The number of new drug approvals has reached a record low. An important contributor to this problem is toxicity: the development of approximately 30% of new drug candidates is halted because of unforeseen animal toxicity profiles and side-effects in clinical studies [1].

Compounds that damage DNA or alter chromosome numbers are ‘genotoxic’ and regarded as potential carcinogens – a factor that contributes to overall attrition rates in new drug development. To guard against genotoxic compounds being developed into drugs, it is a regulatory requirement that all pharmaceutical compounds undergo preclinical genotoxic safety testing. Because there is currently no single test capable of detecting all relevant genotoxic compounds, an array of complementary tests is used.

Although the in vitro test battery demonstrates a high degree of sensitivity in the detection of genotoxic carcinogens, it is poor at correctly identifying non-carcinogens, and there is a growing need for earlier and more accurate screening for genotoxic compounds. In response to this need, Gentronix has developed GreenScreen HC, a novel in vitro mammalian genotoxicity test based on the induction of the human GADD45a gene in human cells.

Data from the GreenScreen HC assay has been used by more than 70 biotech and pharmaceutical companies worldwide. The high specificity of the new assay produces less than 5% false positive predictions of in vivo hazard [2], and its sensitivity is higher than that of the current gold standard Ames test.

The assay was developed for hazard screening early in the development of new chemical entities – enabling early compound ranking or active use in lead optimization programmes, where the breadth of lead chemistry is narrowing – and because it is available as a contract testing service through Gentronix, it could be an alternative method for the rapid evaluation of genotoxic liability with no disruption to development laboratories. Full test reports are available within two weeks of testing initiation.

In addition, Gentronix has just introduced the Micronucleus Test, which can offer a mechanistic insight into earlier results or be used as a bridge to the in vivo MNT assay required by the ICH guidelines; BlueScreen HC, a human cell-based reporter assay that monitors the expression of the P53-linked GADD45a gene; and an in vitro Comet testing service, which provides insight into the mechanism of genotoxic damage.

References

1 McGee, P. (2005) Safety biomarkers help to reduce drug attrition. Drug Discovery & Development (http://www.dddmag.com/safety-biomarkers-help-to-reduce.aspx)
2 Hastwell, P.W. et al. (2006) High specificity and high sensitivity genotoxicity assessment in a human cell line: validation of the GreenScreen HC GADD45a-GFP genotoxicity assay. Mutation Research 607, 160–175