Fiandalo Michael V, Gewirth Daniel T, Mohler James L
Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Hauptman-Woodward Medical Research Institute, Buffalo, NY, USA.
Asian J Urol. 2019 Jan;6(1):50-56. doi: 10.1016/j.ajur.2018.09.002. Epub 2018 Sep 26.
Prostate cancer (PCa) growth and progression rely on the interaction between the androgen receptor (AR) and the testicular ligands, testosterone and dihydrotestosterone (DHT). Almost all men with advanced PCa receive androgen deprivation therapy (ADT). ADT lowers circulating testosterone levels, which impairs AR activation and leads to PCa regression. However, ADT is palliative and PCa recurs as castration-recurrent/resistant PCa (CRPC). One mechanism for PCa recurrence relies on intratumoral synthesis of DHT, which can be synthesized using the frontdoor or primary or secondary backdoor pathway. Androgen metabolism inhibitors, such as those targeting 5α-reductase, aldo-keto-reductase family member 3 (AKR1C3), or cytochrome P450 17A1 (CYP17A1) have either failed or produced only modest clinical outcomes. The goal of this review is to describe the therapeutic potential of combined inhibition of 5α-reductase and 3α-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis. Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation.
前列腺癌（PCa）的生长和进展依赖于雄激素受体（AR）与睾丸配体睾酮和双氢睾酮（DHT）之间的相互作用。几乎所有晚期PCa患者都接受雄激素剥夺治疗（ADT）。ADT可降低循环睾酮水平，这会损害AR的激活并导致PCa消退。然而，ADT是一种姑息性治疗，PCa会复发为去势复发/抵抗性PCa（CRPC）。PCa复发的一种机制依赖于肿瘤内DHT的合成，DHT可通过前门或一级或二级后门途径合成。雄激素代谢抑制剂，如那些靶向5α-还原酶、醛糖还原酶家族成员3（AKR1C3）或细胞色素P450 17A1（CYP17A1）的抑制剂，要么失败，要么仅产生了有限的临床效果。本综述的目的是描述联合抑制5α-还原酶和3α-氧化还原酶的治疗潜力，这些酶促进了DHT合成的前门和一级及二级后门途径的终末步骤。抑制雄激素代谢途径的终末步骤可能是一种克服现有雄激素代谢抑制剂缺点的方法，从而在ADT期间延迟PCa复发或增强CRPC对雄激素轴调控的反应。
