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The Trp53 hemizygous mouse in pharmaceutical development: points to consider for pathologists
Eugenia Floyd1, Peter Mann, Gerald Long
1Pfizer Nagoya Laboratories, Taketoyo, Aichi, Japan. floyd@groton.pfizer.com
Toxicologic Pathology
|March 14, 2002
Summary
The Trp53+/- mouse model offers a validated short-term carcinogenicity test for pharmaceuticals, showing sensitivity to genotoxic agents while avoiding false positives from non-genotoxic compounds. This model requires specific protocol designs and pathologist expertise for accurate interpretation of tumor responses.
Area of Science:
- Toxicology
- Genetics
- Pharmacology
Background:
- The International Life Sciences Institute (ILSI) - Health and Environmental Sciences Institute (HESI) evaluated alternative models for pharmaceutical carcinogenicity testing.
- The Trp53+/- mouse was assessed as a potential short-term carcinogenicity bioassay model.
Purpose of the Study:
- To provide guidance on protocol design and assay interpretation for the Trp53+/- mouse in short-term carcinogenicity testing.
- To evaluate the Trp53+/- mouse model's response to known human and rodent carcinogens and non-carcinogens.
Main Methods:
- Recommended a 26-week study duration with specific group sizes, dose levels (up to maximum tolerated dose/maximum feasible dose), and control groups.
- Emphasized routine in-life evaluations, complete necropsies, and microscopic tissue examination.
- Favored trend tests or pair-wise comparisons for statistical analysis, without survival adjustments.
Main Results:
- The Trp53+/- mouse model demonstrated positive responses to genotoxic carcinogens and negative responses to non-genotoxic rodent carcinogens and non-carcinogens.
- Common spontaneous tumors include thymic lymphomas and subcutaneous sarcomas; rare tumors include osteosarcomas and pulmonary adenomas.
- The model showed appropriate sensitivity, unlike longer-term assays, with positive responses often involving an increase in spontaneous tumor types.
Conclusions:
- The Trp53+/- mouse is a viable model for short-term carcinogenicity testing, offering a balance of sensitivity and specificity.
- Successful implementation requires pathologists to understand Trp53 biology, assay principles, and historical control data.
- Challenges remain in regulatory decision-making due to a lack of precedent for interpreting short-term assay outcomes.