Ivy S Percy, de Bono Johann, Kohn Elise C
Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Drive, Room 5W458, MSC 9739, Bethesda, MD 20852, USA.
ICR, Royal Marsden NHS Foundation Trust, Sycamore House, Downs Road, Sutton, SM2 5PT, UK.
Trends Cancer. 2016 Nov;2(11):646-656. doi: 10.1016/j.trecan.2016.10.014. Epub 2016 Nov 23.
Maintenance of genomic integrity is critical for adaptive survival in the face of endogenous and exogenous environmental stress. The loss of stability and fidelity in the genome caused by cancer and cancer treatment provides therapeutic opportunities to leverage the critical balance between DNA injury and repair. Blocking repair and pushing damaged DNA through the cell cycle using therapeutic inhibitors exemplify the 'pushmi-pullyu' effect of disrupted DNA repair. DNA repair inhibitors (DNARi) can be separated into five biofunctional categories: sensors, mediators, transducers, effectors, and collaborators that recognize DNA damage, propagate injury DNA messages, regulate cell cycle checkpoints, and alter the microenvironment. The result is cancer therapeutics that takes advantage of clinical synthetic lethality, resulting in selective tumor cell kill. Here, we review recent considerations related to DNA repair and new DNARi agents and organize those findings to address future directions and clinical opportunities.
面对内源性和外源性环境压力时，维持基因组完整性对于适应性生存至关重要。癌症和癌症治疗导致的基因组稳定性和保真度丧失为利用DNA损伤与修复之间的关键平衡提供了治疗机会。使用治疗性抑制剂阻断修复并推动受损DNA通过细胞周期体现了DNA修复中断的“双头效应”。DNA修复抑制剂（DNARi）可分为五个生物功能类别：识别DNA损伤的传感器、介质、转导器、效应器和协同因子，它们传播损伤DNA信息、调节细胞周期检查点并改变微环境。其结果是利用临床合成致死性的癌症治疗方法，从而实现选择性肿瘤细胞杀伤。在此，我们综述了与DNA修复和新型DNARi药物相关的最新思考，并整理这些发现以探讨未来方向和临床机遇。
