ANDROGEN SYNTHESIS INHIBITORS FOR PROSTATE CANCER

我们已经发现了几种具有双重活性的有效抑制剂。 睾丸17α-羟基酶/C17，20-裂解酶与前列腺5α-还原酶 这可能对前列腺癌的治疗有用。我们现在希望 优化其对5α-还原酶的活性，同时保留 抑制17α-羟基酶/C17，20-裂解酶。这一点的重点 续签申请是为了追寻我们的重要线索，识别最 活性化合物和对它们的完整临床前评价 我们已经建立了新的制度。这项建议的具体目的是 增强型17α-羟基酶/C 17，20-裂解酶抑制剂的合成 5α-还原酶抑制。新化合物将作为抑制剂进行评估 人睾丸17α-羟基酶/C17，20-裂解酶和前列腺5α- 还原酶，包括I型和II型异构体。我们将决定 抑制剂是导致酶失活还是转化为活性 雄激素，影响其他类固醇生成酶，包括3β- 羟基类固醇脱氢酶/异构酶，17β-羟基类固醇 脱氢酶、胆固醇侧链裂解酶与肾上腺 17α-羟基酶/C17，20-裂解酶。潜在的激动剂或拮抗剂 有效的抑制剂的性质将在两个人身上确定 野生型雄激素受体和突变型雄激素受体在转录水平 激活分析。测定抑制剂对前列腺癌的影响 将携带人类前列腺的生长、细胞培养和组织培养 出去。DATE和强效新药中最有效的缓蚀剂的克量 将为进一步的体内评估准备抑制剂。的影响 最有效的抑制剂将在活体动物模型中进行研究。 正常成年大鼠和荷人前列腺癌PC-82裸鼠。 前列腺癌和肿瘤重量，以及血浆和组织中 雄激素将被测量。此外，治疗的疗效将是 通过研究增殖、凋亡和血管内皮细胞的表达来确定 人前列腺癌和前列腺癌组织培养中雄激素依赖基因的表达 用抑制剂处理的裸鼠。

We have discovered several potent inhibitors with dual activities against testicular 17alpha-hydroxylase/C17,20-lyase and prostatic 5alpha-reductase which could be useful in the treatment of prostatic cancer. We now wish to optimize their activities against 5alpha-reductase while retaining inhibition of 17alpha-hydroxylase/C17,20-lyase. The emphasis of this renewal application is to pursue our important leads, identify the most active compounds and complete preclinical evaluation of them in a series of new systems we have established. The specific aims of the proposal are to synthesize inhibitors of 17alpha-hydroxylase/C 17,20-lyase with enhanced 5alpha-reductase inhibition. New compounds will be evaluated as inhibitors of human testicular 17alpha-hydroxylase/C17,20-lyase and prostatic 5alpha- reductase, including Type I and Type II isoforms. We will determine whether inhibitors cause enzyme inactivation or are converted to active androgens, affect other steroidogenic enzymes including 3beta- hydroxysteroid dehydrogenase/isomerase, 17beta-hydroxysteroid dehydrogenase, the cholesterol side-chain cleavage enzyme and the adrenal 17alpha-hydroxylase/C17,20-lyase. Potential agonistic or antagonistic properties of the potent inhibitors will be determined on both the human wild type androgen receptor (AR) and the mutant AR in transcriptional activation assays. To determine the effect of inhibitors on prostatic growth, cell cultures and histocultures of human prostates will be carried out. Gram quantities of the most active inhibitors ot date and potent new inhibitors will be prepared for further evaluation in vivo. The effects of the most potent inhibitors will be then studied in animal models in vivo in normal adult rats and nude mice with human prostatic PC-82 tumors. Prostate and tumor weights, and plasma and tissue concentrations of androgens will be measured. In addition, the efficacy of treatment will be determined by investigating proliferation, apoptosis and expression of androgen-dependent genes in histoculture of human prostates and tumors from the nude mice treated with inhibitors.