title: High susceptibility of p53 knockout mice to esophageal and urinary bladder carcinogenesis induced by N, N-dibutylnitrosamine.
abstract: In human cancer, alterations in the p53 tumor suppressor gene are the most common genetic alterations. The aim of the present study was to detect sensitivity of the p53 (+/-) mice and their littermates p53 (+/+) mice to N, N-dibutylnitrosamine (DBN) carcinogenicity. In experiment 1, 6-7-week-old p53 (+/-) and p53 (+/+) mice were treated with 0, 0.025 and 0.05% DBN, respectively, in drinking water for 20 weeks. Esophageal squamous cell and urinary bladder transitional cell carcinomas (TCCs) and fibrosarcomas were found to be significantly increased in p53 (+/-) mice treated with doses of DBN compared to p53 (+/+) mice administered similar doses. In experiment 2, 6-7-week-old p53 (+/-) and p53 (+/+) mice were administered 0 or 0.05 % DBN in drinking water for 8 weeks. Immunohistochemical staining revealed a significant increase in numbers of p53 and bromodeoxyuridine (BrdU) positive cells in the esophageal and urinary bladder epithelia of DBN-treated p53 (+/-) mice compared to p53 (+/+) mice administered DBN. Molecular analysis revealed point mutations in the residual p53 allele in four of eight (50%) esophageal mucosa of DBN-treated p53 (+/-) mice, and in three of eight (38%) of treated p53 (+/+) mice. The results show that p53 (+/-) mice were sensitive to DBN treatment with respect to esophageal and bladder tumor development, with a mechanism that could be confined to early mutations of the residual p53 allele and increased cellular proliferation in the target organs.
authors.affiliation: Department of Pathology, Osaka City University Medical School, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Elsayed I
authors.initials: EI
authors.lastname: Salim
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneko
authors.forename: Motome
authors.initials: M
authors.lastname: Ogawa
authors.forename: Anna
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Harushi
authors.initials: H
authors.lastname: Osugi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
mesh_terms: D000483:Alleles; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000235:genetics*; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009602:Nitrosamines; D009929:Organ Size / Q000187:drug effects; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics*
chemical_list: D002273:Carcinogens; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009602:Nitrosamines; C012279:dibutylnitrosamine; D001973:Bromodeoxyuridine