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17 α-羟化酶/C17，20-裂解酶和前列腺5 α-还原酶 其可用于治疗前列腺癌。 我们现在希望 优化它们对5 α-还原酶的活性，同时保留 抑制17 α-羟化酶/C17，20-裂解酶。 这其中的重点 更新申请是为了追求我们的重要线索，确定最 活性化合物和完整的临床前评价，他们在一系列的， 我们建立的新制度。 该提案的具体目标是 合成17 α-羟化酶/C17，20-裂解酶抑制剂 5 α-还原酶抑制。 新化合物将作为抑制剂进行评价 人睾丸17 α-羟化酶/C17，20-裂解酶和前列腺5 α- 还原酶，包括I型和II型同种型。 我们将确定 抑制剂是否导致酶失活或转化为活性 雄激素，影响其他类固醇生成酶，包括3 β- 羟类固醇脱氢酶/异构酶，17 β-羟类固醇 脱氢酶、胆固醇侧链裂解酶和肾上腺皮质激素 17 α-羟化酶/C17，20-裂解酶。 潜在激动或拮抗 有效抑制剂的性质将在两个人身上确定， 野生型雄激素受体（AR）和突变型AR在转录水平上的变化 活化测定。 确定抑制剂对前列腺 将进行人前列腺的生长、细胞培养和组织培养， 出去 克数量的最活跃的抑制剂的日期和有效的新 将制备抑制剂用于进一步的体内评价。 的影响 最有效的抑制剂将在动物模型中进行体内研究， 正常成年大鼠和荷人前列腺PC-82肿瘤的裸鼠。 前列腺和肿瘤重量，以及血浆和组织中的 将测量雄激素。 此外，治疗效果将 通过研究细胞增殖、凋亡和 人前列腺和肿瘤组织培养中的雄激素依赖基因 用抑制剂治疗的裸鼠。

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.