Abbotts Rachel, Thompson Nicola, Madhusudan Srinivasan
University of Nottingham, Academic Unit of Oncology, Division of Oncology, School of Medicine, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK.
Cancer Manag Res. 2014 Feb 19;6:77-92. doi: 10.2147/CMAR.S50497. eCollection 2014.
Genomic deoxyribonucleic acid (DNA) is under constant threat from endogenous and exogenous DNA damaging agents. Mammalian cells have evolved highly conserved DNA repair machinery to process DNA damage and maintain genomic integrity. Impaired DNA repair is a major driver for carcinogenesis and could promote aggressive cancer biology. Interestingly, in established tumors, DNA repair activity is required to counteract oxidative DNA damage that is prevalent in the tumor microenvironment. Emerging clinical data provide compelling evidence that overexpression of DNA repair factors may have prognostic and predictive significance in patients. More recently, DNA repair inhibition has emerged as a promising target for anticancer therapy. Synthetic lethality exploits intergene relationships where the loss of function of either of two related genes is nonlethal, but loss of both causes cell death. Exploiting this approach by targeting DNA repair has emerged as a promising strategy for personalized cancer therapy. In the current review, we focus on recent advances with a particular focus on synthetic lethality targeting in cancer.
基因组脱氧核糖核酸（DNA）不断受到内源性和外源性DNA损伤剂的威胁。哺乳动物细胞已经进化出高度保守的DNA修复机制来处理DNA损伤并维持基因组完整性。DNA修复受损是致癌作用的主要驱动因素，并且可能促进侵袭性癌症生物学行为。有趣的是，在已形成的肿瘤中，需要DNA修复活性来对抗肿瘤微环境中普遍存在的氧化性DNA损伤。新出现的临床数据提供了令人信服的证据，表明DNA修复因子的过表达可能对患者具有预后和预测意义。最近，DNA修复抑制已成为一种有前景的抗癌治疗靶点。合成致死性利用基因间关系，即两个相关基因中任何一个功能丧失都是非致死性的，但两者都丧失会导致细胞死亡。通过靶向DNA修复来利用这种方法已成为个性化癌症治疗的一种有前景的策略。在当前的综述中，我们重点关注近期进展，尤其侧重于癌症中的合成致死性靶向。
