Effect of Intragastric Application of N-Methylnitrosourea in p53 Knockout Mice

Nullizygous p53 knockout (p53−/−) mice are highly susceptible to spontaneous tumorigenesis, in particular malignant lymphomas at an early age. Heterozygous p53 knockout (p53+/−) mice develop spontaneous tumors less frequently but may show increased susceptibility to chemical carcinogens. In this study, p53−/−, p53+/−, and p53 wild-type (p53+/+) mice were treated with N-methylnitrosourea (MNU) by gastric intubation (5 μg/g body weight) three times per week for 5 wk, starting at 5–6 wk of age. The surviving mice were killed when they were 56–57 wk old. All eight p53−/− mice treated with MNU developed malignant lymphomas with a shorter latent period (mean age  =  16.4±0.5 wk) than their spontaneous tumors (61%, at age 23.3±1.4 wk). In p53+/− mice treated with MNU, malignant lymphomas developed at a higher frequency (eight of 27, 30%) than did spontaneous lymphomas (5%). Development of sarcomas in p53−/− and p53+/− mice was also significantly enhanced by treatment with MNU. All eight thymic lymphomas and three sarcomas in the p53+/− mice showed a loss of the remaining wild-type p53 allele. These results indicate that intragastric MNU treatment significantly enhanced spontaneous development of malignant lymphomas and sarcomas in both p53−/− and p53+/− mice. In the stomachs of 12 p53+/− mice, that were killed at the end of the experiment, two adenomas, one carcinoma in situ, and four adenocarcinomas were observed. In the stomachs of 31 p53+/+ mice, eight adenomas and one carcinoma in situ were detected. The overall incidence of tumorous changes in the stomachs of p53+/− (seven of 12, 58%) and p53+/+ (nine of 31, 29%) mice were not significantly different (P = 0.090). However, adenocarcinomas invading the submucosa were observed in p53+/− mice (four of 12, 33%) but not in p53+/+ mice (zero of 31; P = 0.004), suggesting a slightly higher susceptibility to gastric carcinogenesis induced by MNU in p53+/− mice. Mol. Carcinog. 28:97–101, 2000. © 2000 Wiley-Liss, Inc.