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Dr Walmsley, University of Manchester

Development of a new human cell genotoxicity assay to reduce the use of live animals in drug development

Aims

Safety testing of new pharmaceuticals includes screening for the potential to cause cancer. Compounds that test negative in the in vitro regulatory genotoxicity tests then go on to rodent testing. The existing mammalian cell in vitro tests are highly sensitive so most carcinogens are identified, but many safe compounds are falsely identified as potential carcinogens. Because this can lead to needless loss of useful new drugs, the live animal tests are still conducted when there is only one in vitro positive result. By using a new high specificity human cell-based genotoxicity test, the aim will be to reduce the number of compounds tested on animals.

Methods

Preliminary studies with a new human cell genotoxicity test have revealed high specificity and sensitivity in detecting representative chemicals from all types of genotoxin. Some of the compounds (promutagens) are only carcinogenic after passing through the liver, so it is proposed to develop the test in a liver cell line to give a better indication of the genotoxicity. This will be compared with the results of the existing tests using liver extracts, which are currently required by the regulators.

Implications for the 3Rs

The test will be a valuable new tool to confirm positive regulatory data from existing tests and with fewer numbers of compounds going on to animal tests, there will be a reduction in the numbers used. If successful, this will also avoid the considerable costs of carrying out animal tests.

Publications

  1. Jagger C, Tate M, Cahill PA, Hughes C, Knight AW, Billinton N & Walmsley RM (2009) Assessment of the genotoxicity of S9-generated metabolites using the GreenScreen HC GADD45a-GFP assay. Mutagenesis 24 (1), 35-50
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  2. Walmsley RM (2008) Gadd45a-GFP GreenScreen HC genotoxicity screening assay. Expert Opinion in Drug Metabolism and Toxicology 4 (6), 827-835
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