Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers.
Tumor 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 (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), abbreviated as 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 also discuss the choices of relevant samples for γH2AX and PAR analyses.
Redon
Christophe E
CE
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Nakamura
Asako J
AJ
Zhang
Yong-Wei
YW
Ji
Jiuping Jay
JJ
Bonner
William M
WM
Kinders
Robert J
RJ
Parchment
Ralph E
RE
Doroshow
James H
JH
Pommier
Yves
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008495:Medical Oncology / Q000379:methods; D008954:Models, Biological; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000502:physiology; D011379:Prognosis
D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; C468783:H2AX protein, human; D006657:Histones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases
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