PARP inhibitors: its role in treatment of cancer  

作　　者：Alice Chen 

机构地区：[1]Division of Cancer Treatment and Diagnosis National Institutes of Health, National Cancer Institute

出　　处：《Chinese Journal of Cancer》2011年第7期463-471,共9页

摘　　要：PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.PARP is an important protein in DNA repair pathways especially the base excision repair （BER）. BER is involved in DNA repair of single strand breaks （SSBs）. If BER is impaired, inhibiting poly（ADP- ribose） polymerase （PARP）, SSBs accumulate and become double stand breaks （DSBs）. The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination （HR） and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.

关 键 词：PARP抑制剂 癌症治疗 DNA单链断裂 DNA修复 非同源末端连接 基因缺陷 碱基切除修复 临床试验 

分 类 号：R96[医药卫生—药理学]