Alterations of Cell Cycle Regulators in Rat and Mouse Urinary Bladder Carcinogenesis Models.

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Both genotoxic and non-genotoxic carcinogens may cause changes in cell cycle regulatory mechanisms. One of the most frequent genetic alterations observed in human malignancies, including urinary bladder carcinomas, involves the p53 tumor suppressor gene. The H- and K-ras oncogenes also appear to be prime targets in man and experimental animals. In rat urinay bladder carcinogenesis models using N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), most transitional cell car-cinomas (TCCs) produced are of papillary type and invasion is rare. While p53 mutations are relatively frequent in animals continuously exposed to BBN, they are less common when tumors are generated by protocols with a no-treatment interval before terminal sacrifice. The ras gene alterations do not vary under these conditions. In two-stage (initiation-promotion) rat models, p53 mutations are rare but cyclin D1 overexpression is frequently observed in TCCs. No mutations are generally found in rat tumors due to the non-genotoxic carcinogen, uracil. In contrast to rat tumors, mouse urinary bladder tumors induced by BBN aggressively invade and demonstrate occasionally metastasis. In one series, p53 mutations were found in 14 of 18 invasive tumors. Moreover, urinary bladder carcinomas with metastasis harbored more frequent alterations. Loss of heterozygosity of the p53 gene was also evident in about 14% of such carcinomas. In conclusion, genetic alterations differ according to the experimental protocol, the species, and the type of carcinogen used.