Use of cyclopamine in the treatment of basal cell carcinoma and other tumors

• US 20040072914A1
• Filed: 10/09/2003
• Published: 04/15/2004
• Est. Priority Date: 07/02/2001
• Status: Active Grant

• Current Assignee: Oktay Avci, Sinan Tas
• Original Assignee: Sinan Tas
• Inventors: Tas, Sinan, Avci, Oktay
• Granted Patent: US 7,893,078 B2
• Time in Patent Office: Days
• US Class Current: 514/659
• 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 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 8/63 Steroids; Derivatives thereof
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61Q 19/02 for chemically bleaching or whitening the skin

Abstract

This invention concerns the use of cyclopamine in vivo on basal cell carcinomas (BCC'"'"'s) to achieve therapeutic effect by causing differentiation of the tumor cells and, at the same time, apoptotic death and removal of these tumor cells while preserving the normal tissue cells, including the undifferentiated cells of the normal epidermal basal layer and hair follicles. Causation of apoptosis by cyclopamine is by a non-genotoxic mechanism and thus unlike the radiation therapy and most of the currently used cancer chemotherapeutics which act by causing DNA-damage. These novel effects, previously unachieved by a cancer chemotherapeutic, make the use of cyclopamine highly desirable in cancer therapy, in the treatment of BCC'"'"'s and other tumors that use the hedgehog/smoothened signal transduction pathway for proliferation and prevention of apoptosis.

Claims

1. A method for inducing in vivo the cellular differentiation and, at the same time, apoptosis of tumor cells that use the hedgehog/smoothened signalling for proliferation and for prevention of apoptosis and/or for prevention of differentiation, comprising contacting said tumor cells with cyclopamine or a pharmaceutically acceptable salt or derivative thereof.

2. The method according to claim 1, characterized in that transient administration of cyclopamine or a pharmaceutically acceptable salt or derivative thereof suffices for the causation of the differentiation and/or apoptosis of said tumor cells, but normal tissue cells are preserved.

3. The method according to claim 1, for the treatment of cancer.

4. The method of claim 3, wherein the cancer is basal cell carcinoma.

5. The method according to claim 1, characterized in that the cyclopamine or a pharmaceutically acceptable salt or derivative thereof is formulated in a pharmaceutical composition selected from the group of compositions for topical, non-topical or systemic administration.

6. The method according to claim 5, characterized in that the composition for non-topical or systemic administration is in the form of an aqueous solution.

7. The method according to claim 5, characterized in that the composition for non-topical or systemic administration is in the form of liposomes, having the cyclopamine or pharmaceutically acceptable salt or derivative thereof entrapped therein.

8. The method according to claim 6, characterized in that the non-topical administration is direct intratumoral injection.

9. The method according to claim 7, characterized in that the non-topical administration is direct intratumoral injection.

10. The method according to claim 5, characterized in that said pharmaceutical composition is in a controlled release form.

11. The method according to claim 5, characterized in that said pharmaceutical composition is adsorbed onto a dermal patch.

12. The method according to claim 5, characterized in that said pharmaceutical composition for topical administration comprises 18 mM of cyclopamine and is selected from the group of a cream, an ointment, a gel or a hydrogel.

13. A medicament for inducing in vivo the cellular differentiation and, at the same time, apoptosis of tumor cells that use the hedgehog/smoothened signalling for proliferation and for prevention of apoptosis and/or for prevention of differentiation, the medicament comprising cyclopamine or a pharmaceutically acceptable salt or derivative thereof.

14. A medicament according to claim 13, characterized in that normal tissue cells are preserved following transient administration of said medicament but said administration suffices for the causation of the differentiation and/or apoptosis of said tumor cells.

15. A medicament according to claim 13, for the treatment of basal cell carcinoma.

16. A medicament according to claim 13, characterized in that said medicament is formulated for topical, non-topical or systemic administration.

17. A medicament according to claim 16, characterized in that for non-topical or systemic administration cyclopamine is in the form of an aqueous solution, or is entrapped in liposomes.

18. A medicament according to claim 17, characterized in that the non-topical administration is direct intratumoral injection.

19. A medicament according to claim 13, characterized in that said medicament is a pharmaceutical form enabling controlled release.

20. A medicament according to claim 13, characterized in that said medicament is adsorbed onto a dermal patch.

21. A medicament according to claim 13, characterized in that said medicament is manufactured in the form of a cream, ointment, gel, or hydrogel comprising 0,001 mM to 100 mM cyclopamine or a salt or derivative thereof.

22. A medicament according to claim 13, characterized in that said medicament is manufactured in the form of a cream, ointment, gel or hydrogel comprising 18 mM of cyclopamine.

23. A medicament for application on patients having nevi or skin disorders associated with increased pigmentation, the medicament comprising cyclopamine or a pharmaceutically acceptable salt or derivative thereof.

24. A cosmetic formulation comprising cyclopamine or a pharmaceutically acceptable salt or derivative thereof, for application on a person having nevi or increased pigmentation of skin.