Culig Z, Hobisch A, Hittmair A, Cronauer M V, Radmayr C, Bartsch G, Klocker H
Department of Urology, University of Innsbruck, Austria.
Drugs Aging. 1997 Jan;10(1):50-8. doi: 10.2165/00002512-199710010-00005.
Recent studies indicate that androgen receptors are present in all histological types of prostatic tumours, in relapsed prostatic carcinomas and in tumour metastases, even those obtained from patients in whom endocrine therapy was unsuccessful. Several research groups have asked whether structurally altered androgen receptors might be present in human prostatic tumours. The first androgen receptor mutation in prostate cancer was detected in the tumour cell line LNCaP. The frequency of androgen receptor mutations in primary tumours of the prostate is relatively low. In contrast, a high frequency of mutations has been reported in bone metastases from patients who did not respond to endocrine therapy. This fact may reflect genetic instability in these late tumour stages. Mutant androgen receptors detected in human prostate cancer cells are 'promiscuous receptors'; that is, they are activated not only by synthetic and testicular androgens, but also by adrenal androgens, products of dihydrotestosterone metabolism, estrogenic and progestagenic steroids, and even by nonsteroidal antiandrogens. Interestingly, the nonsteroidal antiandrogens hydroxyflutamide and nilutamide, but not bicalutamide, have been reported to have agonistic effects at mutant androgen receptors. It is speculated that the existence of androgen receptor mutations may explain, at least in part, the 'antiandrogen withdrawal syndrome': a temporary improvement in a subpopulation of prostate cancer patients following cessation of an antiandrogen from a therapeutic protocol. Further studies on androgen receptor alterations in prostate cancer should focus on metastatic specimens obtained from the late stages of this disease.
近期研究表明，雄激素受体存在于前列腺肿瘤的所有组织学类型中，存在于复发性前列腺癌及肿瘤转移灶中，甚至在那些内分泌治疗无效患者的肿瘤中也有发现。几个研究小组提出疑问，人类前列腺肿瘤中是否可能存在结构改变的雄激素受体。前列腺癌中的首个雄激素受体突变是在肿瘤细胞系LNCaP中检测到的。前列腺原发性肿瘤中雄激素受体突变的频率相对较低。相比之下，在对内分泌治疗无反应患者的骨转移灶中，已报道有较高的突变频率。这一事实可能反映了这些晚期肿瘤阶段的基因不稳定性。在人类前列腺癌细胞中检测到的突变雄激素受体是“混杂受体”；也就是说，它们不仅被合成雄激素、睾丸雄激素激活，还被肾上腺雄激素、双氢睾酮代谢产物、雌激素和孕激素类固醇激活，甚至被非甾体类抗雄激素激活。有趣的是，据报道非甾体类抗雄激素羟基氟他胺和尼鲁米特，但比卡鲁胺没有，在突变雄激素受体上具有激动作用。据推测，雄激素受体突变的存在可能至少部分解释了“抗雄激素撤药综合征”：在治疗方案中停用抗雄激素后，一部分前列腺癌患者出现暂时改善。对前列腺癌中雄激素受体改变的进一步研究应集中于从该疾病晚期获取的转移标本。
