Mostaghel Elahe A, Page Stephanie T, Lin Daniel W, Fazli Ladan, Coleman Ilsa M, True Lawrence D, Knudsen Beatrice, Hess David L, Nelson Colleen C, Matsumoto Alvin M, Bremner William J, Gleave Martin E, Nelson Peter S
Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
Cancer Res. 2007 May 15;67(10):5033-41. doi: 10.1158/0008-5472.CAN-06-3332.
Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostate-specific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment.
雄激素剥夺疗法（ADT）仍然是晚期前列腺癌的主要治疗方法。ADT的疗效尚未通过在靶组织和分子水平上证明前列腺雄激素活性的抑制来进行严格评估。我们确定了药物去势在抑制前列腺雄激素水平和雄激素调节基因表达方面的疗效和一致性。在一项针对健康男性的临床试验中，使用促性腺激素释放激素拮抗剂阿西立肽（Acyline）与安慰剂进行短期去势（1个月），测量前列腺样本中的雄激素水平和雄激素调节基因表达（通过微阵列分析、定量逆转录PCR和免疫组织化学）。为了评估长期ADT的效果，在局限性前列腺癌男性患者前列腺切除样本中，于新辅助ADT的基线以及3、6和9个月后评估基因表达测量值。药物去势使组织雄激素减少了75%，并降低了几个雄激素调节基因（NDRG1、FKBP5和TMPRSS2）的表达。然而，许多雄激素反应性基因，包括雄激素受体（AR）和前列腺特异性抗原（PSA），在短期去势后或新辅助ADT 9个月后并未受到抑制。在ADT的每个时间点，前列腺癌样本中均观察到PSA和AR蛋白表达存在显著异质性。基于血清睾酮水平的药物去势不能等同于前列腺微环境中的雄激素去除。标准的雄激素剥夺并不能始终抑制雄激素依赖性基因表达。肿瘤雄激素活性的抑制不足可能导致适应性细胞变化，使前列腺癌细胞在低雄激素环境中存活。最佳临床疗效将需要测试针对完全抑制对前列腺雄激素微环境的全身和内分泌贡献的新方法。
