Cell-Based High Throughput Screening for Anti-Androgens

描述(申请人提供)：前列腺癌是最常见的 美国男性确诊癌症和男性癌症的第二大原因 死亡。抗雄激素用于去势以防止病情恶化。 前列腺癌。然而，癌症复发通常在2-3年内发生在 接受这种疗法的患者。这激起了人们对开发 用于前列腺癌治疗的更好的抗雄激素。传统中草药 药物(TCHM)已被证明可以阻止前列腺癌复发。在……里面 我们的初步研究，使用一种新开发的雄激素受体(AR)和 雄激素受体共激活物(ARA)介导的反式激活实验， 发现中药的一些提取物可以抑制AR诱导的基因激活， 提示TCHM是寻找新的抗雄激素药物的极好来源。一个 从这项研究发展起来的基于细胞的雄激素/AR激活分析是 有利于发现发挥抑制作用的抗雄激素 在雄激素诱导基因激活的不同阶段。执行此操作 化验可能导致发现潜在的新的和不同的抗雄激素 毒品。传统的抗雄激素只干扰雄激素和AR的结合， 如HF(羟基氟他胺)或Casodex(比卡鲁胺)。在此应用程序中，我们 建议开发高通量96孔格式AR/ARA反式激活 使用三种前列腺癌细胞系：DU145、PC3和LNCaP进行检测。在……里面 与我们的企业合作伙伴PlantPharmtica Inc.(北卡罗来纳州教堂山)合作， 从中药中提取的大量提取物和化合物已知具有 具有潜在抗雄激素和促雄激素活性的成分将是 已经检查过了。中药提取物中的化合物具有阻断野生型AR和 三种人前列腺癌细胞模型中突变的AR反式激活将 在使用雄激素敏感的前列腺进行增殖试验中进行进一步测试 癌症，LNCaP细胞评估其抑制前列腺癌的生物学效果 癌细胞生长。我们研究发现的化合物具有抗雄激素或 促雄激素活性将具有开发成新药的巨大潜力 这将改善前列腺癌患者和其他雄激素的治疗 相关的障碍。 建议的商业应用： 不可用

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