Abstract
A method of treatment of breast cancer in susceptible animals whose ovarian hormonal secretions were previously blocked by surgical or chemical means, e.g., by use of an LH-RH agonist, e.g., [D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LH-RH ethylamide with a combination therapy comprising administering an antiandrogen, e.g., flutamide and an antiestrogen, e.g., Tamoxifen, pharmaceutical compositions useful for such treatment and two and three component pharmaceutical kits containing such compositions are disclosed.
Filing date: Aug 2, 1984
Issue date: Oct 4, 1988
Inventors: Fernand Labrie, Alain Belanger, Andre Dupont
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What is claimed is:
1. A method of treating breast cancer in a warm-blooded animal in need of such treatment which comprises blocking the ovarian hormonal secretions of said animal by surgical or chemical means and administering to said animal therapeutically effective amounts of an antiandrogen and an antiestrogen, or pharmaceutical compositions thereof.
2. The method of claim 1 wherein the ovaries are surgically removed.
3. The method of claim 1 wherein the ovarian hormonal secretions are blocked by administering an amount of a LH-RH agonist or a LH-RH antagonist or a pharmaceutical composition thereof effective to block said hormonal secretions.
4. The method according to claim 1 wherein the LH-RH agonist is administered parenterally together with a pharmaceutically acceptable parenteral carrier.
5. The method of claim 1 wherein the antiandrogen and the antiestrogen are each administered orally, together with a pharmaceutically acceptable oral carrier.
6. The method of claim 1 wherein the LH-RH agonist is a nonapeptide or a decapeptide represented by the formula: L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-X-Y-L-arginyl-L-prolyl-Z, wherein X is D-tryptophyl, D-leucyl, D-alanyl, 3-(2-naphthyl)-D-alanyl, O-tert-butyl-D-seryl, D-tyrosyl, D-lysyl, D-phenylalanyl or N-methyl-D-alanyl and wherein Y is L-leucyl or D-leucyl or D-alanyl and wherein Z is glycyl-NHR.sub.1 or NHR.sub.1 wherein R.sub.1 is H, lower alkyl or lower haloalkyl.
7. The method of claim 1 wherein the antiestrogen is (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine.
8. The method of claim 1 which further comprises administering aminoglutethimide or ketoconasole or pharmaceutical compositions thereof.
9. The method of claim 1 wherein the antiandrogen is 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethylimidazoline-2,5-dione.
10. The method of claim 1 wherein the antiandrogen is 4'-nitro-3'-trifluoromethylisobutyranilide.
11. A method of treating breast cancer in a warm-blooded animal having breast cancer whose ovarian hormonal secretions have been previously blocked by surgical or chemical means, which comprises administering to said animal therapeutically effective amounts of an antiandrogen and an antiestrogen, or pharmaceutical compositions thereof.
12. The method of claim 11 wherein the ovaries are surgically removed.
13. The method of claim 11 wherein the ovarian hormonal secretions are blocked by administering an amount of a LH-RH agonist or a LH-RH antagonist or a pharmaceutical composition thereof effective to block said hormonal secretions.
14. The method according to claim 11 wherein the LH-RH agonist is administered parenterally together with a pharmaceutically acceptable parenteral carrier.
15. The method of claim 11 wherein the antiandrogen and the antiestrogen are each administered orally, together with a pharmaceutically acceptable oral carrier.
16. The method of claim 11 wherein the LH-RH agonist is a nonapeptide or a decapeptide represented by the formula: L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-X-Y-L-arginyl-L-prolyl-Z, wherein X is D-tryptophyl, D-leucyl, D-alanyl, 3-(2-naphthyl)-D-alanyl, O-tert-butyl-D-seryl, D-tyrosyl, D-lysyl, D-phenylalanyl or N-methyl-D-alanyl and wherein Y is L-leucyl or D-leucyl or D-alanyl and wherein Z is glycyl-NHR.sub.1 or NHR.sub.1 wherein R.sub.1 is H, lower alkyl or lower haloalkyl.
17. The method of claim 11 wherein the anti-estrogen is (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine.
18. The method of claim 11 which further comprises administering aminoglutethimide or ketoconazole or pharmaceutical compositions thereof.
19. The method of claim 11 wherein the antiandrogen is 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethylimidazoline-2,5-dione.
20. The method of claim 11 wherein the antiandrogen is 4'-nitro-3'-trifluoromethylisobutyranilide.
21. A method of treating breast cancer in a warm-blooded animal having breast cancer which comprises administering to said animal therapeutically effective amounts of a LH-RH agonist or a LH-RH antagonist, an antiandrogen and an antiestrogen, or pharmaceutical compositions thereof.
22. The method of claim 21 wherein the LH-RH agonist is administered parenterally together with a pharmaceutically acceptable parenteral carrier.
23. The method of claim 18 wherein the antiestrogen and the antiandrogen are each administered orally, together with pharmaceutically acceptable oral carrier.
24. The method of claim 14 wherein the LH-RH agonist is administered at a daily parenteral dose of between 250 and 500 .mu.g.
25. The method of claim 15 wherein the antiandrogen is administered at a daily oral dose of between about 0.20 and 20 mg and the antiestrogen is administered at a daily oral dose of between about 0.10 and 10 mg.
26. A kit comprising in separate containers pharmaceutical compositions for combined use in treating breast cancer which comprises (1) a pharmaceutical composition comprising an antiandrogen and (2) a pharmaceutical composition comprising an antiestrogen.
27. A kit comprising in separate containers pharmaceutical compositions for combined use in treating breast cancer which comprises (1) a pharmaceutical composition comprising a LH-RH agonist or a LH-RH antagonist (2) a pharmaceutical composition comprising an antiandrogen and (3) a pharmaceutical composition comprising an antiestrogen.
28. The kit of claim 27 wherein the pharmaceutical compositions are oral compositions.
29. The kit of claim 28 wherein the LH-RH agonist pharmaceutical composition comprises the LH-RH agonist in one container and a solvent for parenteral administration in another container.
30. The kit of claim 28 wherein the pharmaceutical compositions of the antiandrogen and the antiestrogen are each oral compositions
31. The method of inhibiting the growth of breast tumors in a warm blood animal whose ovarian hormonal secretions have been previously blocked by surgical or chemical means which comprises administering to the warm-blooded animal having such tumors therapeutically effective amounts of an antiandrogen and an antiestrogen, or pharmaceutical compositions thereof.
32. The method of claim 31 wherein the ovaries are surgically removed.
33. The method of claim 31 wherein the ovarian hrmonal secretions are blocked by administering and amount of a LH-RH agonist or a LH-RH antagonist or a pharmaceutical composition there of effective to block said hormonal secretions.
34. The method according to claim 31 wherein the LH-RH agonist is administered parenterally together with a pharmaceutically acceptable parenteral carrier
35. The method of claim 31 wherein the antiandrogen and the antiestrogen are each administered orally together with a pharmaceutically acceptable oral carrier.
36. The method of claim 31 wherein the LH-RH agonist is a nonapeptide or a decapeptide represented by the formula: L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-X-Y-L-arginyl-L-prolyl-Z, wherein X is D-tryptophyl, D-leucyl, D-alanyl, 3-(2-naphthyl)-D-alanyl, 0-tert-butyl-D-seryl, D-tyrosyl, D-lysyl, D-phenylalanyl or N-methyl-D-alanyl and wherein Y is L-leucyl or D-leucyl or D-alanyl and wherein Z is glycyl-NHR.sub.1 or NHR.sub.1 wherein R.sub.1 is H, lower alkyl or lower haloalkyl.
37. The method of claim 31 wherein the antiestrogen is (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine.
38. The method of claim 31 which further comprises administering aminoglutethimide or ketoconasole or pharmaceutical compositions thereof.
39. The method of claim 31 wherein the antiandrogen is 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethylimidazoline-2,5-dione.
40. The method of claim 31 wherein the antiandrogen is 4'-nitro-3'-trifluoromethylisobutyranilide.