Curtin Nicola J, Wang Lan-Zhen, Yiakouvaki Anthie, Kyle Suzanne, Arris Christine A, Canan-Koch Stacie, Webber Stephen E, Durkacz Barbara W, Calvert Hilary A, Hostomsky Zdenek, Newell David R
Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom.
Clin Cancer Res. 2004 Feb 1;10(3):881-9. doi: 10.1158/1078-0432.ccr-1144-3.
Mismatch repair (MMR) deficiency confers resistance to temozolomide, a clinically active DNA-methylating agent. The purpose of the current study was to investigate the reversal mechanism of temozolomide resistance by the potent novel poly(ADP-ribose) polymerase (PARP)-1 inhibitor, AG14361, in MMR-proficient and -deficient cells.
The effects of AG14361, in comparison with the methylguanine DNA methyltransferase inhibitor, benzylguanine, on temozolomide-induced growth inhibition were investigated in matched pairs of MMR-proficient (HCT-Ch3, A2780, and CP70-ch3) and -deficient (HCT116, CP70, and CP70-ch2) cells.
AG14361 enhanced temozolomide activity in all MMR-proficient cells (1.5-3.3-fold) but was more effective in MMR-deficient cells (3.7-5.2-fold potentiation), overcoming temozolomide resistance. In contrast, benzylguanine only increased the efficacy of temozolomide in MMR-proficient cells but was ineffective in MMR-deficient cells. The differential effect of AG14361 in MMR-deficient cells was not attributable to differences in PARP-1 activity or differences in its inhibition by AG14361, nor was it attributable to differences in DNA strand breaks induced by temozolomide plus AG14361. MMR-deficient cells are resistant to cisplatin, but AG14361 did not sensitize any cells to cisplatin. PARP-1 inhibitors potentiate topotecan-induced growth inhibition, but AG14361 did not potentiate topotecan in MMR-deficient cells more than in MMR-proficient cells.
MMR defects are relatively common in sporadic tumors and cancer syndromes. PARP-1 inhibition represents a novel way of selectively targeting such tumors. The underlying mechanism is probably a shift of the cytotoxic locus of temozolomide to N(7)-methylguanine and N(3)-methyladenine, which are repaired by the base excision repair pathway in which PARP-1 actively participates.
错配修复（MMR）缺陷赋予对替莫唑胺（一种临床活性DNA甲基化剂）的抗性。本研究的目的是研究新型强效聚（ADP - 核糖）聚合酶（PARP）-1抑制剂AG14361在MMR功能正常和缺陷细胞中逆转替莫唑胺抗性的机制。
在MMR功能正常（HCT - Ch3、A2780和CP70 - ch3）和缺陷（HCT116、CP70和CP70 - ch2）的配对细胞中，研究AG14361与甲基鸟嘌呤DNA甲基转移酶抑制剂苄基鸟嘌呤相比，对替莫唑胺诱导的生长抑制的影响。
AG14361增强了所有MMR功能正常细胞中替莫唑胺的活性（1.5至3.3倍），但在MMR缺陷细胞中更有效（增强3.7至5.2倍），克服了替莫唑胺抗性。相比之下，苄基鸟嘌呤仅增加了MMR功能正常细胞中替莫唑胺的疗效，但在MMR缺陷细胞中无效。AG14361在MMR缺陷细胞中的差异效应并非归因于PARP - 1活性的差异或其被AG14361抑制的差异，也不是归因于替莫唑胺加AG14361诱导的DNA链断裂的差异。MMR缺陷细胞对顺铂耐药，但AG14361未使任何细胞对顺铂敏感。PARP - 1抑制剂增强拓扑替康诱导的生长抑制，但AG14361在MMR缺陷细胞中增强拓扑替康的作用并不比在MMR功能正常细胞中更明显。
MMR缺陷在散发性肿瘤和癌症综合征中相对常见。PARP - 1抑制代表了一种选择性靶向此类肿瘤的新方法。潜在机制可能是替莫唑胺的细胞毒性位点转移至N（7）-甲基鸟嘌呤和N（3）-甲基腺嘌呤，它们由PARP - 1积极参与的碱基切除修复途径修复。
