Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Drug Resist Updat. 2009 Dec;12(6):153-6. doi: 10.1016/j.drup.2009.10.001. Epub 2009 Nov 25.
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 single strand DNA breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionising radiation and DNA damaging chemotherapy agents such as the methylating agents and topoisomerase-I inhibitors. There are currently at least eight PARP inhibitors in clinical trial development. In vitro data, in vivo preclinical data and most recently early clinical trial data suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers but also as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA)1 and BRCA2 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. The current clinical data are discussed within this review with reference to the preclinical models which predicted activity and also future directions and the possible dangers/pitfalls of this clinical strategy are explored.
丰富的核酶聚（ADP-核糖）聚合酶-1（PARP-1）代表癌症治疗中的一个重要的新靶点。PARP-1 对于通过碱基切除修复途径修复单链 DNA 断裂至关重要。已经表明，PARP-1 的抑制剂可以增强电离辐射和 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。目前至少有八种 PARP 抑制剂正在临床试验开发中。体外数据、体内临床前数据和最近的早期临床试验数据表明，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，特别是具有乳腺癌相关（BRCA）1 和 BRCA2 基因突变的癌症。通过抑制另一种途径来选择性利用细胞中一种 DNA 修复途径的缺陷的这种理论是癌症治疗中的一个重大突破。目前的临床数据在本文中进行了讨论，并参考了预测活性的临床前模型，还探讨了这种临床策略的未来方向和可能的危险/陷阱。
