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Carcinogenicity

The toxicology, pathology and risk assessment communities have been utilizing in vitro assays in combination with in vivo rodent models for the evaluation of the carcinogenic potential of chemicals for many years. The 2-year chronic bioassay has been in place for over 3 decades and until recently, there have only been minor modifications or additions proposed.

In recent years, alternative models such as transgenic and knockout assays have demonstrated a number of potential advantages and are being utilized as an alternative to the traditional, 2-year chronic bioassays performed in mice.

Realizing the importance of these studies, SNBL USA has invested the time and resources to develop a carcinogenicity program that offers the 2-year chronic bioassays as well as alternative transgenic and knockout models for assessing the potential carcinogenicity of pharmaceuticals.

Currently, SNBL USA features two genetically-altered mouse models:

• The p53+/- heterozygous knockout mouse retains a single copy of the Trp53 gene. The Trp53 gene encodes a tumor suppressor protein (p53) that maintains normal cellular function, arresting the cell cycle and promoting controlled cell death. Mutations in the single Trp53 gene may result in uncontrolled cell proliferation whereby there is an increased susceptibility to tumors.



• The rasH2 hemizygous mouse carries the human c-Ha-ras and endogenous murine oncogenes. Mutation in any of the c-Ha-ras genes can make the RAS proteins independently active, resulting in uncontrollable, active transcription and S-phase entry.