Bruchovsky N, Klotz L H, Sadar M, Crook J M, Hoffart D, Godwin L, Warkentin M, Gleave M E, Goldenberg S L
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Mol Urol. 2000 Fall;4(3):191-9;discussion 201.
The Canadian Prospective Trial of intermittent androgen suppression was a prototype therapeutic initiative started in 1995 for the management of patients in biochemical relapse after radiation for localized prostate cancer. An interim analysis has yielded several observations on the relations between baseline serum prostate specific antigen (PSA), nadir serum PSA, Gleason score, and time off-treatment. In a typical androgen-dependent tumor, the response of serum PSA to androgen withdrawal is biphasic, but with early tumor progression, plateauing of serum PSA is observed. Ligand-independent activation of the androgen receptor, a mechanism subserving the initiation of androgen independence, can be counteracted experimentally with decoy molecules and clinically with nonsteroidal antiandrogens. In some patients, it is possible to lengthen the off-treatment interval by inhibiting the enzyme 5 alpha-reductase, an effect that can be reinforced by lowering serum testosterone with an antigonadotropin. Serial measurements of serum PSA indicate that intermittent androgen suppression engenders a more diverse range of hormone-related responses than previously appreciated. These include: (1) repeated differentiation of tumor with recovery of apoptotic potential; (2) inhibition of tumor growth by rapid restoration of serum testosterone; and (3) restraint of tumor growth by subnormal levels of serum testosterone. These responses are aspects of regulation that should be taken into account when planning long-term treatment of prostate cancer with intermittent androgen suppression.
加拿大间歇性雄激素抑制前瞻性试验是一项始于1995年的治疗性倡议，用于管理局限性前列腺癌放疗后生化复发患者。一项中期分析得出了关于基线血清前列腺特异性抗原（PSA）、最低血清PSA、 Gleason评分和停止治疗时间之间关系的若干观察结果。在典型的雄激素依赖性肿瘤中，血清PSA对雄激素撤除的反应是双相的，但在肿瘤早期进展时，会观察到血清PSA趋于平稳。雄激素受体的非配体依赖性激活是雄激素非依赖性启动的一种机制，可以通过诱饵分子在实验中以及通过非甾体类抗雄激素药物在临床上加以对抗。在一些患者中，通过抑制5α-还原酶可以延长停止治疗的间隔时间，使用促性腺激素释放激素拮抗剂降低血清睾酮可增强这种效果。血清PSA的系列测量表明，间歇性雄激素抑制产生的激素相关反应范围比以前认识到的更为多样。这些反应包括：（1）肿瘤反复分化并恢复凋亡潜能；（2）通过快速恢复血清睾酮抑制肿瘤生长；（3）通过血清睾酮水平低于正常抑制肿瘤生长。在计划用间歇性雄激素抑制进行前列腺癌长期治疗时，这些反应是需要考虑的调节方面。
