PARP抑制剂用于肿瘤治疗的研究进展

Development of poly(ADP-ribose) polymerase inhibitors for cancertherapy

聚腺苷酸二磷酸核糖转移酶(poly(ADP-ribose)polymerase,PARP)是当今癌症治疗的一个新靶点,其能够催化ADP-核糖单元从烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD+)转移至各种受体蛋白。PARP参与DNA修复和转录调控,不但在调节细胞存活和死亡过程中具有关键作用,同时也是肿瘤发展和炎症发生过程中的主要转录因子。PARP在碱基切除修复的DNA单链缺口(SSBs)修复中具有关键作用,抑制其活性能够增强放疗和DNA损伤类化疗药物的效果。目前已有至少8个PARP抑制剂进入临床,最新的体内外实验表明PARP抑制剂不但能够作为放化疗增敏剂,单独使用也能选择性杀伤DNA修复缺陷的肿瘤细胞,如BRCA1和BRCA2缺陷的乳腺癌细胞。大量的临床试验证明:该类药物毒副作用小、效果明确且短期耐受性良好,对于癌症治疗前景广阔。本文主要对PARP抑制剂的原理及其研究进展进行综述。

PARP [poly（ADP-ribose） polymerase] represents an important novel target in cancer therapy.It is a family of cell signaling enzymes that catalyze the transfer of ADP-ribose units from NAD＋ to a number of acceptor proteins.PARP is involved in DNA repair and transcriptional regulation and is now recognized as a key regulator of cell survival and death as well as a master component of transcription factors involved in tumor development and inflammation.PARP is essential to the repair of DNA single-strand breaks via the base excision repair pathway.Inhibitors of PARP have been shown to enhance the cytotoxic effects of ionizing radiation and DNA-damaging chemotherapy agents.There are currently at least 8 PARP inhibitors in clinical trial.Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers,but also as single agents to selectively kill cancer cells defective in DNA repair,such as cancer cells with mutations in the breast cancer-associated genes（BRCA1 and BRCA2）.This kind of agents has great potential of treating cancer for their lesser side effects,potent antitumor activity and excellent short-term tolerance.This paper summarized the mechanism of PARP inhibition and the development of PARP inhibitors.