School of Pharmacy/Institute for Science & Technology in Medicine, Keele University, Keele, Staffordshire, UK.
Curr Mol Pharmacol. 2008 Nov;1(3):244-54. doi: 10.2174/1874467210801030244.
Conventional chemotherapy for cancer utilizes cytotoxic agents which elicit their therapeutic effect in part through the induction of apoptosis. In contrast, drugs which have been developed more recently and which are referred to as "targeted therapy" may exhibit less unwanted toxicity but in some cases these drugs are cytostatic. The recent development of drugs which target the apoptotic machinery offers a means to combine these two approaches. The intrinsic apoptotic pathway is controlled by the balance between anti-apoptotic proteins belonging to the Bcl-2 family and pro-apoptotic proteins bearing a single BH3 domain. Anti-apoptotic Bcl-2 family members are able to sequester the pro-apoptotic proteins by binding their BH3 domain. Compounds which inhibit this interaction are expected to promote apoptosis by preventing sequestration of the pro-apoptotic protein. Recently, a number of drugs have been developed which accomplish this, eg ABT-737, and some of these are progressing to clinical trials in oncology. These drugs may induce apoptosis on their own or synergize with existing chemotherapy. For example, ABT-737 is able to induce apoptosis when used as a single agent to treat leukemic and lung cancer cells and has also been shown to synergize with conventional chemotherapeutic agents in several cancer types. The spectrum of Bcl-2 family members expressed in a tumor cell, and the specificity of the inhibitor for these different anti-apoptotic proteins, helps determine whether Bcl-2 antagonists induce apoptosis when used as single agents. The ability of cytotoxic drugs to alter the expression of pro- and anti-apoptotic proteins is likely to help determine whether Bcl-2 antagonists synergize with cytotoxic therapy. Finally, as we begin to understand the pathways that regulate the expression of pro- and anti-apoptotic pathways, several new therapeutic strategies can be envisioned.
癌症的传统化疗利用细胞毒性药物，这些药物通过诱导细胞凋亡在一定程度上发挥其治疗作用。相比之下，最近开发的被称为“靶向治疗”的药物可能毒性较小，但在某些情况下，这些药物是细胞抑制剂。最近开发的靶向细胞凋亡机制的药物提供了一种结合这两种方法的手段。内源性凋亡途径受属于 Bcl-2 家族的抗凋亡蛋白和具有单个 BH3 结构域的促凋亡蛋白之间的平衡控制。抗凋亡 Bcl-2 家族成员能够通过结合其 BH3 结构域来隔离促凋亡蛋白。预计抑制这种相互作用的化合物通过防止促凋亡蛋白的隔离来促进细胞凋亡。最近，已经开发了许多能够实现这一目标的化合物，例如 ABT-737，其中一些正在进行肿瘤学临床试验。这些药物可以单独诱导细胞凋亡或与现有的化疗药物协同作用。例如，ABT-737 作为单一药物治疗白血病和肺癌细胞时能够诱导细胞凋亡，并且在几种癌症类型中也显示出与常规化疗药物的协同作用。肿瘤细胞中表达的 Bcl-2 家族成员的谱，以及抑制剂对这些不同抗凋亡蛋白的特异性，有助于确定 Bcl-2 拮抗剂作为单一药物使用时是否诱导细胞凋亡。细胞毒性药物改变促凋亡和抗凋亡蛋白表达的能力可能有助于确定 Bcl-2 拮抗剂是否与细胞毒性治疗协同作用。最后，随着我们开始理解调节促凋亡和抗凋亡途径表达的途径，我们可以设想几种新的治疗策略。
