High susceptibility of nullizygous p53 knockout mice to colorectal tumor induction by 1,2-dimethylhydrazine.
OBJECTIVE
The susceptibility of male p53 nullizygote (-/-), heterozygote (+/-), and wild-type (+/+) mice to 1,2-dimethylhydrazine (DMH) induction of colon carcinogenesis was investigated.


METHODS
In a preliminary short-term experiment, male mice of three genotypes were given s.c. of 20 mg/kg DMH once weekly for 5 weeks. In a medium-term experiment, mice were given weekly s.c. of DMH for 15 weeks. In a long-term experiment, male p53 (+/-) and (+/+) mice were given weekly injections of DMH for 15 weeks, and killed at week 30.


RESULTS
In the medium-term experiment, carcinomas were observed in 70% of p53 (-/-) mice, although there were no carcinomas in p53 (+/+) and (+/-) mice. In the long-term experiment, there was no significant difference in incidences of adenomas and carcinomas between p53 (+/+) and (+/-) mice. PCR-single strand conformation polymorphism analysis of exons 5-8 of p53 gene revealed four mutations in one focal atypia, one adenoma, and two carcinomas, out of 56 colonic proliferative lesions in the medium- and long-term experiments.


CONCLUSIONS
These results suggest that p53 might not be a direct target of DMH but complete loss of p53 might elevate susceptibility to DMH-induced colorectal carcinogenesis.
Division of Oncological Pathology, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-ku, 464-8681 Nagoya, Japan.
Hiroki
H
Sakai
Tetsuya
T
Tsukamoto
Masami
M
Yamamoto
Norimitsu
N
Shirai
Takeshi
T
Iidaka
Akihiro
A
Hirata
Tokuma
T
Yanai
Toshiaki
T
Masegi
Lawrence A
LA
Donehower
Masae
M
Tatematsu
D019813:1,2-Dimethylhydrazine / Q000009:adverse effects*; D000818:Animals; D002273:Carcinogens / Q000009:adverse effects*; D002277:Carcinoma / Q000139:chemically induced* / Q000235:genetics* / Q000662:veterinary; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000662:veterinary; D004195:Disease Models, Animal; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D018345:Mice, Knockout
D002273:Carcinogens; D019813:1,2-Dimethylhydrazine