Cotter Finbarr E
St Bartholomew's and the Royal London School of Medicine and Dentistry Queen Mary & Westfield, University of London, London, UK.
Semin Oncol. 2004 Dec;31(6 Suppl 16):18-21; discussion 33. doi: 10.1053/j.seminoncol.2004.10.014.
Cancer cells that express excessive levels of Bcl-2 pose a major problem in the delivery of curative therapy. Most treatments for such cancer involve chemotherapy to induce the apoptotic process. While these therapies often result in disease control for periods of time, failure to initiate apoptosis as a result of acquired resistance limits the effectiveness of treatment for many common hematopoietic and solid malignancies, and ultimately death from the malignancy still occurs. Various anti-apoptotic proteins of the Bcl-2 family that localize to the mitochondria appear to be involved in this resistance mechanism. However, recent advances in the understanding of malignant cell biology, achieved through both genomics and proteomics, have made it possible to explore novel approaches directed at re-establishing sensitivity to chemotherapy, presenting an attractive strategy for cancer treatment. In this article we discuss how this may be achieved by lowering Bcl-2 anti-apoptotic protein expression using antisense oligonucleotides or, alternatively, by functionally antagonizing Bcl-2 using ligands of the mitochondrial benzodiazepine receptor.
表达过量Bcl-2的癌细胞在根治性治疗的实施中构成了一个重大问题。针对此类癌症的大多数治疗方法都涉及化疗以诱导凋亡过程。虽然这些疗法常常能在一段时间内控制疾病，但由于获得性耐药而未能启动凋亡限制了许多常见血液系统恶性肿瘤和实体恶性肿瘤的治疗效果，最终恶性肿瘤导致的死亡仍会发生。定位于线粒体的Bcl-2家族的各种抗凋亡蛋白似乎参与了这种耐药机制。然而，通过基因组学和蛋白质组学在恶性细胞生物学理解方面取得的最新进展，使得探索针对重新建立化疗敏感性的新方法成为可能，为癌症治疗提供了一个有吸引力的策略。在本文中，我们讨论如何通过使用反义寡核苷酸降低Bcl-2抗凋亡蛋白表达，或者通过使用线粒体苯二氮䓬受体配体在功能上拮抗Bcl-2来实现这一点。
