DNA repair targeted therapy: The past or future of cancer treatment?
DNA repair targeted therapy: The past or future of cancer treatment?
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DOI：
10.1016/j.pharmthera.2016.02.003
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发表时间：
2016-04
影响因子：
13.5
通讯作者：
Turchi JJ
中科院分区：
文献类型：
--
作者：
Gavande NS;VanderVere-Carozza PS;Hinshaw HD;Jalal SI;Sears CR;Pawelczak KS;Turchi JJ
DNA损伤的修复是一个复杂的过程，它依赖于特定的途径来修复特定类型的DNA损伤。对DNA的损害范围包括小的，适度的结构变化，包括碱基不匹配和简单的甲基化事件，氧化碱基，DNA链内和链间交联，DNA双链断裂和蛋白质-DNA加合物。修复这些病变所需的途径包括错配修复、碱基切除修复、核苷酸切除修复和同源定向修复/范可尼贫血途径。这些途径中的每一个都有助于遗传稳定性，并且编码这些途径中涉及的蛋白质的基因突变已被证明会促进遗传不稳定性和癌症。事实上，有人认为所有的癌症都表现出DNA修复的缺陷。研究还表明，癌细胞修复治疗性DNA损伤的能力会影响治疗效果。这导致了靶向DNA修复途径和蛋白质来开发抗癌药物，这将增加对传统化疗药物的敏感性。虽然最初的研究受到缺乏特异性和明确的作用机制的困扰，但最近利用合成致命相互作用和开发高亲和力化学抑制剂的方法已被证明相当有效。在这篇综述中，我们将重点介绍最近的进展，并讨论以前的失败靶向DNA修复，为未来的DNA修复靶向药物及其在癌症治疗中的应用铺平道路。
The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.