Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Curr Opin Oncol. 2009 Nov;21(6):516-23. doi: 10.1097/CCO.0b013e328331a7a4.
Members of the Bcl-2 family of proteins are critical components in regulating the intrinsic apoptotic pathway. Bcl-2 protein overexpression is associated with drug resistance and poor clinical outcome in cancer patients. Preclinical and clinical evaluations demonstrate that downregulation of Bcl-2 restores the intrinsic apoptotic pathways with antitumor effects. Thus, Bcl-2 is aggressively pursued as a therapeutic target in cancer with several new drugs undergoing clinical investigations. In this manuscript, we will review clinical information on some of the novel compounds specifically designed to target the Bcl-2 gene product(s).
Extensive clinical evaluations using a Bcl-2-specific antisense have resulted in an overall disappointing experience. But new small molecule inhibitors of the Bcl-2 hold promise with high target affinity, ease of administration and improved toxicity profile. Early stage clinical trials of these agents are revealing promising results alone as well as in combination with existing anticancer therapeutics. Encouraging results from some of these clinical investigations are summarized in this review.
Downregulation of Bcl-2 and restoration of a critical apoptotic pathway in cancer cells remains an important strategy. Novel Bcl-2 inhibitors have started to deliver the therapeutic promise of this target-specific quest.
Bcl-2 蛋白家族成员是调节细胞内在凋亡途径的关键组成部分。Bcl-2 蛋白过表达与癌症患者的耐药性和不良临床结局相关。临床前和临床评估表明，下调 Bcl-2 可恢复内在凋亡途径并发挥抗肿瘤作用。因此，Bcl-2 被积极地作为癌症的治疗靶点进行研究，有几种新的药物正在进行临床试验。本文将综述专门针对 Bcl-2 基因产物设计的一些新型化合物的临床信息。
使用 Bcl-2 特异性反义寡核苷酸进行广泛的临床评估，结果令人失望。但是，新型 Bcl-2 小分子抑制剂具有高靶标亲和力、易于给药和改善的毒性特征，具有很大的应用前景。这些药物的早期临床试验单独使用以及与现有的癌症治疗药物联合使用都显示出了有希望的结果。本综述总结了其中一些临床试验的令人鼓舞的结果。
下调 Bcl-2 并恢复癌细胞中关键的凋亡途径仍然是一个重要的策略。新型 Bcl-2 抑制剂已开始实现这一靶向治疗的承诺。
