Drew Yvette, Calvert Hilary
Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Ann N Y Acad Sci. 2008 Sep;1138:136-45. doi: 10.1196/annals.1414.020.
The abundant nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), represents an important novel target in cancer therapy. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionizing radiation and DNA damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. There are currently at least five PARP inhibitors in clinical trial development. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA) 1 and 2 genes. This theory of selectively exploiting cells defective in one DNA repair pathway by inhibiting another is a major breakthrough in the treatment of cancer. BRCA1/2 mutations are responsible for the majority of genetic breast/ovarian cancers, known as the hereditary breast ovarian cancer syndrome. This review summarizes the preclinical and clinical evidence for the potential of PARP inhibitors in genetic breast and ovarian cancers.
丰富的核酶聚（ADP - 核糖）聚合酶 -1（PARP -1）是癌症治疗中一个重要的新靶点。PARP -1对于通过碱基切除修复途径修复DNA单链断裂至关重要。PARP -1抑制剂已被证明可增强电离辐射和DNA损伤化疗药物（如甲基化剂和拓扑异构酶I抑制剂）的细胞毒性作用。目前至少有五种PARP抑制剂正处于临床试验开发阶段。最近的体外和体内证据表明，PARP抑制剂不仅可以用作化疗/放疗增敏剂，还可以作为单一药物选择性杀死DNA修复缺陷的癌症，特别是乳腺癌相关（BRCA）1和2基因发生突变的癌症。通过抑制另一种DNA修复途径来选择性利用一种DNA修复途径缺陷的细胞这一理论是癌症治疗中的一项重大突破。BRCA1/2突变是大多数遗传性乳腺癌/卵巢癌（即遗传性乳腺癌卵巢癌综合征）的病因。本综述总结了PARP抑制剂在遗传性乳腺癌和卵巢癌中潜在应用的临床前和临床证据。
