The p53 heterozygous knockout mouse as a model for chemical carcinogenesis in vascular tissue.

Carmichael, Neil G.; Debruyne, E.; Bigot-Lasserre, D.

doi:10.1289/ehp.0010861

Cited by 24 publications

(16 citation statements)

References 19 publications

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“…To assess the potential merit of the three transgenic models in a research and testing program, we assembled available information on responses to chemical treatment in each model (Tables 1-3 (Carmichael et al 2000) +d (Spalding et al 1993) +ip (Mori et al 2000;Umemura et al 1999) Oxymetholone 434-07-1 2A Reasonable ±; +; NT; NT -; --g (Stoll et al 1999) +d (Stoll et al 1999 (Stoll et al 1999) NT (NTP 1990b)…”

Section: Merits Of the Modelsmentioning

confidence: 99%

The role of transgenic mouse models in carcinogen identification.

Pritchard

French

Davis

et al. 2003

Environ Health Perspect

127

100

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In this article, we examine existing data on the use of transgenic mouse models for identification of human carcinogens. We focus on the three most extensively studied of these mice, Trp53+/-, Tg/AC, and RasH2, and compare their performance with the traditional 2-year rodent bioassay. Data on 99 chemicals were evaluated. Using the International Agency for Research on Cancer/Report on Carcinogens determinations for the carcinogenicity of these chemicals to humans as the standard for comparison, we evaluated a variety of potential testing strategies ranging from individual transgenic models to combinations of these three models with each other and with traditional rodent assays. The individual transgenic models made the "correct" determinations (positive for carcinogens; negative for noncarcinogens) for 74-81% of the chemicals, with an increase to as much as 83% using combined strategies (e.g., Trp53+/- for genotoxic chemicals and RasH2 for all chemicals). For comparison, identical analysis of chemicals in this data set that were tested in the 2-year, two-species rodent bioassay yielded correct determinations for 69% of the chemicals. However, although the transgenic models had a high percentage of correct determinations, they did miss a number of known or probable human carcinogens, whereas the bioassay missed none of these chemicals. Therefore, we also evaluated mixed strategies using transgenic models and the rat bioassay. These strategies yielded approximately 85% correct determinations, missed no carcinogens, and cut the number of positive determinations for human noncarcinogens in half. Overall, the transgenic models performed well, but important issues of validation and standardization need further attention to permit their regulatory acceptance and use in human risk assessment.

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Section: Merits Of the Modelsmentioning

confidence: 99%

The role of transgenic mouse models in carcinogen identification.

Pritchard

French

Davis

et al. 2003

Environ Health Perspect

127

100

View full text Add to dashboard Cite

show abstract

“…In addition, accelerated tumor development with chemical exposure in p53 (+/-) mice has been reported with regard to lymphomas 51 , mesotheliomas 52 , skin tumors 53 , vascular tumors 14 , urinary bladder tumors 53 , and lung tumors 54 (representative photos of a sarcoma and a lymphoma are shown in Fig. 2, B and C).…”

Section: Target Cells Decide Sensitivity Of P53 (+/-) Micementioning

confidence: 81%

“…The same mouse model has also been widely utilized for functional analysis of the p53 gene in carcinogenesis studies. There have been several reports that p53 (+/-) mice are highly sensitive to genotoxic carcinogens, such as N-butyl-N- (4-hydroxybutyl)nitrosamine (BBN) targeting the urinary bladder 9 , N-ethyl-N-nitrosourea (ENU) inducing uterine endometrial stromal sarcomas 10 , N,Ndibutylnitrosamine (DBN) causing esophagus and urinary bladder tumors 11 , methyl-n-amylnitrosamine (MNAN) active in the esophagus 12 and tongue 13 and urethane inducing vascular tumors 14 . However, p53 (+/-) mice have not been shown to have increased susceptibility to induction of hepatocellular tumors by diethylnitrosamine (DEN) 15 or breast tumors by 7,12-dimethyl[a]benzanthracene (DMBA) 16 .…”

Section: Introductionmentioning

confidence: 99%

Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations

2005

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Abstract:Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers and mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this article, we review the data on the susceptibility of p53 nullizygote (-/-), heterozygote (+/ -), and wild type (+/+) mice to various carcinogens. Induction of esophageal and tongue squamous cell carcinomas (SCCs) by methyl-n-amylnitrosamine was shown to be increased in p53 (+/-) mice, in addition to the high sensitivity shown by p53 (-/-) littermates. N,N-dibutylnitrosamine (DBN) treatment also caused more tumor development in p53 (+/-) than wild-type mice, as with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the urinary bladder. In addition, p53 (+/-) heterozygotes proved more sensitive than wild type littermates to the induction of stromal cell tumors like hemangiomas/hemangiosarcomas by N-bis(2-hydroxypropyl)nitrosamine (BHP) or lymphomas and fibrosarcomas with other carcinogens. Analysis of exons 5-8 of the p53 gene demonstrated mutations in approximately one half of the lesions. With N-methyl-N-nitrosourea, preneoplastic lesions of the stomach, pepsinogen altered pyloric glands (PAPG), and a gastric adenocarcinoma, were found after only 15 weeks in p53 (-/-) mice, although there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/-) mice in the longer-term. Regarding colon carcinogenicity, adenocarcinomas were observed limited to 1, 2-dimethylhydrazine treated p53 (-/-) mice in the short term, but again, no significant difference was evident between the p53 (+/+) and (+/-) cases at the end of the study. Furthermore, diethylnitrosamine or aminophenylnorharman treated p53 (+/-) mice did not demonstrate elevated susceptibility to tumors in the liver. With BHP, which induces tumors in multiple organs, p53 (+/-) mice were not more statistically sensitive with regard to lung tumor development than p53 (+/+). Of the malignant tumors examined in p53 (+/+) and (+/-) mice, as many as 10% demonstrated mutations in the p53 gene. These results suggest that p53 may not be a direct target for mouse adenomas/adenocarcinomas, but rather plays an important role as a gatekeeper in their genesis. In contrast p53 itself is frequently mutated in squamous, urothelial, or stromal tumors with a clear order of susceptibility: p53 (-/-) > p53 (+/-) > p53 (+/+) mice. p53 (-/-) mice are versatile animals for carcinogenicity testing, despite their disadvantage of a high background of spontaneous tumor development, and tissue dependence must be taken into account when exposing p53 (+/-) mice to chemical carcinogens. (J Toxicol Pathol 2005; 18: 121-134)

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“…However, it has been reported that whereas C57BL/6 mice are highly susceptible to hepatic vascular carcinogenesis, susceptibility to urethane-induced lung carcinogenesis is low (Carmichael et al, 2000). Thus, there are clear differences between rasH2 and p53 (+/−) mice in this regard.…”

Section: Introductionmentioning

confidence: 99%

Susceptibilities of p53 Knockout and rasH2 Transgenic Mice to Urethane-Induced Lung Carcinogenesis are Inherited from their Original Strains

Ozaki

Watanabe

et al. 2005

Toxicol Pathol

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In the present study, susceptibility of CB6F1 mice carrying the human prototype c-Ha-ras gene (rasH2 mice) and p53 gene knockout mice (p53 (+/−) mice) to urethane-induced lung carcinogenesis was compared under the same experimental conditions. Both strains were administered 500 ppm urethane in their drinking water for 3 weeks. At week 26, lung adenocarcinomas and adenomas were observed in 53% and 100% of rasH2 mice, respectively, and lung adenomas were observed in 67% of rasH2 littermate (non-Tg) mice. However, lung tumors were not observed in either p53 (+/−) or p53 (+/+) mice. Peliosis hepatis and hepatic hemangiomas were observed in 27% and 67% of p53 (+/−) mice, but only in 6.7% and 6.7% of the rasH2 animals, respectively. Under the same experimental conditions, BALB/c mice, the strain of origin of the rasH2 mice, developed lung adenomas at an incidence of 93%, whereas none of the C57BL/6 original strain for p53 (+/−) mice developed lung tumors. Peliosis hepatis was observed in 40% of the C57BL/6 mice, but not in BALB/c mice; hepatic and splenic hemangiomas were not observed in these animals. These results indicate that organ susceptibility of rasH2 and p53 (+/−) mice is inherited from their strains of origin, the rasH2 and BALB/c lines being much more sensitive to the induction of pulmonary carcinogenesis.

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The p53 heterozygous knockout mouse as a model for chemical carcinogenesis in vascular tissue.

Cited by 24 publications

References 19 publications

The role of transgenic mouse models in carcinogen identification.

The role of transgenic mouse models in carcinogen identification.

Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations

Susceptibilities of p53 Knockout and rasH2 Transgenic Mice to Urethane-Induced Lung Carcinogenesis are Inherited from their Original Strains

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