Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers.
Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers.
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DOI：
10.1158/1078-0432.ccr-10-0523
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发表时间：
2010-09-15
期刊：
影响因子：
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通讯作者：
Pommier Y
中科院分区：
文献类型：
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作者：
Redon CE;Nakamura AJ;Zhang YW;Ji JJ;Bonner WM;Kinders RJ;Parchment RE;Doroshow JH;Pommier Y
肿瘤细胞通常缺乏DNA修复和损伤反应（DDR）途径，并且抗癌疗法通常基于使用辐射和/或药物的遗传毒性治疗，所述辐射和/或药物直接损伤DNA或干扰DNA代谢，导致DNA双链断裂（DSB）的形成，并最终导致细胞死亡。由于DSB诱导断裂位点侧翼的染色质中组蛋白H2 AX（γ H2 AX）的磷酸化，因此可以使用针对γ H2 AX的抗体来测量患者治疗之前和之后的DNA损伤水平。聚（ADP-核糖）聚合酶（PARP 1和PARP 2）也被DNA损伤激活，PARP抑制剂在具有DSB修复缺陷同源重组（HR）途径的癌症中显示出有希望的活性。正在进行的临床试验正在测试PARP抑制剂与DNA损伤剂的组合。聚（ADP-核糖基化）（PAR）可以在临床样品中测量并用于确定PARP抑制剂的效率。本文综述了γ H2 AX和PAR在DDR中的作用及其作为生物标志物用于监测药物反应和指导临床试验，特别是0期临床试验。本文还讨论了γ H_2AX和PAR分析中有关样品的选择。
Tumor cells are often deficient in DNA repair and damage response (DDR) pathways, and anticancer therapies are commonly based on genotoxic treatments using radiation and/or drugs that damage DNA directly or interfere with DNA metabolism leading to the formation of DNA double-strand breaks (DSBs), and ultimately to cell death. Since DSBs induce the phosphorylation of histone H2AX (γH2AX) in the chromatin flanking the break site, an antibody directed against γH2AX can be employed to measure DNA damage levels before and after patient treatment. Poly(ADP-ribose) polymerases (PARP1 and PARP2) are also activated by DNA damage and PARP inhibitors show promising activity in cancers with defective homologous recombination (HR) pathways for DSB repair. Ongoing clinical trials are testing combinations of PARP inhibitors with DNA damaging agents. Poly(ADP-ribosylation) (PAR) can be measured in clinical samples and used to determine the efficiency of PARP inhibitors. This review summarizes the roles of γH2AX and PAR in the DDR and their use as biomarkers to monitor drug response and guide clinical trials, especially Phase 0 clinical trials. We will also discuss the choices of relevant samples for γH2AX and PAR analyses.