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Updated: Jun 9, 2026
Evaluation of the Spatial Distribution of γH2AX following Ionizing Radiation
Published on: August 7, 2010
Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers
Christophe E Redon1, Asako J Nakamura, Yong-Wei Zhang
1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
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 (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.
Insights
DNA damage response (DDR) biomarkers, including phosphorylated histone H2AX (γH2AX) and poly(ADP-ribosylation) (PAR), are crucial for monitoring anticancer therapy effectiveness. These markers aid in guiding clinical trials and personalizing cancer treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumor cells often exhibit deficiencies in DNA damage response (DDR) pathways.
- Genotoxic anticancer therapies, including radiation and DNA-damaging drugs, induce DNA double-strand breaks (DSBs).
- Effective DDR is critical for cancer cell survival following genotoxic stress.
Purpose of the Study:
- To review the roles of γH2AX and poly(ADP-ribosylation) (PAR) in the DDR.
- To highlight their utility as biomarkers for monitoring drug response in clinical trials.
- To discuss sample selection for γH2AX and PAR analyses in clinical settings.
Main Methods:
- γH2AX detection via antibody-based assays to quantify DNA DSBs.
- Measurement of PAR levels to assess poly(ADP-ribose) polymerase (PARP) inhibitor efficacy.
- Review of existing literature on DDR biomarkers and their clinical applications.
Main Results:
- γH2AX serves as a sensitive indicator of DNA damage induced by genotoxic agents.
- PARP inhibitors show efficacy in cancers with homologous recombination (HR) defects.
- PAR levels can effectively monitor the pharmacodynamic effects of PARP inhibitors.
Conclusions:
- γH2AX and PAR are valuable biomarkers for assessing DDR and guiding cancer therapy.
- These biomarkers are instrumental in evaluating drug response and optimizing clinical trial designs, particularly in early-phase trials.
- Appropriate sample selection is essential for accurate biomarker analysis and clinical decision-making.
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