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09:37
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
P53+/- hemizygous knockout mouse: overview of available data
R D Storer1, J E French, J Haseman
1Merck & Co Inc, West Point, Pennsylvania 19486, USA. richard_storer@merck.com
Toxicologic Pathology
|November 7, 2001
Summary
The p53 knockout mouse model accurately identified 75% of genotoxic carcinogens and showed no false positives for non-genotoxic carcinogens. This model shows promise for carcinogenicity testing, aligning with expectations in 88% of cases.
Area of Science:
- Toxicology
- Genetics
- Carcinogenesis
Background:
- The p53 gene plays a crucial role in tumor suppression.
- Evaluating alternative models for carcinogenicity testing is essential for reducing animal use and improving efficiency.
- The International Life Sciences Institute's (ILSI) Alternatives to Carcinogenicity Testing (ACT) project aimed to validate new testing strategies.
Purpose of the Study:
- To assess the performance of the p53-/- transgenic (knockout) mouse model in carcinogenicity testing.
- To evaluate the model's concordance with known genotoxic and non-genotoxic carcinogens and non-carcinogens.
- To identify technical lessons learned from using the p53 knockout model in short-term carcinogenicity studies.
Main Methods:
- Review of data from 31 short-term carcinogenicity studies involving 21 compounds.
- Testing conducted as part of the ILSI ACT project and comparable studies.
- Analysis of results for genotoxic and non-genotoxic carcinogens, including positive and negative controls.
Main Results:
- The p53 knockout model correctly identified 75% (12/16) of genotoxic carcinogens.
- The model showed no false positives for 22 non-genotoxic rodent carcinogens.
- Overall, 88% (42/48) of compounds yielded results concordant with expectations, excluding equivocal results.
Conclusions:
- The p53 knockout mouse model demonstrates significant potential as a tool for carcinogenicity testing.
- The model's performance aligns well with the hypothesis, particularly for genotoxic carcinogens.
- Further technical evaluation is warranted based on the lessons learned from ILSI ACT-sponsored testing.
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