Rapid induction of uterine tumors with p53 point mutations in heterozygous p53-deficient CBA mice given a single intraperitoneal administration of N-ethyl-N-nitrosourea.
To investigate the sensitivity of heterozygous p53-deficient CBA mice to carcinogens, 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 further 26 weeks. Histopathology showed that uterine tumors (endometrial polyps and stromal sarcomas) and lung adenomas were induced in both p53(+/-) and 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 atypical hyperplasias of the endometrial gland in 90% and 63%, respectively, of p53(+/-) mice, with significantly greater incidences than in p53(+/+) mice. 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 examined. Our results suggest that female p53(+/-) CBA mice are very susceptible to uterine carcinogenesis, providing a useful model for ENU-induced uterine tumors.
Mitsumori
K
K
Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. mitsumor@nihs.go.jp
Onodera
H
H
Shimo
T
T
Yasuhara
K
K
Takagi
H
H
Koujitani
T
T
Hirose
M
M
Maruyama
C
C
Wakana
S
S
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D017931:DNA Primers; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D016158:Genes, p53; D006579:Heterozygote; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014594:Uterine Neoplasms / Q000139:chemically induced / Q000235:genetics*
D002273:Carcinogens; D017931:DNA Primers; D005038:Ethylnitrosourea