ANGIOSTATIC ACTIVITIES OF MEDROXYPROGESTERONE ACETATE AND ITS ANALOGS

The effects of medroxyprogesterone acetate (MPA) (I) and related compo unds (II-VI) upon angiogensis induced by basic fibroblast growth facto r (bFGF) or transforming growth factor-alpha (TGF-alpha) were investig ated using a rabbit corneal system for assay of angiogenesis. Dexameth asone (Dex) was used as a positive control. The MPA analogues tested w ere 6,6'-dehydro-MPA (II), megestrol acetate (III), I-dehydromegestrol acetate (IV), melengestrol acetate (V), and I-dehydromelengestrol ace tate (VI). The inhibitory activities of these steroids using bFGF were in the order: Dex = MPA = (VI) = (V) > (IV) > (III). Steroid (II) was inactive. 5 alpha-dihydrotestosterone was weakly active, while estrad iol-I7 beta and progesterone were inactive. The angiostatic activity o f MPA was completeley abolished by mefipristone (RU486) which showed o n anti-angiogenic activity in this assay. With TGF-alpha, the order of angiostatic activities was dex = (VI) > (III) > (V). Steroid (II) was again inactive. Dex, MPA, and all the MPA analogues except steroid (I I) markedly inhibited the activity of plasminogen activator secreted b y cultured calf pulmonary artery endothelial cells, but did not inhibi t growth of these cells. The binding affinities of MPA and its analogu es to glucocorticoid, progesterone and androgen receptors were determi ned, but were found not to be correlated with their angiostatic activi ties. (C) Wiley-Liss, Inc.