Tran Chris, Ouk Samedy, Clegg Nicola J, Chen Yu, Watson Philip A, Arora Vivek, Wongvipat John, Smith-Jones Peter M, Yoo Dongwon, Kwon Andrew, Wasielewska Teresa, Welsbie Derek, Chen Charlie Degui, Higano Celestia S, Beer Tomasz M, Hung David T, Scher Howard I, Jung Michael E, Sawyers Charles L
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Science. 2009 May 8;324(5928):787-90. doi: 10.1126/science.1168175. Epub 2009 Apr 9.
Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.
转移性前列腺癌采用拮抗雄激素作用的药物进行治疗，但大多数患者会进展为一种更具侵袭性的疾病形式，即去势抵抗性前列腺癌，这是由雄激素受体表达升高所驱动的。在此，我们对二芳基硫代乙内酰脲类化合物RD162和MDV3100进行了表征，这两种化合物是从非甾体抗雄激素筛选中优化得到的，在雄激素受体表达增加的情况下仍保持活性。这两种化合物与雄激素受体结合的相对亲和力均高于临床使用的抗雄激素药物比卡鲁胺，降低了其核转位效率，并损害了其与雄激素反应元件的DNA结合以及共激活因子的募集。RD162和MDV3100均可口服，并在去势抵抗性人前列腺癌小鼠模型中诱导肿瘤消退。在一项I/II期临床试验中，首批接受MDV3100治疗的30例患者中，30例中有13例（43%）血清前列腺特异性抗原（一种前列腺癌生物标志物）浓度持续下降（超过50%）。因此，这些化合物似乎是治疗晚期前列腺癌的有前景的候选药物。
