Miyake H, Tolcher A, Gleave M E
The Prostate Centre, Vancouver General Hospital, British Columbia, Canada.
Cancer Res. 1999 Aug 15;59(16):4030-4.
Progression to androgen-independence remains the main obstacle to improving survival for patients with advanced prostate cancer. Although Bcl-2 expression in normal prostatic epithelial cells is low or absent, Bcl-2 is highly up-regulated in prostate cancer cells after androgen withdrawal and during progression to androgen-independence. Here, we test the efficacy of antisense Bcl-2 oligodeoxynucleotide (ODN) therapy administered adjuvantly after castration to delay time to androgen-independent recurrence in the androgen-dependent mouse Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with antisense Bcl-2 ODN inhibited Bcl-2 expression in a dose-dependent and sequence-specific manner. Systemic administration of antisense Bcl-2 ODN in mice bearing Shionogi tumors beginning 1 day postcastration resulted in a more rapid regression of tumors and a significant delay of emergence of androgen-independent recurrent tumors. Furthermore, despite significant reduction of Bcl-2 expression in tumor tissues, antisense Bcl-2 ODN had no effect on Bcl-2 expression in normal mouse organs. These findings illustrate the potential utility of antisense Bcl-2 therapy for prostate cancer in an adjuvant setting with androgen ablation.
进展为雄激素非依赖状态仍然是晚期前列腺癌患者提高生存率的主要障碍。尽管正常前列腺上皮细胞中的Bcl-2表达水平很低或无表达，但在雄激素撤除后及进展为雄激素非依赖状态的过程中，前列腺癌细胞中的Bcl-2会高度上调。在此，我们在雄激素依赖的小鼠狮王瘤模型中，测试去势后辅助给予反义Bcl-2寡脱氧核苷酸（ODN）疗法以延迟雄激素非依赖复发时间的疗效。用反义Bcl-2 ODN体外处理狮王瘤细胞，以剂量依赖和序列特异性方式抑制了Bcl-2表达。在去势后1天开始对荷狮王瘤小鼠全身给予反义Bcl-2 ODN，导致肿瘤消退更快，雄激素非依赖复发性肿瘤出现显著延迟。此外，尽管肿瘤组织中Bcl-2表达显著降低，但反义Bcl-2 ODN对正常小鼠器官中的Bcl-2表达没有影响。这些发现说明了反义Bcl-2疗法在雄激素消融辅助治疗前列腺癌中的潜在效用。
