Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
Clin Cancer Res. 2010 Sep 15;16(18):4517-26. doi: 10.1158/1078-0432.CCR-10-0526. Epub 2010 Sep 7.
Cancer chemotherapy exploits limitations in repairing DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Poly (ADP-ribose) polymerase (PARP) and BRCA proteins are central to the repair of DNA strand breaks and, when defective, lead to the accumulation of mutations introduced by error-prone DNA repair. Breast, ovarian, and other cancers develop in the setting of BRCA deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in BRCA-pathway-deficient tumors. Future studies must seek to identify sporadic cancers that harbor genomic instability, rendering susceptibility to agents that induce additional and lethal DNA damage.
癌症化疗利用了在修复 DNA 损伤方面的局限性，以杀死增殖的恶性细胞。最近的证据表明，不同组织类型的癌症在 DNA 修复途径上存在特定的缺陷，这些缺陷可能使它们对各种细胞毒性药物的敏感性和耐药性有所不同。聚（ADP-核糖）聚合酶（PARP）和 BRCA 蛋白是修复 DNA 链断裂的核心，当它们出现缺陷时，会导致由易错 DNA 修复引入的突变积累。乳腺癌、卵巢癌和其他癌症在 BRCA 缺陷的情况下发生，这些癌症可能对诱导 DNA 链断裂的细胞毒性药物以及 PARP 活性抑制剂更敏感。一系列最近的临床试验已经测试了 PARP 抑制剂是否可以在 BRCA 通路缺陷的肿瘤中实现合成致死性。未来的研究必须努力确定是否存在基因组不稳定的散发性癌症，这些癌症可能对诱导额外致死性 DNA 损伤的药物敏感。
