title: Early development of histiocytic sarcomas in p53 knockout mice treated with N-bis(2-hydroxypropyl)nitrosamine.
abstract: p53 knockout mice have been utilized for the functional analysis of p53 in carcinogenic processes and for the evaluation of the carcinogenic potential of chemicals. In this study, we established that p53 knockout mice have an elevated susceptibility to the induction of histiocytic sarcoma (HS) by N-bis(2-hydroxy-propyl)nitrosamine (BHP). p53 heterozygous (+/-) and wild-type (+/+) mice were treated with 20 or 200 ppm BHP in their drinking water for 15 weeks or with 20 ppm BHP for 40 weeks. An additional group of p53 nullizygous (-/-) mice were treated with 20 ppm BHP for 15 weeks. In a 15-week experiment, hepatic HSs were unexpectedly observed in BHP-treated p53 (-/-) mice (30.8%) but not in p53 (+/-) and (+/+) mice and untreated (-/-) mice, indicating that a complete loss of p53 dramatically accelerates the genesis of HS. In a 40-week experiment, HSs were significantly increased in female p53 (+/-) mice (37.5%) as compared with female (+/+) mice (5.0%). Additionally, PCR-SSCP and sequencing analysis revealed a high frequency of p53 gene mutations in HSs, demonstrating the involvement of p53 gene mutations in HS development. Our data add to the understanding of the carcinogenic susceptibility of p53 knockout mice, and may help to elucidate the pathogenesis of HS development.
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirata
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.forename: Hisayo
authors.initials: H
authors.lastname: Ban
authors.forename: Tokuma
authors.initials: T
authors.lastname: Yanai
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Masegi
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D016158:Genes, p53 / Q000502:physiology*; D015620:Histiocytic Disorders, Malignant / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009602:Nitrosamines / Q000633:toxicity*; D012513:Sarcoma, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology