For decades genotoxic therapy has been a mainstay in the treatment of cancer, based on the understanding that the deregulated growth and genomic instability that drive malignancy also confer a shared vulnerability. Although chemotherapy and radiation can be curative, only a fraction of patients benefit, while nearly all are subjected to the harmful side-effects. Drug repurposing, defined here as retooling existing drugs and compounds as chemo or radiosensitizers, offers an attractive route to identifying otherwise non-toxic agents that can potentiate the benefits of genotoxic cancer therapy to enhance the therapeutic ratio. This review seeks to highlight recent progress in defining cellular mechanisms of the DNA damage response including damage sensing, chromatin modification, DNA repair, checkpoint signaling, and downstream survival and death pathways, as a framework to determine which drugs and natural products may offer the most potential for repurposing as chemo- and/or radiosensitizers. We point to classical examples and recent progress that have identified drugs that disrupt cellular responses to DNA damage and may offer the greatest clinical potential. The most important next steps may be to initiate prospective clinical trials toward translating these laboratory discoveries to benefit patients.

几十年来，基因毒性疗法一直是癌症治疗的中流砥柱，基于这样的认识，即导致恶性肿瘤的生长失调和基因组不稳定性也带来了共同的脆弱性。尽管化学疗法和放射疗法可以治愈，但只有一小部分患者受益，而几乎所有患者都受到有害副作用的影响。药物再利用，在此定义为将现有药物和化合物改造成化学或放射增敏剂，为识别其他无毒药物提供了一条有吸引力的途径，这些药物可以增强基因毒性癌症治疗的益处以提高治疗率。这篇综述旨在强调最近在定义 DNA 损伤反应的细胞机制方面取得的进展，包括损伤感知、染色质修饰、DNA 修复、检查点信号、以及下游的生存和死亡途径，作为确定哪些药物和天然产物最有可能重新用作化学和/或放射增敏剂的框架。我们指出了经典的例子和最近的进展，这些例子已经确定了破坏细胞对 DNA 损伤反应的药物，并可能提供最大的临床潜力。最重要的下一步可能是启动前瞻性临床试验，以将这些实验室发现转化为造福患者。