Evaluation of the Tg.AC transgenic mouse assay for testing the human carcinogenic potential of pharmaceuticals--practical pointers, mechanistic clues, and new questions.
Transgenic mouse strains with genetic alterations known to play a role in the multistage process of carcinogenesis are being used increasingly as models for evaluating the human carcinogenic potential of chemicals and pharmaceuticals. The Tg.AC transgenic mouse is one of the strains currently being used in such alternative short-term carcinogenicity testing protocols. This review is focused on recent data from studies designed to evaluate this model's ability to discriminate carcinogens from noncarcinogens. Details relating to protocol design that can significantly impact study outcome are described. Data relating to mechanisms of chemical tumor induction in the Tg.AC model are reviewed, and questions have been formulated to encourage research to further guide appropriate future applications of this model.
Sistare
Frank D
FD
Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, Maryland 20708, USA. sistare@cder.fda.gov
Thompson
Karol L
KL
Honchel
Ronald
R
DeGeorge
Joseph
J
D000826:Animal Testing Alternatives; D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity*; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions; D011905:Genes, ras / Q000235:genetics; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology
D002273:Carcinogens