Cell-Based High Throughput Screening for Anti-Androgens

基于细胞的抗雄激素高通量筛选

• 批准号: 6484915
• 负责人: CHARLES C-Y SHIH
• 金额: $ 10万
• 依托单位: ANDROSCIENCE CORPORATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2002-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6484915
• 关键词: androgen inhibitor; androgen receptor; bioassay; drug screening /evaluation; folk medicine; high throughput technology; hormone regulation /control mechanism; neoplastic cell; plant extracts; receptor expression; technology /technique development; tissue /cell culture

DESCRIPTION (provided by the applicant): Prostate cancer is the most frequently diagnosed cancer in American men and the second leading cause of male cancer death. Antiandrogens have been used with castration to prevent the progression of prostate cancer. However, cancer relapse often occurs within 2-3 years in patients who received this therapy. This has prompted interest in developing better antiandrogens for prostate cancer treatment. Traditional Chinese Herbal Medicines (TCHM) have been shown to block recurrent prostate cancer growth. In our preliminary study, using a newly-developed androgen receptor (AR) and androgen receptor co-activator (ARA)-mediated transactivation assay, it was found that some extracts from TCHM inhibited AR-induced gene activation, suggesting TCHM is an excellent source to search for new antiandrogen drugs. A cell-based androgen/AR activation assay developed from this study is advantageous in discovering antiandrogens that exert their inhibitory function at different stages of an androgen-induced gene activation. Performing this assay could lead to the discovery of potentially new and different antiandrogen drugs. Conventional antiandrogens only interfere with androgen and AR binding, such as HF (hydroxyflutamide) or casodex (bicalutamide). In this application we propose to develop a high throughput 96-well format AR/ARA transactivation assay using three prostate cancer cell lines: DU145, PC3 and LNCaP. In collaboration with our corporate partner, Plantaceutica Inc. (Chapel Hill, NC), a large number of extracts and compounds from TCHM that are known to possess ingredients with potential antiandrogen and androgenic activities will be screened. Compounds from TCHM extracts with effects to block wild type AR and mutant AR transactivation in all three human prostate cancer cell models will be further tested in a proliferation assay using androgen-sensitive prostate cancer, LNCaP cells to assess their biological efficacy in suppressing prostate cancer cell growth. Compounds discovered by our study with antiandrogenic or androgenic activities will have great potential to be developed into new drugs that will improve the treatment of prostate cancer patients and other androgen related disorders. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述（申请人提供）：前列腺癌是最常的 诊断为美国男性的癌症，是男性癌症的第二大原因 死亡。抗雄激素已被cast割用于防止进展 前列腺癌。但是，癌症复发通常在2 - 3年内发生 接受此疗法的患者。这引起了人们对发展的兴趣 更好的抗雄激素用于前列腺癌治疗。传统的中草药 药物（TCHM）已显示可阻断复发性前列腺癌的生长。在 我们的初步研究，使用新开发的雄激素受体（AR）和 雄激素受体共激活因子（ARA）介导的反式激活测定法，它是 发现一些来自TCHM的提取物抑制AR诱导的基因激活， 提示TCHM是寻找新的抗雄激素药物的绝佳来源。一个 基于细胞的雄激素/AR激活分析是从这项研究开发的 有利于发现其抑制功能的抗雄激素 在雄激素诱导的基因激活的不同阶段。执行此操作 测定可能导致发现潜在的新和不同的抗雄激素 毒品。常规的抗雄激素仅干扰雄激素和AR结合， 例如HF（羟基氟二酰胺）或Casodex（Bicalutamide）。在此应用中，我们 提议开发高吞吐量96孔格式AR/ARA反式激活 使用三种前列腺癌细胞系的测定：DU145，PC3和LNCAP。在 与我们的公司合作伙伴Plantaceutica Inc.（Chapel Hill，NC）合作， 来自TCHM的大量提取物和化合物已知拥有 具有潜在抗雄激素和雄激素活性的成分将是 筛选。来自TCHM提取物的化合物具有效果以阻断野生型AR和 在所有三种人前列腺癌细胞模型中，突变AR反式激活将 使用对雄激素敏感的前列腺在增殖测定中进一步测试 癌症，LNCAP细胞评估其在抑制前列腺方面的生物学功效 癌细胞生长。我们的研究发现的化合物具有抗雄激素或 雄激素活动将有很大的潜力发展为新药 这将改善前列腺癌患者和其他雄激素的治疗 相关疾病。 拟议的商业应用： 无法使用