Prolonged expression of the γ‐H2AX DNA repair biomarker correlates with excess acute and chronic toxicity from radiotherapy treatment

Abstract

The normal tissue tolerance levels to fractionated radiotherapy have been appreciated by a century of careful clinical observations and radiobiological studies in animals. During clinical fractionated radiotherapy, these normal tissue tolerance levels are respected, and severe sequelae of radiotherapy are avoided in the majority of patients. Notwithstanding, a minority of patients experience unexpectedly severe normal tissue reactions. The ability to predict which patients might form this minority would be important. We have conducted a study to develop a rapid and reliable diagnostic test to predict excessive normal tissue toxicity (NTT) in radiotherapy patients. A flow cytometric immunocytochemical assay was used to measure DNA damage in peripheral blood lymphocytes (PBL) from cancer patients exposed to 2-Gy gamma radiation. DNA damage and repair was measured by induction of cellular γ-H2AX in unirradiated and exposed cells at specific time points following exposure. In 12 cancer patients that experienced severe atypical NTT following radiotherapy, there was a failure to repair DNA double-strand breaks (DSB) as measured by γ-H2AX induction and persistence. In ten cancer patients that experienced little or no NTT and in seven normal (noncancer controls), efficient repair of DNA DSB was observed in the γ-H2AX assay. We conclude that a flow cytometric assay based on γ-H2AX induction in PBL of radiotherapy patients may represent a robust, rapid and reliable biomarker to predict NTT during radiotherapy. Further research is required with a larger patient cohort to validate this important study.

The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells

“…Radiotherapy is one of the major therapeutic strategies for cancer treatment and results in DNA damage, including DSBs, which in turn initiates a variety of signaling events in cancer cells (19). DSBs lead to the phosphorylation of H2AX, and we and others have used this as a marker for the cellular response to radiation-induced DNA damage (20)(21)(22). Our results showed that the combined treatment of sorafenib and radiation delayed the clearance of γH2AX, suggesting that sorafenib prevents DNA repair and hence increases radiosensitivity.…”

MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis

“…Transfected cells were exposed to 2 Gy X-rays, an appropriate dose according to most radical radiotherapy protocols (11). The cells were collected and stained with anti-γ-H2AX (Cell Signaling Technology) antibody at different times as previously described (12).…”

Novel anti-cancer role of naphthazarin in human gastric cancer cells

“…As a result, Naph caused the activation of cleaved caspase-3 and subsequently the cleavage of PARP in AGS cells in a dose-dependent manner. Expression of γ-H2AX, which promotes DNA repair and maintains genomic stability (15), was also induced by Naph, but the expression of Bax and Bcl-xL was not altered by Naph. These results indicated that Naph may induce apoptosis in AGS cells.…”