Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Front Biosci (Landmark Ed). 2013 Jun 1;18(4):1392-406. doi: 10.2741/4188.
Poly(ADP-ribose) polymerase (PARP) inhibitors are pharmacologic agents which primarily inhibit the PARP-1 and PARP-2 enzymes within the cell. Inhibition of PARP results in failure of base-excision repair (BER) to correct single-stranded breaks in DNA. This failure results in double-stranded breaks that are subsequently repaired either by homologous recombination (HR) repair, which is error-free, or by non-homologous end joining (NHEJ), which is an error-prone process. Clinically, PARP inhibitors demonstrate activity in tumors which lack a functional HR system (i.e. BRCA1 and BRCA2 mutations) by forcing NHEJ repair. Known as synthetic lethality, the use of NHEJ in these tumors generates genomic instability and eventual cell death due to rapid development of non-viable genetic errors. In addition due their BER effects, PARP inhibitors are being developed as chemotherapy and radiation sensitizers in a number of tumor types. This review will examine the role of the PARP enzymes in DNA repair, PARP inhibitors in HR-deficient tumors, current results of clinical studies of PARP inhibitors and research efforts to expand the clinical activity of PARP inhibitors beyond HR-deficient tumors.
聚（ADP-核糖）聚合酶（PARP）抑制剂是一类主要抑制细胞内 PARP-1 和 PARP-2 酶的药物。PARP 的抑制导致碱基切除修复（BER）无法纠正 DNA 中的单链断裂。这种失败导致双链断裂，随后通过同源重组（HR）修复或非同源末端连接（NHEJ）进行修复，后者是一种易错过程。临床上，PARP 抑制剂在缺乏功能性 HR 系统（即 BRCA1 和 BRCA2 突变）的肿瘤中表现出活性，通过强制 NHEJ 修复。由于 NHEJ 的使用，这些肿瘤表现出合成致死性，由于快速产生不可存活的遗传错误，导致基因组不稳定和最终细胞死亡。此外，由于其 BER 效应，PARP 抑制剂正在多种肿瘤类型中被开发为化疗和放疗增敏剂。这篇综述将探讨 PARP 酶在 DNA 修复中的作用、PARP 抑制剂在 HR 缺陷型肿瘤中的作用、PARP 抑制剂的临床研究结果以及扩大 PARP 抑制剂在 HR 缺陷型肿瘤以外的临床活性的研究努力。
