文章：

DNA修复途径作为癌症治疗的靶点

DNA repair pathways as targets for cancer therapy

原文发布日期：2008-03-01

DOI: 10.1038/nrc2342

类型: Review Article

开放获取: 否

要点：

1. Several cancer chemotherapy drugs work by producing excessive DNA damage that causes cell death directly or following DNA replication. Survival is promoted through repair of these lesions by a number of DNA repair pathways.
2. The efficacy of anticancer drugs is highly influenced by cellular DNA repair capacity. Inhibitors of DNA repair increase the efficacy of DNA-damaging anticancer drugs in preclinical models. Small-molecule inhibitors of DNA repair have been combined with conventional chemotherapy drugs in several phase I–II clinical trials.
3. Tumour development can be associated with perturbed DNA damage response and repair pathways. This perturbation results in reduced DNA repair capacity and increased genetic instability in tumour cells. Defects in one DNA repair pathway can be compensated for by other pathways. Such compensating pathways can be identified in synthetic lethality screens and then specifically targeted for treatment of DNA repair-defective tumours.
4. Evidence indicates that inhibitors of DNA repair pathways can work as single agents for the targeted treatment of DNA repair-defective cancers. This hypothesis is currently being tested in phase II trials in which patients with breast or ovarian cancers that are defective in homologous recombination are being treated with a poly(ADP-ribose) polymerase inhibitor.
5. Tumours often exhibit replication stress as a consequence of oncogene-induced growth signals or hypoxia-induced replication arrest. We propose that DNA repair inhibitors could be used to prevent the repair of replication lesions present in tumour cells and convert them into fatal replication lesions that specifically kill cancer cells.

要点翻译：

1. 多种癌症化疗药物通过造成过量DNA损伤发挥作用，这些损伤会直接或随DNA复制后引发细胞死亡。细胞通过多种DNA修复通路修复这些损伤，从而提升存活率。
2. 抗癌药物的疗效深受细胞DNA修复能力的影响。在临床前模型中，DNA修复抑制剂能增强DNA损伤类抗癌药物的疗效。若干I-II期临床试验已将DNA修复小分子抑制剂与常规化疗药物联合使用。
3. 肿瘤的发生可能与DNA损伤应答及修复通路紊乱有关。这种紊乱导致肿瘤细胞DNA修复能力下降、遗传不稳定性增加。某一DNA修复通路的缺陷可由其他通路代偿。通过合成致死筛选可识别此类代偿通路，进而针对性治疗DNA修复缺陷型肿瘤。
4. 有证据表明，DNA修复通路抑制剂可作为单一制剂，用于DNA修复缺陷型癌症的靶向治疗。这一假说目前正在II期试验中进行验证：同源重组缺陷的乳腺癌或卵巢癌患者正在接受聚ADP核糖聚合酶抑制剂治疗。
5. 由于癌基因诱导的生长信号或缺氧引发的复制停滞，肿瘤常表现出复制应激。我们提出，DNA修复抑制剂可用于阻止肿瘤细胞中复制损伤的修复，将其转化为特异性杀伤癌细胞的致命复制损伤。

英文摘要：

DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. There is evidence that drugs that inhibit one of these pathways in such tumours could prove useful as single-agent therapies, with the potential advantage that this approach could be selective for tumour cells and have fewer side effects.

摘要翻译： 

DNA修复通路可使肿瘤细胞在化疗药物诱导的DNA损伤中存活；因此，特异性DNA修复通路抑制剂与DNA损伤型化疗药物联用可能具有疗效。此外，肿瘤发展过程中出现的DNA修复通路改变，会使某些癌细胞依赖有限的修复通路维持生存。有证据表明，在这些肿瘤中抑制其中一条通路的药物可作为单药治疗，其潜在优势在于对肿瘤细胞具有选择性，且副作用更少。

原文链接：

DNA repair pathways as targets for cancer therapy