Rapid induction of bladder cancer in rats with N-methyl-N-nitrosourea I. Histology

Induction of bladder cancer in rats by fractionated intravesicular doses of N-methyl-N-nitrosourea

“…It had been obtained from the Schuchardt Chemical Company and was recrystallized at the MRC Toxicology Institute, Carshalton, to give a yellow crystalline preparation with a melting point of 122-124°C. This sample gave consistent results, such that a single dose of < 2 mg produced no urothelial tumours, a single dose of > 3 mg was lethal, but 6 mg administered in 4 fractions of 1P5 mg at 2-weekly intervals produced a 100% incidence of bladder cancer (Hicks & Wakefield, 1972). Since the first fraction of 1P5 mg was itself sub-carcinogenic, in subsequent studies into the multistage nature of carcinogenesis in the urinary bladder this dose was used to initiate the urothelium before studying the effect of other promoting agents (Hicks et al, 1975Hicks & Chowaniec, 1977;Hicks, 1980).…”

“…fractionated doses of N-methyl-N-nitrosourea (MNU) to induce rat bladder cancer (Hicks & Wakefield, 1972) was developed to provide a more controllable animal bladder-cancer model than those which were then available, using carcinogens in the diet or drinking water. MNU is a direct-acting carcinogen which does not need to be metabolized to an active intermediate, and produces persistent, multiple methylation of the DNA in tissues with which it comes in contact (Frei & Lawley, 1975;Cox & Irving, 1976).…”

“…The early hyperplasia (i.e. at 2 days to 3 weeks) after a single dose of MNU or a single dose of cyclophosphamide rapidly regresses, and normal differentiation is subsequently restored (Hicks & Wakefield, 1972;Koss & Lavin, 1970). Although a few of the hyperplasias present at the end of the current experiments could possibly have arisen as a late temporary response (e.g.…”

The induction of urothelial hyperplasia by methyl methanesulphonate and ethyl methanesulphonate

“…At any given dose-level, the effects of MMS were more severe than those of EMS. Previous experiments in this laboratory established that the alkylating agent N-methyl-N-nitrosourea (MNU) is both a powerful hyperplastic agent and a bladder carcinogen when administered by intravesicular instillation (Hicks and Wakefield, 1972). This finding has provided a useful model system in which the mechanisms of carcinogenesis and the effects of modulators can be explored (Hicks, 1980;Hicks et al,1975Hicks et al, , 1978Severs et al, 1982).…”

High susceptibility of analbuminaemic rats to induced bladder cancer

“…The mean daily intakes of BBN by analbuminaemic and SD rats are given in the The mechanism by which BBN caused this high incidence of bladder cancer in analbuminaemic rats is not known. Investigations are continuing to examine this phenomenon in terms of BBN metabolism, lipid metabolism, susceptibility of bladder mucosa to other bladder carcinogens such as N-methyl-N-nitrosourea (Hicks et al, 1972) and N-[4-(5 -nitro -2 -furyl) -2-thiazolyl]formamide (Erturk et al, 1969).…”