Labrie Fernand
Laval University, Quebec, Canada.
J Steroid Biochem Mol Biol. 2015 Jan;145:144-56. doi: 10.1016/j.jsbmb.2014.05.012. Epub 2014 Jun 9.
Recently two drugs, namely the antiandrogen MDV-3100 and the inhibitor of 17α-hydroxylase abiraterone have been accepted by the FDA for the treatment of castration-resistant prostate cancer (CRPC) with or without previous chemotherapy, with a prolongation of overall survival of 2.2-4.8 months. While medical (GnRH agonist) or surgical castration reduces the serum levels of testosterone by about 97%, an important concentration of testosterone and dihydrotestosterone remains in the prostate and activates the androgen receptor (AR), thus offering an explanation for the positive data obtained in CRPC. In fact, explanation of the response observed with MDV-3100 or enzalutamide in CRPC is essentially a blockade of the action or formation of intraprostatic androgens. In addition to the inhibition of the action or formation of androgens made locally by the mechanisms of intracrinology, increased AR levels and AR mutations can be involved, especially in very advanced disease. Future developments look at more efficient inhibitors of the action or formation of intraprostatic androgens and starting treatment earlier when blockade of androgens can exert long-term control and even cure prostate cancer treated at a stage before the appearance of metastases. This article is part of a Special Issue entitled 'Essential role of DHEA'.
最近，两种药物，即抗雄激素药物MDV - 3100和17α - 羟化酶抑制剂阿比特龙，已被美国食品药品监督管理局（FDA）批准用于治疗既往接受或未接受过化疗的去势抵抗性前列腺癌（CRPC），可使总生存期延长2.2 - 4.8个月。虽然药物去势（促性腺激素释放激素激动剂）或手术去势可使睾酮血清水平降低约97%，但前列腺中仍存在重要浓度的睾酮和双氢睾酮，并激活雄激素受体（AR），这就解释了在CRPC中获得的阳性数据。事实上，MDV - 3100或恩杂鲁胺在CRPC中观察到的反应本质上是对前列腺内雄激素作用或形成的阻断。除了通过内分泌学机制抑制局部产生的雄激素的作用或形成外，AR水平升高和AR突变也可能起作用，尤其是在疾病非常晚期时。未来的发展方向是寻找更有效的前列腺内雄激素作用或形成的抑制剂，并在雄激素阻断能够实现长期控制甚至治愈处于转移出现前阶段的前列腺癌时更早开始治疗。本文是名为“脱氢表雄酮的重要作用”的特刊的一部分。
