Assay for DNA damage

STORY UPDATE

MANCHESTER, U.K.—March 6, 2007—Looking to leverage its IP in the early identification of genotoxic chemicals (GreenScreen HC), Genotronix announced it secured £1 million investment from NVM Private Equity. As company Chairman and CEO John Nicholson explains, the financing will allow Genotronix to market the screening system not only to pharmaceutical and biotechnology companies, but also cosmetic, environmental, and fine chemical markets.

MANCHESTER, U.K.—Toxicity in drug discovery is often the result of compounds that damage DNA or perturb its function within a cell. Unfortunately, the high specificity of many existing genotoxicity assays is offset by throughput challenges. And other assays offer poor specificity. To address this problem, researchers at the University of Manchester, GSK and Gentronix developed a high-throughput assay that links green fluorescent protein (GFP) expression to regulatory sequences of a human gene involved in DNA damage response.

As they described in Mutation Research, the GreenScreen HC assay involves expression of a GADD45a promoter-GFP hybrid gene in human lymphoblastoid cells, which can be grown in 96-well plates. Thus, in the presence of genotoxic substances, the GADD45a promoter turns on GFP expression and the well glows. To validate their assay, the researchers screened a panel of 34 known genotoxins and 41 non-genotoxic compounds, some of which give false positive results in mammalian cell assays.

The researchers noted that the assay responded positively to almost all of the genotoxins regardless of the compound's mechanism of action, and negatively to all non-genotoxic chemicals. The assay generally required higher toxin concentrations than is typically used as an endpoint, but it still fits within ICH standards. As such, the researchers suggest that the assay offers the best features of microbial and mammalian cell genotoxicity assays.