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Carcinogenesis Advance Access published online on January 9, 2009
Carcinogenesis, doi:10.1093/carcin/bgp013
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

DNA repair-deficient Xpa/p53 knockout mice are sensitive to the non-genotoxic carcinogen cyclosporine A: escape of initiated cells from immunosurveillance?

Petra C.E. van Kesteren, Rudolf B. Beems, Mirjam Luijten, Joke Robinson, Annemieke de Vries and Harry van Steeg

Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands

Corresponding author: Harry van Steeg, Laboratory for Health Protection Research, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, the Netherlands., Phone: 31-30-274-2102; Fax: 31-30-274-4446; E-mail: Harry.van.Steeg{at}rivm.nl.

The DNA repair-deficient Xpa-/-p53 (Xpa/p53) mouse is a potent model for carcinogenicity testing, representing increased sensitivity towards genotoxic but surprisingly also towards true human non-genotoxic carcinogens. The mechanism of this increased sensitivity in Xpa/p53 mice towards non-genotoxic carcinogens is still unknown. Here, we investigated the mechanism of the human non-genotoxic carcinogen cyclosporine A (CsA) in the Xpa/p53 mouse model.

Xpa/p53 mice exposed to CsA for 39 weeks showed a significantly increased lymphoma incidence as compared to untreated Xpa/p53 mice and CsA-treated wild type mice. We excluded concealed genotoxicity of CsA in Xpa/p53 mice by mutant frequency analyses. As a next step, we used a genetic approach: immune-deficient DNA-PKcs mice were crossed with Xpa and Xpa/p53 mice. Xpa/p53 mice had an increased lymphoma incidence with shorter latency times as compared to DNA-PKcs-deficient wild type and Xpa mice. Surprisingly, also 6 out of 15 DNA-PKcs/Xpa/p53 females had developed an adenocarcinoma of the mammary gland. Tumor responses in CsA-treated and DNA-PKcs-deficient Xpa/p53 mice were comparable as both genotypes developed mainly splenic lymphomas enriched in B lymphocytes.

From our present studies, we hypothesize that levels of initiated pre-cancerous cells are elevated in Xpa/p53 mice. These cells are insufficiently eliminated due to either suppression of the immune system by CsA or through immune-related DNA-PKcs deficiency. Based on the current studies and those conducted previously, we conclude that the Xpa/p53 model is an excellent adjunct to the current chronic rodent bioassay.

Key Words: DNA repair • non-genotoxic carcinogen • cyclosporine A • immunosurveillance • DNA-PKcs

Received August 19, 2008; revised January 5, 2009; accepted January 5, 2009.


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[Abstract] [Full Text] [PDF]


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