The induction of urothelial hyperplasia by methyl methanesulphonate and ethyl methanesulphonate

Abstract

Summary The early and late morphological changes induced in rat bladder urothelium by intravesicular administration of the alkylating agents methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) are described. In the short-term, both compounds produced dose-related toxic damage followed by a regenerative hyperplasia of the urothelium. 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). Intravesicular instillation of two other alkylating agents, viz. methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) in the short-term produced toxic damage followed by urothelial hyperplasia (Wakefield & Hicks, 1974

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

“…One was a large exophytic papillary tumour very comparable to that illustrated previously in an MMS-treated animal (Tudor et al, 1983). It had early invasion of the underlying lamina propria (Plb) and a small area of squamous metaplasia.…”

“…I and II. The criteria used in the diagnosis of urothelial lesions are those currently in use in this laboratory and have been published previously Tudor et al, 1983 Group C. MMS alone In animals that received six doses of MMS, urothelial hyperplasias were also numerous, affecting 68% of the animals (Table I). Although most were mild and focal, moderate simple hyperplasia was present in five animals.…”

“…In addition, subsequent treatment with MMS reduced the time to detection of the first MNU-induced bladder tumour by 15 weeks, and the mean latent period by 10 weeks (Table II). 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).…”

“…Recently, we showed that over longer periods, multiple doses of MMS induce a milder but more persistent urothelial hyperplasia with little or no dysplasia (Tudor et al, 1983). In addition, fotur well-differentiated lesions with abnormal growth patterns were observed (either papillary/nodular hyperplasia or papillary carcinoma), but their occurrence was not doserelated.…”

“…The alkylating agent, methyl methanesulphonate (MMS) is cytotoxic and produces regenerative urothelial hyperplasia when instilled directly into the rat bladder (Wakefield & Hicks, 1974;Tudor et al, 1983). Recently, we showed that over longer periods, multiple doses of MMS induce a milder but more persistent urothelial hyperplasia with little or no dysplasia (Tudor et al, 1983).…”