An industry perspective on the utility of short-term carcinogenicity testing in transgenic mice in pharmaceutical development.
International guidelines allow for use of a short-term cancer bioassay (twenty-six weeks) in transgenic mice as a substitute for one of the two required long-term rodent bioassays in the preclinical safety evaluation of pharmaceuticals. The two models that have gained the widest acceptance by sponsors and regulatory authorities are the CB6F1-RasH2 mouse hemizygous for a human H-ras transgene and the B6.129N5-Trp53 mouse heterozygous for a p53 null allele. The p53(+/-) model is of particular value for compounds with residual concern that genotoxic activity may contribute to tumorigenesis. The rasH2 model is an appropriate alternative without regard to evidence of genotoxic potential. Since results from a short-term bioassay can be obtained relatively early in drug development, there is the potential for more timely assessment of cancer risk for individuals in long-term clinical trials. Use of these models in preclinical safety evaluation also significantly reduces animal use, time, and manpower. Preliminary findings indicate that prediction of two-year rat bioassay outcomes based on data from chronic rat toxicity studies, together with early assessment of carcinogenic potential in short-term transgenic models, may have the potential to increase the timeliness and efficiency of strategies for the identification of human carcinogenic hazards.
Storer
Richard D
RD
Dept. of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. richard_storer@merck.com
Sistare
Frank D
FD
Reddy
M Vijayaraj
MV
DeGeorge
Joseph J
JJ
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D004195:Disease Models, Animal; D055808:Drug Discovery; D004345:Drug Industry; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D016159:Tumor Suppressor Protein p53