PARP inhibitors: its role in treatment of cancer.
PARP inhibitors: its role in treatment of cancer.
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DOI：
10.5732/cjc.011.10111
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发表时间：
2011-07
影响因子：
--
通讯作者：
Chen A
中科院分区：
文献类型：
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作者：
Chen A
PARP是DNA修复途径中的重要蛋白，尤其是碱基切除修复（BER）。BER参与单链断裂（SSB）的DNA修复。如果BER受损，抑制聚（ADP-核糖）聚合酶（PARP），SSB积累并成为双链断裂（DSB）。随着DSB数量的增加，细胞变得更加依赖于其他修复途径，主要是同源重组（HR）和非同源末端连接。有缺陷的HR患者，如BRCA缺陷细胞系，更容易受到BER通路受损的影响。PARP抑制剂优先杀死BRCA突变癌细胞系中的癌细胞，而不是正常细胞。此外，PARP抑制剂通过在诱导SSB的化疗存在下抑制修复来增加细胞毒性。这两个原则已经在临床上得到验证。在过去的几年里，由于在BRCA 1或BRCA 2相关的卵巢癌或乳腺癌中作为单一药物的活性以及与三阴性乳腺癌中的化疗联合使用，对这类药物的兴奋已经升级。这篇综述涵盖了测试这两个原则的临床试验的当前结果。它还评估了PARP抑制剂开发领域的未来方向。
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.