Chen Yu, Clegg Nicola J, Scher Howard I
Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Lancet Oncol. 2009 Oct;10(10):981-91. doi: 10.1016/S1470-2045(09)70229-3.
Activation of the androgen receptor is crucial for prostate cancer growth at all points of the illness. Current therapies targeting the androgen receptor, including androgen-depletion approaches and anti-androgens, do not completely inhibit the receptor activity. Prostate cancer cells develop resistance to castration by acquiring changes that include androgen-receptor overexpression and overexpression of enzymes involved in androgen biosynthesis, which result in reactivation of the receptor. Based on an understanding of these resistance mechanisms and androgen biosynthesis pathways, new anti-androgens and androgen-depleting agents have been developed. Notably, promising activity has been shown in early phase trials by MDV3100, a new anti-androgen designed for activity in prostate cancer model systems with overexpressed androgen receptor, and by abiraterone acetate, a CYP17A inhibitor that blocks steroid biosynthesis in the adrenal gland and possibly within the tumour. Both agents are undergoing phase 3 testing. Here, we review the basic science and clinical development of these and other agents.
雄激素受体的激活在前列腺癌病程的各个阶段对其生长都至关重要。目前针对雄激素受体的疗法，包括雄激素剥夺疗法和抗雄激素药物，并未完全抑制受体活性。前列腺癌细胞通过获得包括雄激素受体过表达以及雄激素生物合成相关酶的过表达等变化来产生去势抵抗，这些变化会导致受体重新激活。基于对这些抵抗机制和雄激素生物合成途径的理解，已研发出新型抗雄激素药物和雄激素剥夺药物。值得注意的是，新型抗雄激素药物MDV3100在早期试验中显示出了有前景的活性，MDV3100是一种针对雄激素受体过表达的前列腺癌模型系统设计的新型抗雄激素药物，醋酸阿比特龙也显示出了有前景的活性，醋酸阿比特龙是一种CYP17A抑制剂，可阻断肾上腺以及可能在肿瘤内的类固醇生物合成。这两种药物都正在进行3期试验。在此，我们综述这些药物及其他药物的基础科学和临床进展。
