Rapid induction of uterine tumors with p53 point mutations in heterozygousp53-deficient CBA mice given a single intraperitoneal administration of N-ethyl-N-nitrosourea

To investigate the sensitivity of heterozygous p53-deficient CBA mice to ca rcinogens, 20 female mice [p53(+/-)] and 20 wild-type littermates [p53(+/+) ] were given an intraperitoneal injection of 120 mg/kg body wt of N-ethyl-N -nitrosourea (ENU) and were maintained without any other treatment for a fu rther 26 weeks. Histopathology showed that uterine tumors (endometrial poly ps and stromal sarcomas) and lung adenomas mere induced in both p53(+/-) an d p53(+/+) mice. The incidence of uterine tumors and lung adenomas (94% and 81%, respectively) in p53(+/-) mice was significantly greater than that in p53 (+/+) mice (37% and 42%, respectively). Malignant lymphomas were only induced in p53(+/-) mice, at an incidence of 31%. Concerning uterine tumors and preneoplastic lesions, there were endometrial stromal sarcomas and aty pical hyperplasias of the endometrial gland in 90% and 63%, respectively, o f p53(+/-) mice, with significantly greater incidences than in p53(+/+) mic e. Gene analysis revealed GCG-->GTG point mutations in codon 135 of exon 5 of the p53 allele in all of the uterine endometrial stromal sarcomas examin ed. Our results suggest that female p53(+/-) CBA mice are very susceptible to uterine carcinogenesis, providing a useful model for ENU-induced uterine tumors.