| First Author | Floyd E | Year | 2002 |
| Journal | Toxicol Pathol | Volume | 30 |
| Issue | 1 | Pages | 147-56 |
| PubMed ID | 11890468 | Mgi Jnum | J:75222 |
| Mgi Id | MGI:2176105 | Doi | 10.1080/01926230252824860 |
| Citation | Floyd E, et al. (2002) The Trp53 hemizygous mouse in pharmaceutical development: points to consider for pathologists. Toxicol Pathol 30(1):147-56 |
| abstractText | ILSI-HESI sponsored an international consortium for the evaluation of alternative models, including the TrpS3+/- mouse. for use in short-term carcinogenicity testing of pharmaceuticals. Products of the ILSI evaluation included guidance for protocol design and assay interpretation, spontaneous tumor incidences, diagnostic criteria for common proliferative lesions, and results of assays for pharmaceutical agents that are known human and/or rodent carcinogens and non-carcinogens. Based on the ILSI evaluation, recommended protocol elements for this model include: 26-week study duration, groups > or = 15/sex/dose, a positive control group (benzene or p-cresidine), a negative control group and 3 dose groups, the high dose set at MTD or MFD, routine in-life evaluations, and complete necropsies with microscopic evaluation of tissues. Favored statistical analyses are trend tests or pair-wise comparisons, with no adjustments for survival. For an assay to be valid, positive control groups must demonstrate an effect, and the MTD or MFD must be reached in both sexes. Criteria for a negative response include a valid assay, no statistical increase in common tumors, no biologically significant numerical increase in rare tumors, and no tumor incidence above that of historical controls. Positive responses can consist of statistically significant increases in the incidence of a common tumor or numerical increases in a rare tumor, which may not be statistically significant. In either case, the incidence should be clearly above historical control values. Evidence of a dose response or occurrence of hyperplasia in a tissue with a neoplastic response can support interpreting an assay as positive. The two most common spontaneous tumors (> 1 %) in Trp53+/- mice are malignant thymic lymphomas and subcutaneous sarcomas. Use of implanted electronic transponders can increase the incidence of sarcomas. Important rare spontaneous tumors (incidence < or = 1%) are osteosarcomas and pulmonary adenomas. Many other tumor types have been reported to occur sporadically in Trp53+/- mice. Diagnostic challenges for this model include differentiating lymphoma from atypical thymic hyperplasia and recognizing the variable histopathology of subcutaneous sarcomas. In reported bioassays, Trp53+/- mice responded positively to genotoxic carcinogens, negatively to non-genotoxic rodent carcinogens, and negatively to noncarcinogens, indicating that unlike the 2-year mouse assay, this short-term assay is not overly sensitive. Positive responses often elicited an increase in tumors that occur spontaneously. To successfully use this model, pathologists must understand the biology of the Trp53 tumor suppressor gene and the principles of protocol design and data interpretation for short-term bioassays. They must also know the historical response pattern of Trp53+/- mice to test agents and be able to accurately diagnose tumors in this model. Use of the Trp53+/- mouse presents the pharmaceutical industry with several challenges, one of which is managing the uncertainty created by a lack of precedents for regulatory decisions about some possible outcomes for short-term carcinogenicity assays. |
