Singer Eric A, Golijanin Dragan J, Messing Edward M
Department of Urology, University of Rochester Medical Center, Rochester, New York USA.
Can J Urol. 2008 Dec;15(6):4381-7.
Androgen deprivation therapy (ADT) has been the cornerstone of treatment for advanced prostate cancer for over 65 years. Although there can be worrisome side effects, data will be presented that for men with metastatic prostate cancer, immediate ADT can reduce the likelihood of developing the rare but catastrophic sequellae of metastatic disease, although it is unlikely to prolong survival compared with waiting for symptoms before initiating ADT. Additionally, for patients with extremely high risk prostate cancer that is not distantly metastatic (e.g. have a life expectancy from prostate cancer less than 10 years with all other available treatments except immediate ADT) and, whose life expectancy from non-prostate cancer diseases is excellent during this period, early ADT both alone and in conjunction with definitive local treatment prolongs survival. Moreover, ADT seems to be most effective when the cancer volume is low. However, eventually most men receiving ADT experience disease progression. The biological mechanisms explaining how prostate cancer escapes from ADT's control include: 1) Alterations in the androgen receptor (AR) and in the AR co-factors (which modify the responsiveness of the AR to androgens) allow molecules and medications which are not normally AR agonists to act as agonists. 2) The human prostate gland, and particularly prostate cancer, may be able to synthesize androgens from both cholesterol and adrenal androgens. This may occur because prostate cancer tissue has higher concentrations of androgens than does the serum in patients receiving ADT. Thus, castrated men may not be starving their prostate cancers of androgens. 3) The AR in prostatic stroma far more strongly stimulates both malignant and benign prostatic epithelial growth than the epithelial AR does. Indeed, the epithelial AR, particularly in advanced prostate cancer, may have anti-proliferative and anti-tumor progression properties. That is, the AR in the prostatic epithelial cells, particularly malignant ones, may act as a tumor suppressor. Thus, by inhibiting the epithelial AR, its protective effects may be abrogated. The controversial nature of these concepts, as well as the clinical and experimental data which support and question them, will be presented. Additionally, strategies for addressing each of these escape mechanisms, which may be able to prolong responsiveness to ADT, will be discussed.
雄激素剥夺疗法（ADT）65多年来一直是晚期前列腺癌治疗的基石。尽管可能会有令人担忧的副作用，但将展示的数据表明，对于转移性前列腺癌男性患者，立即进行ADT可降低发生转移性疾病罕见但灾难性后遗症的可能性，尽管与等待出现症状后再开始ADT相比，它不太可能延长生存期。此外，对于非远处转移的极高风险前列腺癌患者（例如，除立即进行ADT外，所有其他可用治疗方案下前列腺癌预期寿命小于10年），且在此期间非前列腺癌疾病预期寿命良好，单独使用早期ADT以及与确定性局部治疗联合使用均可延长生存期。此外，当癌体积较小时，ADT似乎最有效。然而，最终大多数接受ADT的男性会出现疾病进展。解释前列腺癌如何逃避ADT控制的生物学机制包括：1）雄激素受体（AR）及其辅助因子（调节AR对雄激素反应性）的改变，使通常不是AR激动剂的分子和药物发挥激动剂作用。2）人类前列腺，尤其是前列腺癌，可能能够从胆固醇和肾上腺雄激素合成雄激素。这可能是因为前列腺癌组织中的雄激素浓度高于接受ADT患者的血清。因此，去势男性可能并未使前列腺癌缺乏雄激素。3）前列腺基质中的AR比上皮AR更强烈地刺激恶性和良性前列腺上皮生长。实际上，上皮AR，尤其是在晚期前列腺癌中，可能具有抗增殖和抗肿瘤进展特性。也就是说，前列腺上皮细胞，尤其是恶性细胞中的AR可能起肿瘤抑制作用。因此，通过抑制上皮AR，其保护作用可能会被消除。将介绍这些概念的争议性质，以及支持和质疑它们的临床和实验数据。此外，还将讨论针对每种逃逸机制的策略，这些策略可能能够延长对ADT的反应性。
