Kuil C W, Brinkmann A O
Department of Endocrinology and Reproduction, Erasmus University Rotterdam, The Netherlands.
Eur Urol. 1996;29 Suppl 2:78-82. doi: 10.1159/000473845.
Information on the molecular structure of the human androgen receptor has increased insight into the molecular mechanism of action of androgens and antiandrogens. It has also facilitated the study of molecular defects in the androgen receptor gene associated with prostate cancer. Several somatic mutations have been detected in tumour specimens of patients with prostate cancer. Most of the reported mutations are localised in the ligand binding domain. A relatively high frequency of the Thr868Ala mutation (originally reported for the human prostate cancer cell line androgen receptor) is particularly found in metastatic lesions (bone metastases) of prostate cancer and can be considered as a hot spot. It could be speculated that this specific mutant androgen receptor provides a selective growth advantage in a subset of advanced prostate cancers. For a limited number of mutations it has been shown that ligand responsiveness to adrenal androgens, progestagens, oestrogens and some antiandrogens of the mutant receptors has been increased. The consequences of these mutations could be that the androgen receptor can still be activated in castrated patients and during antiandrogen therapy. The observation, therefore, that antiandrogen withdrawal can be beneficial for some prostate cancer patients, might be understood in the light of an altered ligand responsiveness of mutant androgen receptors.
关于人类雄激素受体分子结构的信息增进了我们对雄激素和抗雄激素作用分子机制的了解。它还推动了与前列腺癌相关的雄激素受体基因分子缺陷的研究。在前列腺癌患者的肿瘤标本中已检测到几种体细胞突变。大多数报道的突变位于配体结合域。Thr868Ala突变（最初报道于人类前列腺癌细胞系雄激素受体）在前列腺癌的转移病灶（骨转移）中出现频率相对较高，可被视为一个热点。可以推测，这种特定的突变雄激素受体在一部分晚期前列腺癌中提供了选择性生长优势。对于少数突变，已表明突变受体对肾上腺雄激素、孕激素、雌激素和一些抗雄激素的配体反应性有所增加。这些突变的后果可能是雄激素受体在去势患者和抗雄激素治疗期间仍可被激活。因此，抗雄激素撤药对某些前列腺癌患者有益这一观察结果，可能鉴于突变雄激素受体配体反应性的改变而得到理解。
