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Histone yH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers

  1. Author:
    Redon, C. E.
    Nakamura, A. J.
    Zhang, Y. W.
    Ji, J. P.
    Bonner, W. M.
    Kinders, R. J.
    Parchment, R. E.
    Doroshow, J. H.
    Pommier, Y.

  2. Author Address

    [Redon, Christophe E.; Nakamura, Asako J.; Zhang, Yong-Wei; Bonner, William M.; Doroshow, James H.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Ji, Jiuping (Jay)] NCI, Natl Clin Target Validat Lab, SAIC Frederick Inc, Frederick, MD USA. [Kinders, Robert J.; Parchment, Ralph E.] NCI, Lab Human Toxicol & Pharmacol, SAIC Frederick Inc, Frederick, MD 21701 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA.;Pommier, Y, NCI, NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA.;pommier@nih.gov
    1. Year: 2010
    2. Date: Sep
  2. Journal: Clinical Cancer Research
    1. 16
    2. 18
    3. Pages: 4532-4542
  4. Type of Article: Article
  5. ISSN: 1078-0432
  1. Abstract:

    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 (gamma H2AX) in the chromatin flanking the break site, an antibody directed against gamma H2AX 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 gamma H2AX 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 gamma H2AX and PAR analyses. Clin Cancer Res; 16(18); 4532-42. (c) 2010 AACR.

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External Sources

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  2. DOI: 10.1158/1078-0432.ccr-10-0523
  3. View record in Web of Science®
  4. WOS: 000281910400008

Library Notes

  1. Fiscal Year: FY2009-2010
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