PARP inhibitors for cancer therapy
PARP inhibitors for cancer therapy
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DOI：
10.1017/s146239940500904x
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发表时间：
2005-03-30
影响因子：
6.2
通讯作者：
Curtin, Nicola J.
中科院分区：
文献类型：
--
作者：
Curtin, Nicola J.
聚（ADP-核糖）聚合酶 1 (PARP-1) 是一种锌指 DNA 结合酶，通过与 DNA 断裂结合而被激活。 PARP-1 对核蛋白的聚（ADP-核糖基）化将 DNA 损伤转化为细胞内信号，通过碱基切除途径激活 DNA 修复或细胞死亡。已鉴定出 18 个 PARP 家族，但只有最丰富的 PARP-1 和 PARP-2（均为核酶）会被 DNA 损伤激活。自发现 PARP-1 以来的 40 年来，已开发出效力不断增强的 PARP 抑制剂，既可作为研究 PARP-1 功能的工具，又可作为 DNA 修复介导的细胞毒性治疗耐药性的潜在调节剂。由于 PARP-1 和 PARP-2 催化结构域之间的高度同源性，抑制剂可能会影响这两种酶。令人信服的生化证据（已通过 PARP-1 活性的基因操作得到证实）表明，PARP 抑制与对 DNA 烷化剂、拓扑异构酶 I 毒物和电离辐射的敏感性增加有关。新型 PARP 抑制剂具有足够的效力和合适的药代动力学特性，可以在动物模型中进行评估，已被证明可以增强替莫唑胺（一种 DNA 甲基化剂）、拓扑异构酶毒物和电离辐射的抗肿瘤活性；事实上，在两项独立研究中，与替莫唑胺联合使用导致肿瘤完全消退。 PARP抑制剂和替莫唑胺的组合目前正在首次进行临床评估。
Poly(ADP-ribose) polymerase 1 (PARP-1) is a zinc-finger DNA-binding enzyme that is activated by binding to DNA breaks. Poly(ADP-ribosyl)ation of nuclear proteins by PARP-1 converts DNA damage into intracellular signals that activate either DNA repair by the base-excision pathway or cell death. A family of 18 PARPs has been identified, but only the most abundant, PARP-1 and PARP-2, which are both nuclear enzymes, are activated by DNA damage. PARP inhibitors of ever-increasing potency have been developed in the 40 years since the discovery of PARP-1, both as tools for the investigation of PARP-1 function and as potential modulators of DNA-repair-mediated resistance to cytotoxic therapy. Owing to the high level of homology between the catalytic domains of PARP-1 and PARP-2, the inhibitors probably affect both enzymes. Convincing biochemical evidence, which has been corroborated by genetic manipulation of PARP-1 activity, shows that PARP inhibition is associated with increased sensitivity to DNA-alkylating agents, topoisomerase I poisons and ionising radiation. Novel PARP inhibitors of sufficient potency and suitable pharmacokinetic properties to allow evaluation in animal models have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation; indeed, the combination with temozolomide resulted in complete tumour regression in two independent studies. The combination of a PARP inhibitor and temozolomide is currently undergoing clinical evaluation for the first time.