Common (surface) epithelial cancer of the ovary is an insidious disease with a high mortality rate. Proteolytic enzymes released from membrane vesicles have been implicated in the metastatic potential of ovarian carcinomas of surface epithelial origin. Novel results of preliminary experiments indicate that high-dose progesterone inhibits, via a receptor-independent mongenomic mechanism, secretion of urokinase plasminogen activator (uPA) by human SKOV-3 ovarian cancer cells; plasma membrane blebbing and in vitro invasive capacity were likewise attenuated. Using SKOV-3 cells as a model for ovarian carcinoma, the specific objectives of the proposed project are to characterize the dose and temporal effects of sterid hormones (progesterone, medroxyprogesterone acetate, testosterone, estradiol) on plasma membrane fluid dynamics (fluorescence polarization), enzymatic (uPA, matrix metalloproteinases) secretions, membrane morphology (to include light and transmission electron microscopic enzyme immunochemistry), in vitro (Matrigel) invasiveness, and in vivo (intraperitoneal transplantation of athymic nude mice) tumorigenes. It is predicted that responses will be selective for the lipophilic progestogens. Results from these fundamental studies may provide a basis for the prophylactic and therapeutic applications of progestogens in individuals at high-risk for the development of ovarian carcinoma and after diagnosis of early-stage disease, respectively.
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