Fischer Ute, Janssen Katja, Schulze-Osthoff Klaus
Institute of Molecular Medicine, Heinrich-Heine University, Düsseldorf, Germany.
BioDrugs. 2007;21(5):273-97. doi: 10.2165/00063030-200721050-00001.
Defects in programmed cell death or apoptosis are major hallmarks of cancer contributing to tumorigenesis, tumor progression, and therapy resistance. In the past decade, many of the pathways leading to apoptosis, as well as the molecular mechanisms blocking the death of tumor cells, have been elucidated. This detailed knowledge of the core apoptosis machinery is now being exploited for translation into novel cancer therapies in order to restore apoptosis induction in tumor cells. Strategies include activation of proapoptotic mediators such as death receptors, tumor protein p53, and second mitochondria-derived activator of caspases (SMAC)/DIABLO as well as inhibition of endogenous apoptosis inhibitors such as IAPs (inhibitor of apoptosis proteins) and BCL-2 (B-cell chronic lymphoid leukemia/lymphoma) proteins. Several approaches employing gene therapy and antisense strategies, recombinant biologics, or classic organic and combinatorial chemistry, have advanced into clinical trials or are already approved. This review looks at recent developments in apoptosis-based cancer therapies and highlights some very promising advances in drug design.
程序性细胞死亡或凋亡缺陷是癌症的主要特征，与肿瘤发生、肿瘤进展和治疗抗性有关。在过去十年中，许多导致凋亡的途径以及阻断肿瘤细胞死亡的分子机制已被阐明。目前，关于核心凋亡机制的这些详细知识正被用于转化为新型癌症疗法，以恢复肿瘤细胞中的凋亡诱导。策略包括激活促凋亡介质，如死亡受体、肿瘤蛋白p53和第二线粒体衍生的半胱天冬酶激活剂（SMAC）/DIABLO，以及抑制内源性凋亡抑制剂，如凋亡抑制蛋白（IAP）和BCL-2（B细胞慢性淋巴细胞白血病/淋巴瘤）蛋白。几种采用基因治疗和反义策略、重组生物制品或经典有机和组合化学的方法已进入临床试验或已获批准。本综述着眼于基于凋亡的癌症治疗的最新进展，并强调了药物设计中一些非常有前景的进展。
