Progestogen Inhibition of Ovarian Cancer Cell Metastasis

描述（由申请人提供）：常见（表面）上皮癌， 卵巢是一种具有高死亡率的隐匿性疾病。蛋白水解 从膜囊泡中释放的酶与转移性 卵巢癌的潜在表面上皮起源。新的结果 初步的实验表明，高剂量孕酮通过一种 受体非依赖性单基因组机制，尿激酶纤溶酶原分泌 人卵巢癌细胞SKOV-3的uPA激活物;质膜 起泡和体外侵袭能力同样减弱。使用SKOV-3 细胞作为卵巢癌模型， 拟议的项目是表征剂量和时间效应的sterid 激素（孕酮、醋酸甲羟孕酮、睾酮、雌二醇） 对质膜流体动力学（荧光偏振），酶（uPA， 基质金属蛋白酶）分泌物，膜形态（包括光 和透射电镜酶免疫化学），在体外 （Matrigel）侵袭性和体内（腹膜内移植） 无胸腺裸鼠）肿瘤基因。据预测，反应将是 对亲脂性孕激素具有选择性。这些基本的结果 研究可为预防和治疗应用提供基础 卵巢癌高危人群中孕激素的作用 癌和早期疾病诊断后，分别。

DESCRIPTION (provided by applicant): 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.