Xpa and Xpa/p53+/- knockout mice: overview of available data
| Autor: | C F, van Kreijl, P A, McAnulty, R B, Beems, A, Vynckier, H, van Steeg, R, Fransson-Steen, C L, Alden, R, Forster, J W, van der Laan, J, Vandenberghe |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Mice Knockout Societies Scientific DNA Repair Dose-Response Relationship Drug Carcinogenicity Tests International Cooperation Academies and Institutes RNA-Binding Proteins Mice Transgenic Neoplasms Experimental Animal Testing Alternatives Genes p53 Xeroderma Pigmentosum Group A Protein DNA-Binding Proteins Disease Models Animal Mice Carcinogens Animals Female Mutagens |
| Zdroj: | Toxicologic pathology. |
| ISSN: | 0192-6233 |
| Popis: | DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life 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 deficient models respond to genotoxic carcinogens. 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 nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model. |
| Databáze: | OpenAIRE |
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