Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.

中文翻译：

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DNA-PKcs的选择性抑制扩展了局部放疗和化疗的治疗指数

通过抑制DNA损伤修复来增强放疗和化疗被认为是改善实体瘤患者预后的治疗策略。但是，这种方法冒着增加正常组织毒性和肿瘤毒性的风险，从而限制了其翻译影响。使用NU5455（一种新近鉴定的DNA依赖性蛋白激酶催化亚基（DNA-PKcs）活性的高选择性口服抑制剂），我们发现确实有可能在不影响急性DNA损伤的情况下优先增强针对人原位肺肿瘤的靶向放疗效果或后期辐射诱发的对正常小鼠肺部的毒性（纤维化）。此外，虽然NU5455给药既可以提高肠胃外给药拓扑异构酶抑制剂的疗效和毒性，它增强了在肝肿瘤异种移植物中局部释放的阿霉素的活性，而没有引起任何不良影响。该策略与肝细胞癌特别相关，该肝癌在临床上使用局部药物洗脱珠进行治疗，并且据报道其DNA-PKcs活性赋予治疗抗性。我们得出的结论是，与局部DNA损伤疗法结合使用时，DNA-PKcs活性的瞬时药理抑制作用是有效且可耐受的，因此具有广阔的临床潜力。