A transgenic mouse has emerged as an alternative animal model of choice in carcinogenicity testing
For over 30 years, drug developers were required to run two-year studies on mice in order to determine whether their compounds could potentially cause cancer. These trials were expensive, needed many animals, and delayed the development of potentially life-changing drugs. Charles River pathologist Madhav Paranjpe has been working with the alternative Tg.rasH2 mouse model for 15 years.
“Tg.rasH2 mice were developed at the Central Institute for Experimental Animals (CIEA) in Japan,” he said. “The Tg.rasH2 mouse is a hemizygous transgenic mouse carrying multiple copies of human c-Ha-ras gene with its own promoter and enhancer.”
The human c-Ha-ras gene is an oncogene, or a gene that is known to potentially cause cancer. That means that the Tg.rasH2 mouse, which has multiple oncogene copies and enhancers to that gene, is therefore especially sensitive to cancerous substances.
After the development of the Tg.rasH2 mouse at CIEA, the International Life Sciences Institute (ILSI) and their Health and Environmental Sciences Institute (HESI) conducted the first research project on the mouse in the late 1990s.
“Under the ILSI HESI project, 26-week carcinogenicity studies in Tg.rasH2 mice were conducted for 21 compounds at different facilities in the United States, Japan, and Europe,” said Paranjpe. “Since then the use of Tg.rasH2 mice began steadily and it has really taken off.”
Currently 75 percent of carcinogenicity studies now use these mice. Only 25 Tg.rasH2 mice per group are needed in their studies, as opposed to at least 50 conventional mice per group on a standard 2 year carcinogenicity study. The mice respond more quickly to carcinogens, so the tests only take six months as opposed to two years.
The improved research model uses fewer animals, fewer resources, and takes less time than traditional models, conforming nicely to two of Russell and Burch’s Three R’s for ethical animal research (Replacement, Reduction and Refinement). Paranjpe says that the Tg.rasH2 mice even experience lower mortality and lower incidence of spontaneous tumors, improving the outcome for both the mice and the drug developers.
There is always room for more research, regardless of the obvious benefits of Tg.rasH2 mice. In the next few years, Paranjpe and his colleagues plan to collect and compile additional data and presenting their findings at conferences and in journals.
Paranjpe’s work on the mice was acknowledged in 2016 by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), a nonprofit devoted to the humane treatment of lab animals. They presented him with the Global 3R’s award for North America for his research on Tg.rasH2 mice, which involved a thorough review of 29 carcinogenicity studies performed with the mice. His research concluded that fewer mice were needed in future studies, reducing the number of required animals by 25 percent, and increasing the reliability and human applicability of study results.
Charles River has commenced more than 60 studies in this model since 2013 to support transgenic rasH2 mouse models as an alternative to the full 2-year carcinogenicity study design.