumor cell, a brain tumor cell, a kidney tumor cell, a skin tumor cell and an ovarian tumor cell.

32. The method of claim 1, wherein said tumor cell is selected from the group consisting of a squamous cell carcinoma, a non-squamous cell carcinoma, a glioblastoma, a sarcoma, an adenocarcinoma, a myeloma, a melanoma, a papilloma, a neuroblastoma and a leukemia cell.

33. The method of claim 1, used in the treatment of a proliferative disorder selected from the group consisting of a pancreatic cancer, renal cell cancer, Kaposi'"'"'s sarcoma, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, lymphoma, mastocytoma, lung cancer, mammary adenocarcinoma, pharyngeal squamous cell carcinoma, gastrointestinal cancer, stomach cancer, myeloma, or prostate cancer.

34. The method of claim 1, wherein said partially depolymerized pectin is a substantially demethoxylated polygalacturonic acid which is interrupted with rhamnose residues.

35. The method of claim 1, wherein said partially depolymerized pectin comprises a pH modified pectin, an enzymatically modified pectin, and/or a thermally modified pectin.

36. The method of claim 35, wherein said modified pectin comprises a modified citrus pectin.

37. The method of claim 1, wherein said partially depolymerized pectin is administered simultaneously with said therapeutic treatment, chemotherapeutic or cytostatic agent.

38. The method of claim 1, wherein said partially depolymerized pectin is administered before treatment with said therapeutic treatment, chemotherapeutic or cytostatic agent.

39. The method of claim 1, wherein said partially depolymerized pectin is administered after treatment with said therapeutic treatment, chemotherapeutic or cytostatic agent.

40. The method of claim 1, wherein said partially depolymerized pectin is administered by intravenous infusion.

41. The method of claim 1, wherein said partially depolymerized pectin is administered orally.

42. The method of claim 1, wherein said partially depolymerized pectin is administered by intramuscular or intraperitoneal injection or infusion.

43. The method of claim 1, wherein said partially depolymerized pectin is administered by inhalation.

44. The method of claim 1, wherein said partially depolymerized pectin is administered by topically.

45. The method of claim 1, wherein said partially depolymerized pectin is administered by subcutaneous injection.

46. The method of claim 1, wherein the effective dose (ED50) for said therapeutic treatment, chemotherapeutic or cytostatic agent used in combination with said partially depolymerized pectin is at least 5 fold less than the ED50 for said therapeutic treatment, chemotherapeutic or cytostatic agent alone.

47. The method of claim 1, wherein the therapeutic index (TI) for said therapeutic treatment, chemotherapeutic or cytostatic agent used in combination with said partially depolymerized pectin is at least 5 fold greater than the TI for said therapeutic treatment, chemotherapeutic or cytostatic agent alone.

2. A method for enhancing the pro-apoptotic effect of a chemotherapeutic agent that interferes with DNA replication fidelity or cell-cycle progression of cells undergoing unwanted proliferation in a patient, comprising the conjoint administration to said patient of a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone.

6. The method of claim 2, 3 or 4, wherein the chemotherapeutic agent induces mitochondrial dysfunction and/or caspase activation.

7. The method of claim 2, 3 or 4, wherein the chemotherapeutic agent induces cell cycle arrest at G2/M in the absence of said partially depolymerized pectin.

8. The method of claim 2, 3 or 4, wherein said chemotherapeutic is an inhibitor of chromatin function.

9. The method of claim 8, wherein said chemotherapeutic is a topoisomerase inhibitor.

10. The method of claim 9, wherein said topoisomerase inhibitor is selected from the group consisting of adriamycin, amsacrine, camptothecin, daunorubicin, dactinomycin, doxorubicin, eniposide, epirubicin, etoposide, idarubicin and mitoxantrone.

11. The method of claim 8, wherein said inhibitor is a microtubule targeting drug.

12. The method of claim 11, wherein said microtubule targeting drug is a taxane.

13. The method of claim 11, wherein said microtubule targeting drug is selected from the group consisting of paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilones and navelbine.

14. The method of claim 2, 3 or 4, wherein said chemotherapeutic is a DNA damaging agent.

15. The method of claim 14, wherein said DNA damaging agent is selected from the group consisting of actinomycin, amsacrine, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxan, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, paclitaxel, plicamycin, procarbazine, teniposide, triethylenethiophosphoramide and etoposide (VP16).

16. The method of claim 2, 3 or 4, wherein said chemotherapeutic is an antimetabolite.

17. The method of claim 16, wherein said antimetabolite is selected from the group consisting of folate antagonists, pyrimidine analogs, purine analogs, and sugar-modified analogs.

18. The method of claim 2, 3 or 4, wherein said chemotherapeutic is a DNA synthesis inhibitor.

19. The method of claim 18, wherein said DNA synthesis inhibitor is a thymidilate synthase inhibitors, such as 5-fluorouracil.

20. The method of claim 18, wherein said DNA synthesis inhibitor is a dihydrofolate reductase inhibitor, such as methoxtrexate.

21. The method of claim 18, wherein said DNA synthesis inhibitor is a DNA polymerase inhibitor, such as fludarabine.

22. The method of claim 2, 3 or 4, wherein said chemotherapeutic is a DNA binding agent.

23. The method of claim 22, wherein said DNA binding agent is an intercalating agent.

24. The method of claim 2, 3 or 4, wherein said chemotherapeutic is a DNA repair inhibitor.

25. The method of any of claims 2-5, wherein said chemotherapeutic is a corticosteroid.

26. The method of claim 25, wherein said corticosteroid is selected from the group consisting of cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prenisolone.

27. The method of any of claims 2-5, wherein said chemotherapeutic is a combinatorial therapy selected from the group consisting of ABV, ABVD, AC (Breast), AC (Sarcoma), AC (Neuroblastoma), ACE, ACe, AD, AP, ARAC-DNR, B-CAVe, BCVPP, BEACOPP, BEP, BIP, BOMP, CA, CABO, CAF, CAL-G, CAMP, CAP, CaT, CAV, CAVE ADD, CA-VP16, CC, CDDP/VP-16, CEF, CEPP(B), CEV, CF, CHAP, ChlVPP, CHOP, CHOP-BLEO, CISCA, CLD-BOMP, CMF, CMFP, CMFVP, CMV, CNF, CNOP, COB, CODE, COMLA, COMP, Cooper Regimen, COP, COPE, COPP, CP—

Chronic Lymphocytic Leukemia, CP—

Ovarian Cancer, CT, CVD, CVI, CVP, CVPP, CYVADIC, DA, DAT, DAV, DCT, DHAP, DI, DTIC/Tamoxifen, DVP, EAP, EC, EFP, ELF, EMA 86, EP, EVA, FAC, FAM, FAMTX, FAP, F-CL, FEC, FED, FL, FZ, HDMTX, Hexa-CAF, ICE-T, IDMTX/6-MP, IE, IfoVP, IPA, M-2, MAC-III, MACC, MACOP-B, MAID, m-BACOD, MBC, MC, MF, MICE, MINE, mini-BEAM, MOBP, MOP, MOPP, MOPP/ABV, MP—

multiple myeloma, MP—

prostate cancer, MTX/6-MO, MTX/6-MP/VP, MTX-CDDPAdr, MV—

breast cancer, MV—

acute myelocytic leukemia, M-VAC Methotrexate, MVP Mitomycin, MVPP, NFL, NOVP, OPA, OPPA, PAC, PAC-I, PA-CI, PC, PCV, PE, PFL, POC, ProMACE, ProMACE/cytaBOM, PRoMACE/MOPP, Pt/VM, PVA, PVB, PVDA, SMF, TAD, TCF, TIP, TTT, Topo/CTX, VAB-6, VAC, VACAdr, VAD, VATH, VBAP, VBCMP, VC, VCAP, VD, VelP, VIP, VM, VMCP, VP, V-TAD, 5+2, 7+3, “

8 in 1”

.

30. The method of any of claims 2-4, wherein the chemotherapeutic is selected from the group consisting of aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine

3. A method for treating chemoresistant tumors in a patient, wherein said tumors have elevated levels of anti-apoptotic Bcl-2 proteins (relative to wild-type), comprising the conjoint administration to said patient of

(i) a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone, and

(ii) a chemotherapeutic agent that induces apoptosis in a manner influenced by the anti-apoptotic Bcl-2 protein status of the tumor cell.

4. A method for enhancing the cytotoxicity of a chemotherapeutic for killing cells undergoing unwanted proliferation in a patient, comprising the conjoint administration to said patient of a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone.

5. A method for rendering a cytostatic agent cytotoxic for cells undergoing unwanted proliferation, wherein said agent'"'"'s cytotoxicity is influenced by the status of an anti-apoptotic Bcl-2 protein, comprising the conjoint administration of a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone with said cytostatic agent.

29. The method of claim 5, wherein cytostatic agent is selected from the group consisting of tamoxifen, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline, 4-(3-ethynylphenylamino)-6,7-bis(2-metho-xyethoxy)quinazoline, hormone, steroids, steroid synthetic analogs, 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex, antiangiogenics, matrix metalloproteinase inhibitors, VEGF inhibitors, ZD6474, SU6668, SU11248, anti-Her2 antibodies (ZD1839 and OS1774), EGFR inhibitors, EKB-569, Imclone antibody C225, src inhibitors, bicalutamide, epidermal growth factor inhibitors, Her-2 inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, P13 inhibitors, PDGF inhibitors, combretastatins, MET kinase inhibitors, MAP kinase inhibitors, inhibitors of non-receptor and receptor tyrosine kinases (imatinib), inhibitors of integrin signaling, and inhibitors of insulin-like growth factor receptors.

48. A kit comprising (i) a chemotherapeutic agent that interferes with DNA replication fidelity or cell-cycle progression of cells undergoing unwanted proliferation, (ii) a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone;

and (iii) instructions and/or a label for conjoint administration of the chemotherapeutic agent and the partially depolymerized pectin.

49. A packaged pharmaceutical comprising (i) a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone;

and (ii) instructions and/or a label for conjoint administration of the partially depolymerized pectin with a chemotherapeutic agent.

50. A method for treating a tumor comprising:

(i) obtaining a sample of tumor cells from a patient;

(ii) ascertaining the anti-apoptotic Bcl-2 protein status of the tumor cell sample; and

(iii) for patients having a wild-type or elevated level or anti-apoptotic Bcl-2 proteins, treating the patient with a regimen including administering a therapeutically effective amount of a partially depolymerized pectin having a galacturan backbone which may be disrupted by rhamnose and low branched neutral sugars dependent from said backbone.

51. The method of claim 50, wherein said treatment regimen further includes treating the patient with a chemotherapeutic agent that interferes with DNA replication fidelity or cell-cycle progression of cells undergoing unwanted proliferation.