ToxSci Advance Access originally published online on September 8, 2005
Toxicological Sciences 2005 88(2):340-345; doi:10.1093/toxsci/kfi313
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Azoxymethane Is a Genetic Background-Dependent Colorectal Tumor Initiator and Promoter in Mice: Effects of Dose, Route, and Diet
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* Curriculum in Toxicology, Department of Genetics, Department of Cell Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599; and ¶ Center for Environmental Health and Susceptibility and the Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599
Received July 21, 2005; accepted August 31, 2005
The azoxymethane (AOM) model has been widely used to investigate the pathology and genetics of colorectal cancer in rodents. However, there has been wide variation in treatment regimes, making it difficult to compare across studies. Consequently, standardizing AOM treatment and identifying sources of experimental variation would allow better comparisons across studies. In order to establish an optimal dosing regime for detecting experiment-dependent differences in tumorigenesis, we performed a dose curve analysis using AKR/J, SWR/J, and A/J mouse strains previously reported to vary widely in susceptibility to AOM. Although intraperitoneal or subcutaneous administration, but not in utero exposure, resulted in similar levels of tumor induction, significant dose- and strain-dependent effects of AOM were observed. No sex-dependent differences were observed. Increasing the number of treatments uncovered a significant strain-dependent effect on tumor promotion, independent of susceptibility to tumor initiation. Similarly, we used C57BL/6J and DBA/2J intercrosses to demonstrate that small diet modifications can significantly alter AOM-induced tumorigenesis in a background-dependent manner. These results provide experimental support for a standardized AOM treatment and for the importance of controlling both genetic and non-genetic factors when using this model.
Key Words: azoxymethane; dose curve; colorectal tumorigenesis; genetic susceptibility.
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