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Xpa and Xpa/p53+/- Knockout Mice: Overview of Available Data

RIVM, Laboratory of Health Effects Research, Bilthoven, The Netherlands, cf.van.kreyl{at}rivm.nl

Peter A. Mcanulty

Scantox AS, Lille Skensved, Denmark

Rudolf B. Beems

RIVM, Laboratory of Pathology and Immunobiology, Bilthoven, The Netherlands

AN Vynckier

Janssen Research Foundation, Beerse, Belgium

Harry Van Steeg

RIVM, Laboratory of Health Effects Research, Bilthoven, The Netherlands

Ronny Fransson-Steen

AstraZeneca AB, Sodertalje, Sweden

Carl L. Alden

Pharmacia, St. Louis, MO 63167, USA

Roy Forster

CIT, Miserey, Evreux, France

Jan-Willem Van der Laan

EU/CPMP, Safety Working Party, RIVM, Bilthoven, The Netherlands

John Vandenberghe

Janssen Research Foundation, Beerse, Belgium

DNA repair defi cient Xpa^-/- and Xpa^-/- /p53 ^+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigatedinthe international collaborative research program coordinated by InternationalLife Sciences Institute(ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair defi cient models respond to genotoxiccarcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxicILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxicnature. In general, the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.

Key Words: Carcinogens • carcinogenicity testing • DNA repair • genotoxic • nucleotide excision repair • short-term assay • tumor suppressor gene • xeroderma pigmentosum • XPA.

Toxicologic Pathology, Vol. 29, No. 1 suppl, 117-127 (2001)
DOI: 10.1080/019262301301418928


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