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.
Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, 412-8513, Japan, mishimamsy@chugai-pharm.co.jp.
Masayuki
M
Mishima
D024422:Aneugens / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics; D002869:Chromosome Aberrations; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D006657:Histones / Q000235:genetics; D006801:Humans; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D024422:Aneugens; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C468783:H2AX protein, human; D006657:Histones; D009153:Mutagens