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CC2-LUMC: Gene Expression Profiling in DNA Repair-Deficient XPA Transgenic Mice Following Treatment With Benzo[A]Pyrene and Cyclosporin-A: Lymphomagens with Different Modes of Action

Principal Investigator

Dr. Harry van Steeg
Leiden University Medical Centre (LUMC)
Wassenaarseweg 72
2333 AL Leiden
The Netherlands

H.van.Steeg@rivm.nl
Tel: +31 30 274 2102
Fax: +31 30 274 4446

Collaborators

Dr. Jan Vijg - University of Texas Health Science Center, Texas US
vijg@uthscsa.edu
Dr. Harry Vrieling - LUMC
h.vrieling@lumc.nl

Description

Many environmental chemicals which have been shown to cause cancer in rodents have been implicated in human cancer. However, establishing cause and effect in humans is often impossible. Today, the only accepted test for human carcinogenicity is the two-year rodent bioassay. This has many ethical and practical disadvantages: it requires large numbers of laboratory animals and is time-consuming and expensive. There is also considerable scientific doubt about its reliability. Many chemicals give false positive results due to the extremely high doses used, which bear no relation to likely levels of human exposure. Tests to establish mutagenic potential of a chemical in vivo are also limited and restricted to a few tissues and organs. The researchers involved in this project have developed sensitive strains of transgenic mice which can be used in combined low dose mutagenesis and carcinogenesis studies. Their potential in short-term carcinogenicity testing is being evaluated under a global programme co-ordinated by the International Life Sciences Institute (Washington, DC). Initial results are encouraging, giving an accurate prediction of the human carcinogenicity of compounds tested. This project will study molecular mechanisms of the carcinogenic response of mice to human carcinogens. It aims to identify gene clusters that respond specifically to these carcinogens. if these exist, they could form the basis of a revolutionary approach to identifying human carcinogens, without the need for extensive animal testing.

Related Publications

 

KA Baken, JL Pennings, MJ Jonker, MM Schaap, A de Vries, H van Steeg, TM Breit, H van Loveren, Overlapping gene expression profiles of model compounds provide opportunities for immunotoxicity screening, Toxicology and Applied Pharmacology 2008, 226, 46-59.

KA Baken, JLA Peniings, A de Vries, TM Breit, H van Steeg, H van Loveren, Gene expression profiling of TBTO induced immunotoxicity in mice and rats, Journal of Immunotoxicology 2006, 3, 227-244. 

EM Hoogervorst, H van Steeg, A de Vries, Nucleotide excision repair- and p53-deficient mouse models in cancer research, Mutatation Research 2005, 574, 3-21.

FA Van den Berg, KA Baken, JP Vermeulen, ER Gremmer, H Van Steeg, H Van Loveren, Use of the Local Lymph Node Assay in assessment of immune function, Toxicology 2005, 211, 107-114.

EM Hoogervorst, CTM Van Oostrom, RB Beems, J Van Benthem, J Van den Berg, CF Van Kreijl, JG Vos, A De Vries, H Van Steeg, 2-AAF-induced tumor development in nucleotide excision repair-deficient mice is associated with a defect in global genome repair but not with transcription coupled repair, DNA Repair 2005, 4, 3-9.

 

EM Hoogervorst, CTM Van Oostrom, RB Beems, J Van Benthem, S Gielis, JP Vermeulen, PW Wester, JG Vos, A De Vries, H Van Steeg, p53 Heterozygosity Results in an Increased 2-Acetylaminofluorene-Induced Urinary Bladder but not Liver Tumor Response in DNA Repair-Deficient Xpa Mice, Cancer Research 2004, 64, 5118-5126.

Timeline: January 2001 > December 2003

LRI funding: €704,940

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