Evaluation of a new model to detect bladder carcinogens or co-carcinogens; results obtained with saccharin, cyclamate and cyclophosphamide

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.

Section: The Intravesicular Instillation Ofmentioning

confidence: 99%

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

Severs¹,

Barnes²,

Wright³

et al. 1982

“…Because they have the ability to increase tumour yield above that produced by a low dose of carcinogen alone, they have been regarded as promoters, but the data supporting the possibility that they have stage 1 promoting activity is not conclusive (Hicks, 1983b). With one exception (Hicks et al, 1975), the carcinogen in these studies was not used at a subthreshold or initiating dose, but at a level sufficient to produce a few neoplasms on its own. Furthermore, there is no biochemical evidence that these agents activate protein kinase C to catalyse stage 1 promoting events in the bladder analogous to those produced, for example, by TPA in the skin.…”

Section: Pathology Of Other Organsmentioning

confidence: 99%

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

Tudor¹,

Severs²,

Hicks³

1984

Summary The carcinogenic activity of the alkylating agent methyl methanesulphonate (MMS) was investigated in the F344 rat bladder, both untreated and pretreated with a single threshold dose of N-methyl-N-nitrosourea (MNU). On its own, 6 doses of 2.5mg MMS produced a 7% incidence of bladder cancer. After a single intravesical instillation of MNU, the same MMS treatment produced a bladder cancer incidence of 56%. This was significantly higher than the incidence (24%) observed after treatment with MNU alone, and greater than the sum of the lesions produced by either treatment alone. By reference to the mouse skin multistage carcinogenesis model, it is argued that MMS is a complete, albeit weak carcinogen with little initiating but powerful late-stage activity. Its promoting activity is most probably attributable to its potent mitogenic action and in this model it is analogous to a stage 2, rather than a stage 1 skin promoter.

“…However, neoplasms were first detected in the saccharin-treated groups (B and D) and the mean latent period was also shorter in these groups (Table XI). (Hicks et al, 1973a(Hicks et al, , 1975 or a threshold dose of FANFT (Cohen et al, 1979) produced a high incidence of tumours of the urinary bladder.…”

Section: Urine Studies and Kidney Weightsmentioning

confidence: 99%

“…In the present experiments, it had been intended to use a non-carcinogenic dose of MNU also, but in practice the dose administered, although the same as had been used in earlier studies (Hicks et al, 1975) produced bladder neoplasms in 27% of rats in Exp. 1, and 38% in Exp.…”

Section: Urine Studies and Kidney Weightsmentioning

confidence: 99%

“…50% in the diet (Taylor & Friedman, 1974;Tisdel et al, 1974;Arnold et al, 1977b). Furthermore, the administration of saccharin either in the drinking water (2 g/kg/day) or diet (4 g/kg/day) to rats previously given a single sub-carcinogenic dose of N-methyl-N-nitrosourea (MNU) produced a high incidence of bladder tumours (Hicks et al, 1973a(Hicks et al, , 1975(Hicks et al, , 1978Hicks & Chowaniec, 1977;Hicks et al, 1978). These findings suggested that saccharin could promote carcinogenesis initiated by MNU, and recent work by Cohen et al (1979) confirmed a promoting effect of saccharin on bladder neoplasia after a threshold dose of N(4-(5-nitro-2-furyl)-2-thiazolyl) formamide (FANFT).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Ortho-toluene sulphonamide and saccharin in the promotion of bladder cancer in the rat

Hooson¹,

Hicks²,

Grasso³

et al. 1980

Summary.-The importance of the contaminant OTS in the promoting activity of commercial saccharin on rat bladder neoplasia was investigated. OTS, OTS-free and OTS-contaminated saccharin were administered in the drinking water or diet for 2 years to groups of rats pretreated with an intravesical instillation of MNU; OTS alone and OTS-free saccharin were also given to groups of rats not pretreated with MNU.Administration of OTS was not associated with changes in urinary pH, crystalluria or calculus formation, had no effect on the histology of normal rat bladder, and did not increase the incidence of bladder hyperplasia or neoplasia elicited by pretreatment with MNU. No differences could be found between the effect of OTS-free or OTS-contaminated saccharin on bladders of rats pretreated with MNU. These results indicate that OTS contamination played no part in the reported promoting activity of saccharin on the rat bladder.Administration of saccharin did not increase urinary pH, crystalluria or calculus formation, and failed to promote bladder neoplasia after a carcinogenic dose of MNU, though the numbers of proliferative lesions in the bladder were increased.