Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Curr Opin Oncol. 2013 Nov;25(6):609-14. doi: 10.1097/CCO.0000000000000016.
Poly (ADP-ribose) polymerase (PARP) and other DNA repair inhibitors are currently tested in numerous clinical trials, with variable success. Inhibitors are used in monotherapy, for example, PARP inhibitors in BRCA mutated cancers, or more widely in combination treatments. DNA repair inhibitors have, as chemotherapy, great potential for long-term disease control, or potentially even cures. However, the design of clinical trials using DNA repair inhibitors is intricate, as these inhibitors may also potentiate normal tissue toxicity without improving overall disease control.
Recent findings of mechanism of action of PARP inhibitors and other DNA repair inhibitors are presented, and how the underlying genetic background and interplay between DNA repair pathways influence the choice of tumour location and combination strategies. The hallmark of individualized cancer therapy is to be able to genetically distinguish the responding subclass of cancer patients, and it is widely used when targeting oncogenes. The PARP inhibitors in BRCA mutated cancers also demonstrate that this approach is possible in a synthetic lethal context.
There is strong proof-of-concept for DNA repair inhibitors being a useful anticancer strategy in well designed clinical trials.
聚（ADP-核糖）聚合酶（PARP）和其他 DNA 修复抑制剂目前正在大量临床试验中进行测试，取得了不同程度的成功。抑制剂可单独使用，例如 PARP 抑制剂用于 BRCA 突变型癌症，或更广泛地联合使用。与化疗一样，DNA 修复抑制剂具有长期控制疾病甚至潜在治愈疾病的巨大潜力。然而，使用 DNA 修复抑制剂进行临床试验的设计非常复杂，因为这些抑制剂在不改善整体疾病控制的情况下，也可能增强正常组织的毒性。
本文介绍了 PARP 抑制剂和其他 DNA 修复抑制剂的作用机制，以及潜在的遗传背景和 DNA 修复途径之间的相互作用如何影响肿瘤部位的选择和联合治疗策略。个体化癌症治疗的标志是能够在基因上区分出反应亚类的癌症患者，当靶向致癌基因时，这种方法被广泛应用。BRCA 突变型癌症中的 PARP 抑制剂也证明了在合成致死的情况下，这种方法是可行的。
在精心设计的临床试验中，DNA 修复抑制剂作为一种有用的抗癌策略，具有很强的概念验证。
