Carcinogenesis, Vol. 21, No. 10, 1891-1897,
October 2000
© 2000 Oxford University Press
Carcinogenesis |
p53 knockout mice (–/–) are more susceptible than (+/–) or (+/+) mice to N-methyl-N-nitrosourea stomach carcinogenesis
Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa, Nagoya 464-8681, Japan,
1 Unit of Molecular Pathology, International Agency for Research on Cancer, F-69372 Lyon Cedex 08, France,
2 College of Science and Engineering, Aoyama Gakuin University, 1-1 Morinosato-Aoyama, Atsugi, Kanagawa 243-0123, Japan,
3 Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA and
4 The First Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi-Gakuin University, 1-100 Kusumoto-cho, Chikusa, Nagoya 464-8650, Japan
Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers. Mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this study we have investigated the susceptibility of p53 nullizygote (–/–), heterozygote (+/–) and wild-type (+/+) mice to N-methyl-N-nitrosourea (MNU) gastric carcinogenesis. p53 knockout mice were treated with 30 p.p.m. MNU in the drinking water 1 week on and 1 week off and killed after 5 weeks. The numbers of pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were 1.8, 1.7 and 22.6 in p53 (+/+), (+/–) and (–/–) mice, respectively. In a 15 week experiment, adenomas were found in 0 of 19 (+/+) (0%), 2 of 21 (+/–) (9.5%) and 6 of 10 (–/–) (60.0%) animals. Also, one well-differentiated adenocarcinoma was observed in a p53 (–/–) mouse. After 40 weeks treatment with 120 or 30 p.p.m. MNU there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/–) mice. However, mortality from carcinogen-induced lymphomas, leukemias and sarcomas was very much greater in the latter group. Homozygous knockout animals could not be maintained long term. PCR–single strand conformation polymorphism analysis of exons 5–8 of the p53 gene of DNA extracts from 68 gastric tumors consisting of 16 and 20 30 p.p.m. MNU-treated p53 (+/+) and (+/–) mice and 14 and 18 120 p.p.m. MNU-treated p53 (+/+) and (+/–) mice demonstrated no mutations. These results suggest that p53 may not be a direct target of MNU but rather play an important role as a gatekeeper in mouse stomach carcinogenesis induced by this direct acting agent.
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