Use of γH2AX and other biomarkers of double-strand breaks during radiotherapy.

The rapid phosphorylation of histone H2AX at serine 139 (γH2AX) serves as a sensitive marker for DNA double-strand breaks induced by ionizing radiation or other genotoxic agents. The potential clinical applications of γH2AX detection in tissues from cancer patients during fractionated radiotherapy and the sensitivity for detection of in vivo drug effects on radiation-induced DNA damage responses (DDRs) are discussed. The quantification of γH2AX foci in the nuclei of peripheral blood lymphocytes allows estimation of the applied integral body dose by conformal radiotherapy to tumors in different sites of the body. The limits of precision of biodosimetry in peripheral blood lymphocytes with a γH2AX assay shortly after radiation exposure are shown. The high sensitivity of the in vitro radiation dose-γH2AX foci response allows monitoring of drug effects on DDR pathways after in vivo drug exposure and in vitro irradiation. Drugs are under clinical investigation that modify radiation-induced damage response. If interindividual or intertumoral differences in drug sensitivity exist, the measurement of radiation-induced foci formation and resolution after in vivo drug exposure and in vitro or in vivo irradiation of a cellular probe can serve as a functional assay that may predict the individual gain of a combination therapy. Validation by prospective studies is needed.