AROMATASE AND ANDROGEN INHIBITORS IN PROSTATE CANCER

在以前的资助期间，芳香酶抑制剂被开发用于 在治疗依赖癌症方面。 一种化合物，4- 羟基雄烯二酮（4-OHA），现在正成功地用于 治疗绝经后乳腺癌患者。 但在 初步研究，4-OHA没有导致客观缓解， 转移性前列腺癌患者的疾病。 以试图 改善对这种疾病患者的治疗， 研究人员已经合成了几种有效的抑制剂化合物 雄激素生物合成（抑制17 α-羟化酶/17，20裂解酶 和5 α-还原酶）。 它们也可能通过限制雌激素的分泌来减少雌激素的产生。 芳香酶底物。 这项建议的具体目标是： 合成和评价（体外和大鼠）甾族化合物 是雄激素生物合成的更有效的抑制剂; 2）为了确定 最有效的抑制剂是否会导致前列腺癌的消退 在大鼠Dunning前列腺肿瘤模型和携带PC-82的无胸腺小鼠中 人前列腺癌异种移植物;和3）确定 雄激素最有效的抑制剂和较新的芳香酶抑制剂 肿瘤组织中程序性细胞死亡的受体水平和标志物 治疗小鼠。 雄激素和雌激素生物合成的有效抑制剂 可能对前列腺癌的治疗有价值。

In previous grant periods, aromatase inhibitors were developed for use in the treatment of hormone-dependent cancers. One compound, 4- hydroxyandrostenedione (4-OHA), is now being used successfully in the treatment of postmenopausal breast cancer patients. However, in preliminary studies, 4-OHA did not result in objective remission of disease in patients with metastatic prostate cancer. In an attempt to improve treatment for patients with this disease, the principal investigator has synthesized several compounds that are potent inhibitors of androgen biosynthesis (inhibiting both 17 a-hydroxylase/17,20 lyase and 5 a-reductase). They may also reduce estrogen production by limiting substrate for aromatase. The specific aims of this proposal are: 1) To synthesize and evaluate (both in vitro and in rats) steroid compounds that are more potent inhibitors of androgen biosynthesis; 2) To determine whether the most potent inhibitors cause regression of prostate cancers in the rat Dunning prostate tumor model and in athymic mice bearing PC-82 human prostate carcinoma xenografts; and 3) To determine the effects of the most potent inhibitors and newer aromatase inhibitors on androgen receptor levels and markers of programmed cell death in tumor tissue of treated mice. Effective inhibitors of androgen and estrogen biosynthesis could be of value in the treatment of prostate cancer.