Method for increasing therapeutic gain in radiotherapy and chemotherapy

• US 20050272644A1
• Filed: 03/11/2004
• Published: 12/08/2005
• Est. Priority Date: 07/25/2002
• Status: Active Grant

• Current Assignee: Sunny Pharmtech Inc.
• Original Assignee: Sunny Pharmtech Inc.
• Inventors: Chung, Yih-Lin
• Granted Patent: US 9,370,524 B2
• Time in Patent Office: Days
• US Class Current: 424/85.200
• CPC Class Codes: A61K 31/075 Ethers or acetals
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: A61K 38/15 Depsipeptides; Derivatives thereof
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/127 Liposomes

Abstract

The present invention provides compositions and methods for increasing therapeutic gain in radiotherapy and chemotherapy for proliferating malignant or nonmalignant disease to produce high probability of tumor control with low frequency of sequelae of therapy by administering a therapeutically effective amount of a histone deacetylase inhibitor. The compounds are capable of simultaneously stimulating the epithelium regrowth, inhibiting the fibroblast proliferation, decreasing the collagen deposit, suppressing the fibrogenic growth factor, subsiding the proinflammatory cytokine and modulating the expression of cell cycle genes, tumor suppressors and oncogenes, and are useful to increase the therapeutic gain in radiotherapy and chemotherapy, which results in decrease of skin swelling and inflammation, promotion of epithelium healing in mucosa and dermis, decrease of xerostomia, prevention/reduction of severity of plantar-palmar syndrome, prevention of tissue fibrosis, ulceration, necrosis and tumorigenesis, and increase of tumor growth inhibition and tumor therapy effectiveness.

Claims

1. A method for increased therapeutic gain in chemotherapy and/or radiotherapy for proliferating malignant or nonmalignant disease to produce high probability of tumor control with low frequency of sequelae of therapy, comprising administrating a composition of a histone hyperacetylating agent and a pharmaceutically acceptable carrier or a pharmaceutically acceptable salt thereof to a subject in need.

2. The method as claimed in claim 1, wherein the increased therapeutic gain is simultaneously enhancing tumor radiosensitization or sensitizing tumors to chemotherapy, increasing tumor growth inhibition, promoting wound healing in mucositis and dermatitis, preventing/reducing severity of plantar-palmar syndrome, decreasing tissue fibrosis, protecting normal tissue from cell death, preventing xerostomia, and suppressing tumorigenesis.

3. The method as claimed in claim 1, wherein the hyperacetylating agent is a histone deacetylase inhibitor.

4. The method as claimed in claim 1, wherein the radiotherapy is teletherapy, brachytherapy, or ionizing radiation.

5. The method as claimed in claim 1, wherein the proliferating malignant disease is selected from a group consisting of melanoma, Kaposi'"'"'s sarcoma, osteosarcoma, neuroblastoma, rhabdomyosarcoma, Ewing'"'"'s sarcoma, Soft tissue sarcoma, skin cancer, lymphoma, leukemia, breast cancer, germ cell tumor, primitive neuroectodermal tumor, brainglioma, brainmeningioma, headandneckcancer, thyroid cancer, thymic cancer, cervical cancer, anus cancer, colorectal cancer, prostate cancer, lung cancer, hepatocellular carcinoma, cholangiocarcinoma, stomach cancer, pancreatic cancer, esophageal cancer, virus-associated tumors, and disease receiving bone marrow transplantation.

6. The method as claimed in claim 1, wherein the nonmalignant disease is selected from a group consisting of pterygium, Graves'"'"' ophthalmopathy, orbital pseudotumor, macular degeneration, keloid, wart, keratoacanthoma, hemangioma, arteriovenous malformation, bursitis, tendinitis, desmoid tumor, Peyronie'"'"'s disease, vascular stenosis, ameloblastoma, aneurysmal bone cyst, heterotopic bone formation, gynecomastia, ovarian castration, parotitis, eczema, atopic dermatitis, psoriasis, periarthritis humeroscapularis, epicondylitis, knee arthrosis, hydradenitis, panaritium, autoimmune inflammatory arthritis, histocytosis X, and disease from receiving organ transplantation.

7. The method as claimed in claim 1, wherein the histone hyperacetylating agent is trichostatin A or trichostatin C.

8. The mehtod as claimed in claim 1, wherein the histone hyperacetylating agent is selected from a group consisting of oxamflatin, trapoxin A, FR901228, apicidin, HC-Toxin, WF27082, and chlamydocin.

9. The method as claimed in claim 1, wherein the histone hyperacetylating agent is selected from a group consisting of salicylihydroxamic acid, suberoylanilide hydroxamic acid, and azelaic bishydroxamic acid.

10. The mehtod as claimed in claim 1, wherein the histone hyperacetylating agent is selected from a group consisting of azelaic-1-hydroxamate-9-an-ilide, M-carboxycinnamic acid bishydroxamide, 6-(3-chlorophenylureido)carp-oic hydroxamic acid, MW2796, and MW2996.

11. The method as claimed in claim 1, wherein the histone hyperacetylating agent is selected from a group consisting of sodium butyrate, isovalerate, valerate, 4-phenylbutyrate, Sodiumphenylbutyrate, propionate, butrymide, isobutyramide, phenylacetate, 3-bromopropionate, valproic Acid, and tributyrin.

12. The method as claimed in claim 1, wherein the histone hyperacetylating agent is MS-27-275 or the 3′

-amino derivatives thereof.

13. The method as claimed in claim 1, wherein the histone hyperacetylating agent is depudecin or scriptaid.

14. The method as claimed in claim 1, wherein the administrating is non-oral.

15. The method as claimed in claim 1, wherein the composition is a cream, an ointment, a gel, a paste, a powder, a lotion, a patch, a suppository, a liposome formation, a suspension, a mouth wash, an enema, an injection solution, or a drip infusion.

16. The method as claimed in claim 1, wherein the hyperacetylating agent is from 0.001% to 100% by weight of the composition.

17. The method as claimed in claim 1, wherein the composition further comprises a second agent selected from a group consisting of a cytokine, an interleukin, an anti-cancer agent or an anti-neoplastic agent, an anti-angiogenesis agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, an antibiotic, retinoic acid, a tyrosine kinase inhibitor, a hormone antagonist, and a growth stimulant.

18. The method as claimed in claim 17, wherein the conjugated antibody is selected from a group consisting of Trastuzumab, c225, Rituximab, and Cetuximab.

19. The method as claimed in claim 17, wherein the chemotherapeutic agent is selected from a group consisting of an alkylating agent, a purine analog, a pyrimidine analog, a vinca alkaloid, a vinca-like alkaloid, etoposide, an etoposide-like drug, a corticosteroid, a nitrosourea, an antimetabolite, a platinum-based cytotoxic drug, an anti-androgen, and an anti-estrogen.

20. The method as claimed in claim 17, wherein the anti-angiogenesis agent is selected from a group consisting of thalidomide, SU5416, SU6668, Thrombospondin-1, endostatin, and angiostatin.

21. The method as claimed in claim 17, wherein the antibiotic is Ganciclovir, Acyclovir, or Famciclovir.