P53+/- hemizygous knockout mouse: overview of available data.
The performance of the p53-/- transgenic (knockout) mouse model was evaluated through review of the data from 31 short-term carcinogenicity studies with 21 compounds tested as part of the International Life Sciences Institute's (ILSI) Alternatives to Carcinogenicity Testing (ACT) project, together with data from other studies which used comparable protocols. As expected based on the hypothesis for the model, a significant number (12/16 or 75%) of the genotoxic human and/or rodent carcinogens tested were positive and the positive control, p-cresidine, gave reproducible responses across laboratories (18/19 studies positive in bladder). An immunosuppressive human carcinogen, cyclosporin A, was positive for lymphomas but produced a similar response in wild type mice. Two hormones that are human tumorigens, diethylstilbestrol and 17beta-estradiol, gave positive and equivocal results, respectively, in the pituitary with p53-deficient mice showing a greater incidence of proliferative lesions than wild type. None of the 22 nongenotoxic rodent carcinogens that have been tested produced a positive response but 2 compounds in this category, chloroform and diethylhexylphthalate, were judged equivocal based on effects in liver and kidney respectively. Four genotoxic noncarcinogens and 6 nongenotoxic, noncarcinogens were also negative. In total (excluding compounds with equivocal results), 42 of 48 compounds or 88% gave results that were concordant with expectations. The technical lessons learned from the ILSI ACT-sponsored testing in the p53+/- model are discussed.
Storer
R D
RD
Merck & Co Inc, West Point, Pennsylvania 19486, USA. richard_storer@merck.com
French
J E
JE
Haseman
J
J
Hajian
G
G
LeGrand
E K
EK
Long
G G
GG
Mixson
L A
LA
Ochoa
R
R
Sagartz
J E
JE
Soper
K A
KA
D000826:Animal Testing Alternatives; D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009153:Mutagens / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D015203:Reproducibility of Results
D002273:Carcinogens; D009153:Mutagens