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Carcinogenesis Advance Access originally published online on January 9, 2009
Carcinogenesis 2009 30(3):538-543; 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), PO Box 1, 3720 BA Bilthoven, The Netherlands

* To whom correspondence should be addressed. Tel: +31 30 274 2102; Fax: +31 30 274 4446; Email: 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 toward genotoxic but surprisingly also toward true human non-genotoxic carcinogens. The mechanism of this increased sensitivity in Xpa/p53 mice toward 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 with untreated Xpa/p53 mice and CsA-treated wild-type (WT) mice. We excluded concealed genotoxicity of CsA in Xpa/p53 mice by mutant frequency analyses. As a next step, we used a genetic approach: immunodeficient DNA-PKcs mice, defective in the catalytic subunit of the DNA-dependent protein kinase, were crossed with Xpa and Xpa/p53 mice. Xpa/p53 mice had an increased lymphoma incidence with shorter latency times as compared with DNA-PKcs-deficient WT and Xpa mice. Surprisingly, also six 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 precancerous 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.

Abbreviations: CsA, cyclosporine A; FACS, fluorescence-activated cell sorting; MLN, mesenteric lymph node; DNA-PKcs, catalytic subunit of the DNA-dependent protein kinase; WT, wild-type

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


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[Abstract] [Full Text] [PDF]


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