Inhibition by 9alpha-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, 9alpha-fluoromedoroxyprogesterone acetate (FMPA), by fluorinating MPA, and we also previously reported that FMPA displays more potent anti-angiogenic activity in the chorioallantoic membrane assay than MPA. In the present study, we investigated (1) the effects of FMPA on rat mammary carcinomas induced by dimethylbenz[a]anthracene (DMBA) to determine the anti-tumor activity, (2) the effect on angiogenesis in rabbit corneal assays, and (3) compared these results 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 of the carcinomas was observed at doses of 30 and 120 mg/kg. MPA also inhibited the growth of carcinomas at doses of 30 and 120 mg/kg, but no involution 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 treatments. In rabbit corneal assays, FMPA significantly inhibited angiogenesis (IC50 value=0.085 microg/pellet). MPA also significantly inhibited angiogenesis (IC50 value=0.60 microg/pellet). From these results, we conclude that FMPA is potentially more effective in the treatment of mammary carcinomas than MPA.
Uchida
M
M
Meiji Institute of Health Science, Meiji Milk Products Co., Ltd., 540 Naruda, Kanagawa, Odawara, Japan.
Tsuboi
H
H
Yamaji
T
T
Murata
N
N
Kohno
T
T
Sugino
E
E
Hibino
S
S
Shimamura
M
M
Oikawa
T
T
D015127:9,10-Dimethyl-1,2-benzanthracene; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003315:Cornea / Q000098:blood supply / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D011374:Progesterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
C105228:17-acetoxy-9-fluoro-6-methylprogesterone; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011374:Progesterone; D015127:9,10-Dimethyl-1,2-benzanthracene; D017258:Medroxyprogesterone Acetate