Angiogenic activity of rat mammary carcinomas induced by 7,12-dimethylbenz[a]anthracene and its inhibition by medroxyprogesterone acetate: possible involvement of antiangiogenic action of medroxyprogesterone acetate in its tumor growth inhibition.

The significant inhibitory activity of medroxyprogesterone acetate (MPA) against mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) was confirmed in female Sprague-Dawley (SD) rats, and was found to be independent of the estrogen receptor (ER) level. To facilitate elucidation of the mechanism underlying the antitumor activity of MPA against the rat mammary tumors (RMTs) regardless of ER status, the present study was conducted to determine whether or not a DMBA-induced RMT had the capacity to elicit angiogenic activity on tissue implantation into a rabbit cornea, and, if so, to determine whether or not the angiogenic activity of the RMT was inhibited by MPA. The RMTs obtained were classified into two groups based on the ER level; ER-positive and -negative groups. Both groups exhibited relatively strong angiogenic activity, the activity of the ER-negative group being significantly higher than that of the ER-positive one. The angiogenesis produced by both groups of RMTs was significantly inhibited by MPA, as judged from the results of the rabbit cornea assay. Similarly, MPA almost entirely suppressed not only the angiogenesis but also the growth of rabbit VX2 tumors without ER, included as a positive control as to the induction of angiogenic activity. In vitro experiments using neoplastic epithelioid RMT-1 and -2 cells cloned from DMBA-induced RMTs demonstrated that MPA had little or no suppressive effect on the growth of these epithelial cells. These results suggest that the inhibitory action of MPA toward the angiogenic activity of RMTs, at least in part, involves its antitumor activity toward the RMTs.