Chromosomal aberrations, clastogens vs aneugens

Current anticancer therapy may be one of the most important exogenous sources of exposure to genotoxic agents in US, Japan, and Europe, where approximately 40-55 percent of the population is diagnosed with cancer at a certain point in their life. This review focuses on recent efforts to integrate a novel biomarker, gamma-H2AX, into anticancer drug screening to classify the mode of action (MoA) for genotoxic outcome into clastogenicity and aneugenicity, a distinction that has considerable impact on risk assessment and control strategy. The emerging biomarker gamma-H2AX is applicable to high throughput assay platforms and is therefore changing in vitro mammalian genotoxicity screening from traditional positive/negative selection to MoA elucidation. Because gamma-H2AX is not only a sensitive biomarker for DNA double strand break but is also induced by apoptosis, the key for successful screening is using additional biomarkers of caspase-3 and/or phosphorylated histone H3 to discriminate between relevant and irrelevant elevation of gamma-H2AX. Establishment of a standard methodology and a consensus threshold for its positive criteria will further support the application of gamma-H2AX to drug screening.