STRUCTURE-FUNCTION RELATIONSHIP OF ANTIESTROGENS

抗雌激素的结构-功能关系

• 批准号: 3170576
• 负责人: VIRGIL CRAIG JORDAN
• 金额: $ 9.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-08-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3170576
• 关键词: breast neoplasms; chemical structure function; clone cells; drug metabolism; estrogens; hormone inhibitor; pituitary gland; progesterone; prolactin releasing /inhibiting factor; tissue /cell culture

The non-steroidal antiestrogen, tamoxifen, is now accepted as a useful therapeutic agent for the treatment of hormone-dependent breast cancer. However, the pharmacology of antiestrogens has not been systemically investigated and their molecular mechanism of action is unknown. To address these problems, we have developed an estrogen-sensitive pituitary cell culture system. The structure-activity relationship of antiestrogenic ligands in the modulation of prolactin synthesis in rats and mice will be studied following either in vivo treatment of animals or addition of compounds to cultured rat and mouse pituitary cells. We will investigate whether the profound species differences in the action of antiestrogens (rats vs mice) are due to altered ligand requirements or to differential drug metabolism. The basis for the opposite effects on prolactin synthesis of estrogens and antiestrogens GH3 clonal rat pituitary tumor cells - compared to normal pituitary cells - will be studied. In selected experiments, the relative abilities of antiestrogens to inhibit prolactin synthesis and induce progesterone receptors will be compared. Since carcinogen-induced rat mammary cancer is known to be prolactin dependent, our studies will provide precise data on an antitumor mechanism of antiestrogens.

非甾体类抗雌激素，他莫昔芬，现在被接受为有用 治疗激素依赖性乳腺癌的治疗剂。 但是，抗雌激素的药理学尚未系统地 研究及其分子作用机理尚不清楚。 到 解决这些问题，我们已经开发了一种对雌激素敏感的垂体 细胞培养系统。 抗雌激素的结构活性关系 在大鼠和小鼠中催乳素合成调节中的配体将是 在体内治疗动物或添加后进行了研究 对培养的大鼠和小鼠垂体细胞的化合物。 我们将调查 抗雌激素作用的深刻物种差异是否存在 （大鼠与小鼠）是由于配体要求改变或差异 药物代谢。 对催乳素合成的相反作用的基础 雌激素和抗雌激素GH3克隆大鼠垂体肿瘤细胞 - 与正常的垂体细胞相比 - 将研究。 在选定中 实验，抗雌激素抑制催乳素的相对能力 将比较合成和诱导孕激素受体。 自从 致癌物诱导的大鼠乳腺癌是催乳素依赖性的， 我们的研究将提供有关抗肿瘤机制的精确数据 抗雌激素。