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ToxSci Advance Access published online on December 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh037
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received August 21, 2003; accepted November 3, 2003
© 2003 Society of Toxicology

Forum

The Utility of Genetically-Modified Mouse Assays for Identifying Human Carcinogens - A Basic Understanding and Path Forward

James MacDonald 1, John E. French 2, Ronald J. Gerson 3, Jay Goodman 4, Tohru Inoue 5, Abigail Jacobs 6, Peter Kasper 7, Douglas Keller 8, Amy Lavin 9*, Gerald Long 10, Bruce McCullough 11, Frank D. Sistare 6, Richard Storer 12, and Jan Willem van der Laan 13

1 Schering-Plough Research Institute, Kenilworth, NJ 07033
2 National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709
3 Endo Pharmaceuticals, Chadds Ford, PA, 19352
4 Michigan State University, East Lansing, MI 48824
5 National Institute of Health Sciences, Tokyo 158-8501, Japan
6 U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD, 20857
7 Federal Institute for Drugs and Medical Devices (BfArM), D-53175 Berlin, Germany
8 Sanofi-Synthelabo Research, Malvern, PA, 19355
9 ILSI Health and Environmental Sciences Institute, Washington, DC 20005
10 Eli Lilly & Company, Greenfield, IN 46140
11 Aventis Pharmaceuticals, Inc. , Bridgewater, NJ, 08807
12 Merck Research Laboratories, West Point, PA, 19486
13 National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands

* To whom correspondence should be addressed. E-mail: alavin{at}ilsi.org.


  Abstract

The Alternatives to Carcinogenicity Testing Committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) conducted a large-scale, multinational collaborative research program to evaluate several genetically-modified mouse assays for assessing the human carcinogenic potential of compounds. The data from this testing program have made an important contribution to the general understanding of how these models can be best applied in hazard identification; however, questions still exist regarding methodology and data interpretation. To address these issues, ILSI HESI hosted a February 2003 workshop on the Utility of Transgenic Assays for Risk Assessment. The purpose of this workshop was to reach an understanding of how data from genetically-modified mouse models are viewed by different regulatory bodies in the pharmaceutical sector, and based on this understanding, to identify areas in which more experimental work may be needed to increase the utility of data derived from these assays. In the course of discussions, various data gaps related to model selection and protocol issues were identified. Based on the outcome of the workshop, various studies are proposed to provide data to improve the utility of currently available assays for cancer hazard identification and risk assessment purposes.

Key Words: carcinogenicity, p53+/- knockout mouse, regulatory perspective, risk assessment, Tg.rasH2 transgenic mouse, genetically-modified mice .


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