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

Abstract

Summary.-Experiments were conducted to determine the dose response of rat bladder urothelium to a range of different single and fractionated intravesicular doses of the carcinogen, N-methyl-N-nitrosourea (MNU). A dose-related response of bladder-tumour incidence to single graded doses of MNU was found, and a threshold dose suitable for use in multistage carcinogenesis experiments was derived from these data. For any given total dose of MNU, the tumour incidence was greater if the MNU had been administered in several small fractions than if it had been administered in fewer larger ones. Extending the interval between doses did not reduce the tumour incidence. It is argued that these results support the multistage theory of carcinogenesis. The histopathology and cell-surface alterations which characterize the development of MNU-induced bladder cancer are described and the contribution of hyperplasia and calculi are discussed.

The “promoting” activity of methyl methanesulphonate in rat bladder carcinogenesis

“…The increased tumour incidence, reduced induction time and potent hyperplastic activity of MSS (Tudor et al, 1983) are all characteristic of the action of skin promoters (Boutwell et al, 1982) and in an operational sense, MMS clearly acts as a promoter of carcinogenesis in the rat urinary bladder. In the present experiment, however, as in many other bladder promotion studies (see Hicks, 1983b) (Severs et al, 1982 (Bralow et al, 1973;Martin et al, 1974).…”

“…Wallis in the Courtauld Institute of Biochemistry, Middlesex Hospital Medical School, by the method of Werner (1919). Its purity was checked by melting-point determination and high pressure liquid chromatography as detailed previously (Severs et al, 1982). MMS was obtained from Cambrian Chemicals Ltd., Croydon, Surrey and used as supplied.…”

Urinary System

“…It induces hyperplastic lesions and tumors after a single intravesical pulse dose (5mg/kg body weight) or several fractionated lower doses Hicks 1980;Hooson et al 1980;Severs et al 1982;Kunze and Gassner 1986;Kunze et al 1989). It induces hyperplastic lesions and tumors after a single intravesical pulse dose (5mg/kg body weight) or several fractionated lower doses Hicks 1980;Hooson et al 1980;Severs et al 1982;Kunze and Gassner 1986;Kunze et al 1989).…”

The induction of urothelial hyperplasia by methyl methanesulphonate and ethyl methanesulphonate

“…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). Intravesicular instillation of two other alkylating agents, viz.…”

“…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). Intravesicular instillation of two other alkylating agents, viz.…”