Inhibition by 9 alpha-fluoromedoroxyprogesterone acetate (FMPA) against mammary carcinoma induced by dimethylbenz[a]anthracene in rats and angiogenesis in the rabbit cornea - comparison with medroxyprogesterone acetate (MPA)

Medroxyprogesterone acetate (MPA) is currently used therapeutically in the treatment of mammary and endometrial carcinomas, In order to develop a more potent and useful drug, we synthesized the novel compound, 9 alpha -fluoro medoroxyprogesterone acetate (FMPA), by fluorinating MPA, and we also previ ously reported that FMPA displays more potent anti-angiogenic activity in t he chorioallantoic membrane assay than MPA. In the present study, we invest igated (1) the effects of FMPA on rat mammary carcinomas induced by dimethy lbenz[a]anthracene (DMBA) to determine the anti-tumor activity, (2) the eff ect on angiogenesis in rabbit corneal assays, and (3) compared these result s with those for MPA. FMPA inhibited the growth of mammary carcinomas in a dose-dependent manner (7.5, 30 and 120 mg/kg). Almost complete involution o f thr carcinomas was observed at doses of 30 and 120 mg/kg, MPA also inhibi ted the growth of carcinomas at doses of 30 and 120 mg/kg, but no involutio n of carcinomas was observed even at 120 mg/kg. FMPA significantly and MPA to a lesser degree inhibited carcinogenesis at 120 mg/kg within their treat ments. In rabbit corneal assays, FMPA significantly inhibited angiogenesis (IC50 value - 0.085 mug/pellet). MPA also significantly inhibited angiogene sis (IC50 value = 0.60 mug/pellet). From these results, we conclude that FM PA is potentially more effective in the treatment of mammary carcinomas tha n MPA. (C) 2000 Published by Elsevier Science Ireland Ltd. Published by Els evier Science Ltd.