Herter-Sprie G S, Chen S, Höpker K, Reinhardt H C
Medizinische Klinik I, Universitätsklinik Köln.
Dtsch Med Wochenschr. 2011 Jul;136(30):1526-30. doi: 10.1055/s-0031-1281549. Epub 2011 Jul 25.
Following DNA damage, cells activate a complex DNA-damage-response (DDR) signaling network to arrest the cell cycle, repair DNA and, if the extend of damage is beyond repair capacity, induce apoptosis. DDR genes are among the most commonly mutated genes in human cancer and it is believed that these lesions promote a "MUTATOR-PHENOTYPE" that fuels the runaway proliferation of cancer cells. However, these genetic lesions can also be seen as the "Achilles heel" of cancer. These tumor cell-specific vulnerabilities are of extraordinary clinical interest, since they allow genetically-guided novel therapeutic regimens for the treatment of cancer. Here, we discuss such a novel therapeutic concept - synthetic lethality. We focus on the first successful clinical applications of synthetic lethality for the treatment of different cancer entities. In addition, we give a brief review of recently developed, synthetic lethality-based approaches that are close to clinical testing.
DNA损伤后，细胞会激活一个复杂的DNA损伤反应（DDR）信号网络，以阻止细胞周期、修复DNA，并且，如果损伤程度超出修复能力，则诱导细胞凋亡。DDR基因是人类癌症中最常发生突变的基因之一，据信这些损伤会促进一种“突变表型”，从而推动癌细胞的失控增殖。然而，这些基因损伤也可被视为癌症的“阿喀琉斯之踵”。这些肿瘤细胞特异性的脆弱性具有非凡的临床意义，因为它们使得针对癌症治疗的基因导向新型治疗方案成为可能。在此，我们讨论这样一种新型治疗概念——合成致死性。我们聚焦于合成致死性在不同癌症实体治疗中的首个成功临床应用。此外，我们简要综述了最近开发的、接近临床试验的基于合成致死性的方法。
