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lüll Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers Redon CE; Nakamura AJ; Zhang YW; Ji JJ; Bonner WM; Kinders RJ; Parchment RE; Doroshow JH; Pommier YClin Cancer Res 2010[Sep]; 16 (18): 4532-42Tumor cells are often deficient in DNA 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 (DSB), and ultimately to cell death. Because DSBs induce the phosphorylation of histone H2AX (gammaH2AX) in the chromatin flanking the break site, an antibody directed against gammaH2AX 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), abbreviated as PAR, can be measured in clinical samples and used to determine the efficiency of PARP inhibitors. This review summarizes the roles of gammaH2AX and PAR in the DDR, and their use as biomarkers to monitor drug response and guide clinical trials, especially phase 0 clinical trials. We also discuss the choices of relevant samples for gammaH2AX and PAR analyses.|*Biomarkers, Pharmacological/analysis/metabolism[MESH]|Animals[MESH]|Antineoplastic Agents/pharmacology/therapeutic use[MESH]|Biomarkers, Tumor/analysis/metabolism/*physiology[MESH]|DNA Damage/drug effects/genetics[MESH]|Histones/genetics/metabolism/*physiology[MESH]|Humans[MESH]|Medical Oncology/methods[MESH]|Models, Biological[MESH]|Neoplasms/*diagnosis/drug therapy/genetics/metabolism[MESH]|Poly Adenosine Diphosphate Ribose/analysis/metabolism/*physiology[MESH]|Poly(ADP-ribose) Polymerase Inhibitors[MESH]|Poly(ADP-ribose) Polymerases/metabolism/physiology[MESH]|Prognosis[MESH] |