ANDROGEN SYNTHESIS INHIBITORS FOR PROSTATE CANCER

前列腺癌的雄激素合成抑制剂

• 批准号: 6469926
• 负责人: ANGELA M. BRODIE
• 金额: $ 3.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-09-30 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6469926
• 关键词: SCID mouse; androgen inhibitor; androgen receptor; antineoplastics; apoptosis; athymic mouse; dosage; drug design /synthesis /production; drug screening /evaluation; genetic transcription; human tissue; laboratory rat; male; neoplasm /cancer chemotherapy; neoplastic process; nonhuman therapy evaluation; oxidoreductase inhibitor; pharmacokinetics; proliferating cell nuclear antigen; prostate neoplasms; radiotracer; steroid 17alpha monooxygenase; steroid hormone biosynthesis; testosterone 5 alpha reductase; tissue /cell culture

The goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen dependent prostatic cancer. Our strategy is to identify compounds which achieve total androgen blockade. During the current grant period, we have discovered a number of potent inhibitors of 17alpha-hydroxylase/C17,20-lyase. Several of these also inhibit 5alpha-reductase and/or are antiandrogens. We plan to continue studies of these compounds utilizing the methods we have established to characterize their activity. Because mutations of the androgen receptor appear to play an important role in resistance to current therapy, we will modify inhibitors in order to increase their activity as androgen receptor antagonists for both the wild type receptor and the mutated forms common in prostate cancer. We propose methods to improve the bioavailability of our most potent inhibitors including synthesis of analogs of our inhibitors to increase efficacy in vivo. We will also synthesize radiolabeled inhibitors to determine their pharmacokinetics and metabolism. The specificity of inhibitors will be determined by investigating their effects on other steroidogenic enzymes. We will determine whether the inhibitors are androgen receptor agonists or antagonists by their effects on transcriptional activation assays, prostate cancer cells in culture, and in histocultures of samples from patients. We will study their effects in vivo on androgen concentrations and prostate weight in normal male rats. The antitumor efficacy of the most potent inhibitors at optimal dose/route will be investigated in mouse xenograft models with human prostate cancers (PC-82 and LNCaP) including the effects of inhibitors on tumor proliferation/apoptosis. These studies should enable us to select the most effective inhibitors by the end of the grant period, that can then be advanced to phase I trials.

本项目的目标是开发具有可能对雄激素依赖性前列腺癌提供有效抗肿瘤活性的特征的化合物。 我们的策略是确定实现雄激素完全阻断的化合物。 在目前的资助期内，我们发现了许多17 α-羟化酶/C17，20-裂解酶的有效抑制剂。其中几种也抑制5 α-还原酶和/或抗雄激素。 我们计划继续研究这些化合物，利用我们已经建立的方法来表征其活性。 由于雄激素受体的突变似乎在对当前治疗的抗性中起重要作用，我们将修饰抑制剂以增加其作为野生型受体和前列腺癌中常见的突变形式的雄激素受体拮抗剂的活性。 我们提出了提高我们最有效的抑制剂的生物利用度的方法，包括合成我们的抑制剂的类似物以增加体内功效。 我们还将合成放射性标记的抑制剂，以确定其药代动力学和代谢。抑制剂的特异性将通过研究其对其他类固醇生成酶的影响来确定。 我们将通过其对转录激活试验、培养中的前列腺癌细胞和患者样本的组织培养的影响来确定抑制剂是雄激素受体激动剂还是拮抗剂。 我们将研究它们对正常雄性大鼠体内雄激素浓度和前列腺重量的影响。将在人前列腺癌（PC-82和LNCaP）小鼠异种移植模型中研究最有效抑制剂在最佳剂量/途径下的抗肿瘤疗效，包括抑制剂对肿瘤增殖/细胞凋亡的影响。 这些研究应该使我们能够在资助期结束前选择最有效的抑制剂，然后可以推进到I期试验。