Carcinogenicity Studies

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Carcinogenicity Studies

 

Evaluation of tumorigenic potential is a key regulatory requirement for novel therapeutics or chemicals to which humans will receive chronic exposure. Carcinogenicity studies are most often conducted prior to application for marketing approval of a new therapeutic. IITRI offers both the traditional 2-year rodent and 6-month transgenic mouse carcinogenicity studies in rasH2 mice.

2-Year Rodent Bioassays

The two-year rodent bioassay is generally considered to be the “gold standard” for experimental assessment of carcinogenicity.1 These studies involve exposure of large (≥50 per sex) groups of rats or mice to a drug or chemical for two years, followed by a complete necropsy and comprehensive microscopic evaluation of tissues by a board-certified veterinary pathologist. Historical databases for 2-year studies are available at IITRI for several rodent strains.

6-Month Transgenic Mouse Studies

The FDA and other regulatory agencies commonly accept data from a 6-month transgenic study in the rasH2 mouse in lieu of data from a 2-year carcinogenicity study in mice. Carrying both the human homolog of the Hras oncogene and the murine Ha-ras oncogene, rasH2 mice are highly sensitive to tumor induction and offer a model suitable for accelerated evaluation of carcinogenicity. At study termination, tissues are also evaluated by a board-certified veterinary pathologist.

Advantages of 6-month rasH2 mouse studies include:

  • Accelerated study completion
  • Reduced animal utilization (25 versus ≥50/sex/group)
  • Substantially reduced study cost

The IITRI team has worked extensively with transgenic mouse models for carcinogenicity testing, including the p53+/– (p53 knockout) mouse and several models expressing or overexpressing ras oncogenes. An extensive historical control database is available for rasH2 transgenic mouse studies.

 

IITRI Expertise in Carcinogenesis

IITRI has performed carcinogenicity studies in rodent models for over 40 years for commercial and government sponsors. We have been a major preclinical contractor to the National Cancer Institute for decades, and our scientists are known as leaders in carcinogenicity evaluation and in studies of mechanisms of carcinogenesis. Studies performed by IITRI scientists have resulted in over 200 published papers and book chapters in the fields of carcinogenesis, cancer chemoprevention, and cancer chemotherapy. In 2015, we completed the largest single agent carcinogenicity studies (~3000 animals) ever performed for the National Toxicology Program.2

1McCormick DL, 2016. Preclinical Evaluation of Carcinogenicity Using Standard-Bred and Genetically Engineered Rodent Models. In: Faqi, A.S. (ed), A Comprehensive Guide to Toxicology in Nonclinical Drug Development, 2nd Edition, Elsevier.

2McCormick DL, 2017. Two-year oncogenicity evaluations of cell phone radiofrequency radiation in Sprague-Dawley rats and B6C3F1 mice. Proc. Eurotox., 2017.

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