High frequency, single-dose model of renal adenoma/carcinoma induction using dimethylnitrosamine in Crl:(W)BR rats

Following discovery that the type of kidney neoplasm induced in protein-deprived Wistar rats by a single dose of dimethylnitrosamine (DMN) was age-dependent, this study aimed to refine the system in order to develop a high frequency model for the induction of cortical epithelial tumors with low mesenchymal tumor incidence. Using outbred female Crl:(W)BR (Charles River Wistar) rats, DMN at a dose of 30 mg/kg was administered at 9-10 weeks of age following a 5-day period of high-carbohydrate/no-protein diet. From a total of 49 rats, 43 survived the early toxicity and 91% of these developed renal tumors. Mesenchymal tumors were present in only 9% of the tumor-bearing animals. In contrast, 70% of the rats developed epithelial tumors of the tubules classifiable on a size and histological basis as adenocarcinomas/carcinomas in response to DMN. A further 21% of rats had smaller proliferative lesions designated as adenomas, making the total cortical epithelial tumor incidence in excess of 90%. The malignant potential of the epithelial tumors was underscored by the presence of metastatic invasion, mainly involving the lungs, in 15% of the tumor-bearing rats. Metastatic behavior correlated with progressive growth of the carcinomas over a period of time exceeding 1.5 years to dimensions usually exceeding 2.9 cm diameter. Of the tumors approaching or exceeding this size, the metastatic rate was almost 50%. Thus, the administration of DMN to 65-70 days old, protein-deprived Wistar rats provides a potent, single dose model for the study of renal epithelial carcinogenesis with insignificant mesenchymal tumor induction and without the continuing toxicity which perturbs regimens based on repeated or continuous exposures.