p53 knockout mice (-/-) are more susceptible than (+/-) or (+/+) mice to N-methyl-N-nitrosourea stomach carcinogenesis

Mutations of the p53 tumor suppressor gene constitute one of the most frequ ent molecular changes in a wide variety of human cancers. Mice deficient in p53 have recently attracted attention for their potential to identify chem ical genotoxins, In this study we have investigated the susceptibility of p 53 nullizygote (-/-), heterozygote (+/-) and wild-type (+/+) mice to N-meth yl-N-nitrosourea (MNU) gastric carcinogenesis. p53 knockout mice were treat ed with 30 p.p.m. MNU in the drinking water 1 week on and 1 week off and ki lled 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 foun d in 0 of 19 (+/+) (0%), 2 of 21 (+/-) (9.5%) and 6 of 10 (-/-) (60.0%) ani mals. 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, leuk emias and sarcomas was very much greater in the latter group. Homozygous kn ockout animals could not be maintained long term. PCR-single strand conform ation polymorphism analysis of exons 5-8 of the p53 gene of DNA extracts fr om 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-trealted 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.