RESOLUTION & ANTI-TUMOR TESTING OF CHIRAL ANTIESTROGENS

解决

• 批准号: 3180446
• 负责人: ROBERT A MAGARIAN
• 金额: $ 15.62万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3180446
• 关键词: X ray crystallography; antineoplastics; benzanthracenes; breast neoplasms; chemical structure function; cyclopropanes; drug adverse effect; drug design /synthesis /production; estrogen inhibitor; estrogen receptors; flow cytometry; high performance liquid chromatography; isomer; laboratory rat; neoplasm /cancer chemotherapy; tamoxifen; tissue /cell culture

The purpose of this study is to prepare and evaluate a new class of nonsteroidal antiestrogens which are superior to those currently used in the treatment of breast cancer. Presently, no antiestrogens are available which are devoid of estrogenic (uterotropic) activity. Data presented in this proposal indicate that a lead compound, Analog II, is devoid of uterotropic activity in mouse uteri, which is unlike other antiestrogens in existence. Analog II has been found to be either as effective or more effective than tamoxifen (a clinically used antiestrogen with uterotropic activity) in the treatment of established tumors and the prevention of tumorigenesis in the 7,12-dimethylbenz( )anthracene (DMBA)-induced rat mammary tumor model. Based on these findings with Analog II and the steric features in existing antiestrogens, a new class of antiestrogens is proposed. Consequently, these new analogs, when prepared, will be prepared, will be examined in assay systems for their estrogenic, antiestrogenic and effect on gonadotropin secretion in vivo and receptor binding activity in vitro. All compounds will be evaluated further in a MCF-7 human breast cancer cell line to assess antitumor activity. Active members of this novel class of antiestrogens which lack estrogen agonist activity in humans would significantly improve the treatment of estrogen-dependent tumors in patients with breast cancer. Also, those compounds which have very few side effects would be useful prophylactically in preventing the genesis of estrogen-dependent tumors in women who are in the high risk category.

本研究的目的是准备和评估一类新的 非甾体抗雌激素，优于目前使用的药物 乳腺癌的治疗。 目前尚无可用的抗雌激素药物 缺乏雌激素（促子宫）活性。 数据呈现于 该提案表明先导化合物 Analog II 不含 在小鼠子宫中具有促子宫活性，这与其他抗雌激素药物不同 存在。 Analog II 已被发现同样有效或更加有效 比他莫昔芬（一种临床上使用的具有促子宫作用的抗雌激素）有效 活性）在治疗已形成的肿瘤和预防 7,12-二甲基苯并蒽 (DMBA) 诱导的大鼠肿瘤发生 乳腺肿瘤模型。 基于 Analog II 和空间位阻的这些发现 与现有抗雌激素药物的特点相比，一类新的抗雌激素药物是 建议的。 因此，这些新的类似物在制备后将被 准备好，将在测定系统中检查其雌激素， 抗雌激素以及对体内促性腺激素分泌和受体的影响 体外结合活性。 所有化合物将在 MCF-7 人乳腺癌细胞系，用于评估抗肿瘤活性。 积极的 这类缺乏雌激素激动剂的新型抗雌激素药物的成员 人类活动将显着改善治疗 乳腺癌患者的雌激素依赖性肿瘤。 还有，那些 副作用很少的化合物将有助于预防 预防女性雌激素依赖性肿瘤的发生 高风险类别。