Miyake H, Monia B P, Gleave M E
The Prostate Centre, Vancouver General Hospital, Vancouver, Canada.
Int J Cancer. 2000 Jun 15;86(6):855-62. doi: 10.1002/(sici)1097-0215(20000615)86:6<855::aid-ijc15>3.0.co;2-8.
We have reported that antisense Bcl-2 oligodeoxynucleotide (ODN) delays progression to androgen independence in the androgen-dependent (AD) mouse Shionogi tumor model. Here, we characterize changes in bcl-xL, another important anti-apoptotic gene, and test the efficacy of adjuvant antisense Bcl-xL ODN therapy either alone or in combination with antisense Bcl-2 ODN and chemotherapy after castration in the Shionogi tumor model. Bcl-xL mRNA levels increased up to 3-fold postcastration and remained 1. 5-fold higher in androgen-independent (AI) recurrent tumors compared with AD tumors before castration. Treatment of Shionogi cells with antisense Bcl-xL ODN inhibited Bcl-xL expression in a dose-dependent and sequence-specific manner. Systemic administration of antisense Bcl-xL ODN in mice bearing Shionogi tumors after castration delayed emergence of AI recurrent tumors. We then examined whether combined adjuvant antisense Bcl-xL and/or Bcl-2 ODNs plus taxol (paclitaxel) therapy further delays time to AI progression. Combined treatment of Shionogi cells with antisense Bcl-xL and Bcl-2 ODNs significantly enhanced taxol chemosensitivity compared with either agent alone, reducing the IC(50) of taxol by more than 1 log. Apoptotic DNA laddering and cleavage of poly(ADP-ribose) polymerase were more substantial after treatment with combined antisense Bcl-2 and Bcl-xL ODNs plus taxol than that with either 2 agents. Adjuvant administration of antisense Bcl-xL and Bcl-2 ODNs plus micellar taxol resulted in a significantly delayed time to AI recurrence compared with administration of either 2 agents. Our findings suggest that Bcl-xL represents a suitable molecular target for antisense ODN strategy and illustrate the potential additive effects of multi-target pharmacology for cancer therapy.
我们曾报道，在雄激素依赖型（AD）小鼠的狮王瘤模型中，反义Bcl-2寡脱氧核苷酸（ODN）可延缓肿瘤进展至雄激素非依赖状态。在此，我们对另一个重要的抗凋亡基因bcl-xL的变化进行了表征，并在狮王瘤模型中测试了去势后辅助性反义Bcl-xL ODN单独治疗或与反义Bcl-2 ODN及化疗联合治疗的疗效。与去势前的AD肿瘤相比，bcl-xL mRNA水平在去势后升高至3倍，并在雄激素非依赖型（AI）复发性肿瘤中仍比AD肿瘤高1.5倍。用反义Bcl-xL ODN处理狮王瘤细胞可剂量依赖性且序列特异性地抑制Bcl-xL表达。在去势后的狮王瘤小鼠中全身给予反义Bcl-xL ODN可延缓AI复发性肿瘤的出现。然后，我们研究了辅助性反义Bcl-xL和/或Bcl-2 ODN联合紫杉醇治疗是否能进一步延缓至AI进展的时间。与单独使用任何一种药物相比，用反义Bcl-xL和Bcl-2 ODN联合处理狮王瘤细胞可显著增强紫杉醇的化疗敏感性，使紫杉醇的IC50降低超过1个对数。与单独使用两种药物中的任何一种相比，用反义Bcl-2和Bcl-xL ODN联合紫杉醇处理后，凋亡DNA梯状条带和聚（ADP-核糖）聚合酶的裂解更为明显。与单独给予两种药物中的任何一种相比，辅助性给予反义Bcl-xL和Bcl-2 ODN联合胶束紫杉醇可显著延缓至AI复发的时间。我们的研究结果表明，Bcl-xL是反义ODN策略的合适分子靶点，并说明了多靶点药理学在癌症治疗中的潜在累加效应。
