PHARMACOLOGY OF AROMATASE INHIBITORS FOR BREAST CANCER

雌激素参与多种生理过程，包括 女性性器官的发育和维持，生殖 周期、生殖和各种神经内分泌功能。这些 荷尔蒙在某些疾病状态中也起着关键作用，尤其是 在乳腺癌和子宫内膜癌中。雌激素抑制剂 生物合成具有潜在的药理作用和治疗作用 治疗各种雌激素依赖型疾病的药物， 比如晚期乳腺癌。芳香酶抑制剂将有效地 降低所有产生组织(如脂肪)中的雌激素水平 绝经后妇女的组织)，并导致肿瘤消退。几个 芳香酶抑制剂正在进行临床试验，并正在生产 激素依赖型乳腺癌患者的阳性结果。更新的 具有更高效力、更高选择性和更少的芳香酶抑制剂 副作用是需要的。几种7α取代的类固醇芳香酶 由我们实验室开发的缓蚀剂具有最高的 芳香化酶的亲和力及体外最大抑制活性 都是已知的芳香酶抑制剂。体内药理学知识， 这些有效抑制剂的药代动力学和代谢是 对进一步发展至关重要。这次合作的目标是， 多学科研究是进行临床前药理学 新型甾体芳香酶抑制剂的研究进展 晚期雌激素依赖型乳腺癌的治疗。新的 竞争性芳香酶抑制剂(7α-取代4-雄烯-3，17- 双酮)和酶激活的抑制剂(7α-取代的1，4- 雄二烯-3，17-二酮)已在我们的实验室制备。 这些新类似物在细胞培养系统和体内的进一步研究 在这些抑制剂的开发中是必不可少的有效的 雌激素依赖型癌症的治疗药物。 具体目的是(1)检测芳香酶抑制剂对 癌细胞培养中的细胞生长和类固醇生化，(2)到 研究7α-对其他类固醇生成酶的抑制作用 取代的甾体芳香酶抑制剂，(3)体内评价 抗肿瘤活性，检查药理作用，并确定 这些药物的药代动力学，以及(4)表现急性毒性 在大鼠身上测试选定的抑制剂。这些研究将提供 关于化合物药用潜力的重要信息 治疗乳腺癌的药物，并将提供所需的数据 提交IND申请进行首次临床评估 7α-取代类固醇类药物治疗慢性阻塞性肺疾病 晚期雌激素依赖型乳腺癌。

Estrogens are involved in numerous physiological processes including the development and maintenance of the female sexual organs, the reproductive cycle, reproduction, and various neuroendocrine functions. These hormones also have crucial roles in certain disease states, particularly in mammary and endometrial carcinomas. Inhibitors of estrogen biosynthesis have potential use as pharmacological tools and therapeutic agents in the treatment of various estrogen-dependent disease states, such as advanced breast cancer. Aromatase inhibitors would effectively lower estrogen levels in all tissues where produced (such as adipose tissue in post-menopausal women) and result in tumor regression. Several aromatase inhibitors are being examined in clinical trials and produced positive results in women with hormone-dependent breast cancer. Newer aromatase inhibitors with higher potency, greater selectivity, and fewer side effects are needed. Several 7alpha-substituted steroidal aromatase inhibitors have been developed by our laboratory and have the highest affinities for aromatase and greatest inhibitory activities in vitro of all known aromatase inhibitors. Knowledge of in vivo pharmacology, pharmacokinetics, and metabolism of these effective inhibitors are critical for further development. the objective of this collaborative, multi-disciplinary research is to perform preclinical pharmacology investigations of new steroidal aromatase inhibitors being developed for the treatment of advanced estrogen-dependent breast cancer. New competitive aromatase inhibitors (7alpha-substituted 4-androstene-3, 17- diones) and enzyme-activated inhibitors (7alpha-substituted 1,4- androstadiene-3,17-diones) have been prepared in our laboratories. Further studies of these new analogs in cell culture systems and in vivo are essential in the development of these inhibitors as effective therapeutical agents for the treatment of estrogen-dependent cancers. The specific aims are (1) to examine effects of aromatase inhibitors on cell growth and steroid biochemistry in cancer cell cultures, (2) to investigate inhibition of other steroidogenic enzymes by 7alpha- substituted steroidal aromatase inhibitors, (3) to assess in vivo antitumor activity, to examine the pharmacology, and to determine pharmacokinetics of these agents, and (4) to perform acute toxicity testing of selected inhibitors in rats. These studies will provide important information on the potential of the compounds as medicinal agents in the treatment of breast cancer and will provide the data needed to submit an IND application for the first clinical evaluation of a 7alpha-substituted steroidal agent for the treatment of patients with advanced estrogen-dependent breast cancer.