去势抵抗性前列腺癌中雄激素生物合成的研究进展

Androgen biosynthesis in castration-resistant prostate cancer: Advances in studies

前列腺癌是男性泌尿生殖系统最常见的恶性肿瘤之一。目前去势抵抗性前列腺癌(CRPC)患者中位生存期仅12个月,预后极差,成为了前列腺癌的治疗难题。尽管雄激素剥夺治疗(ADT)去除了循环中绝大多数雄激素,但CRPC仍可通过前列腺癌瘤内自身合成的雄激素或者改变雄激素受体(AR)来适应患者体内低水平雄激素。本文综述了CRPC中T和双氢睾酮(DHT)的主要合成途径及其所涉及的主要酶和不同阶段的患者体内雄激素水平的变化。由于在雄激素合成途径中存在多条通路,阻断单一通路可能导致另一条通路的上调,从而导致雄激素阻断不彻底,进而出现耐药性。因此,明确雄激素的生物合成途径可以为研发靶向阻断关键雄激素合成通路的药物或阻断肿瘤内雄激素生物合成并拮抗雄激素受体的双功能药物提供契机。

Prostate cancer is a most common malignant tumor in the male urogenital system. Currently, castration-resistant prostate cancer(CRPC) is a bottleneck in the treatment of prostate cancer, which has a very poor prognosis, with a median survival of merely 12 months. Although androgen-deprivation therapy eliminates the majority of the androgens in circulation, CRPC patients adapt to low-level androgens by synthesizing intratumoral androgens or altering androgen receptors. This review summarizes the main ways of synthesizing testosterone and dihydrotestosterone(DHT), the enzymes involved, and changes of the androgen level in different stages of CRPC. Blocking any one of the pathways of androgen biosynthesis is likely to upregulate another and lead to incomplete androgen elimination and consequently drug resistance. Therefore, identifying the pathways of androgen biosynthesis may provide an opportunity for the development of the drugs for blocking the major pathways of androgen and introtumoral androgen biosynthesis and antagonizing androgen receptors.