Walter Westerink - Articles and news items


Segregation of molecular mechanisms of genotoxicity and carcinogenicity across human, yeast and Salmonella species

Issue 1 2010, Toxicology / 22 February 2010 /

Screening assays for in vitro toxicity are the way to reduce the attrition rates in the preclinical development of new drugs. Here a test battery is presented for screening of genotoxic and carcinogenic compounds by means of VitotoxTM, RadarScreen, and four human liver HepG2 cell lines with two different promoters as well as responsive element (RE) settings in combination with a luminescent read-out. The VitotoxTM assay in Salmonella is a substitute for the Ames test and the RadarScreen assay for in vitro clastogenicity. Moreover, HepG2 assays with RAD51C and Cystatin A promoters, and p53-RE are more predictive for in vivo clastogenicity. The Nrf2-RE can be used for analysis of reactive oxygen species production. The validity of this battery is checked for 62 compounds of an ECVAM list for genotoxicity and for 190 other references or in house drugs.

In vitro toxicity screening as pre-selection tool

Issue 3 2008, Past issues / 19 June 2008 /

Drug discovery relies on massive screening of compound libraries with in vitro cell-based target assays. These pharmacological screens have been well accepted. For in vitro toxicological screening, this privilege has only been obtained for the Ames, chromosomal aberration and eye irritation tests. At the moment, a number of cellular assays for cytotoxicity, genotoxicity, embryotoxicity, cellular metabolic activation processes and endocrine disruption await general acceptance. From that point onwards, tools will become available to identify unwanted pharmacological or toxicological effects at a much earlier stage in the drug development process.


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