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. 1982 Mar;45(3):337–351. doi: 10.1038/bjc.1982.60

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

N J Severs, S H Barnes, R Wright, R M Hicks
PMCID: PMC2010936  PMID: 7073931

Abstract

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 does suitable for use of 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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ANDERVONT H. B., EDGCOMB J. H. Responses of seven inbred strains of mice to percutaneous applications of 3-methylcholanthrene. J Natl Cancer Inst. 1956 Oct;17(4):481–495. [PubMed] [Google Scholar]
  2. Chapman W. H., Kirchheim D., McRoberts J. W. Effect of the urine and calculus formation on the incidence of bladder tumors in rats implanted with paraffin wax pellets. Cancer Res. 1973 Jun;33(6):1225–1229. [PubMed] [Google Scholar]
  3. Chowaniec J., Hicks R. M. Response of the rat to saccharin with particular reference to the urinary bladder. Br J Cancer. 1979 Apr;39(4):355–375. doi: 10.1038/bjc.1979.68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clayson D. B. Editorial: Bladder carcinogenesis in rats and mice: possibility of artifacts. J Natl Cancer Inst. 1974 Jun;52(6):1685–1689. doi: 10.1093/jnci/52.6.1685. [DOI] [PubMed] [Google Scholar]
  5. Cohen S. M., Arai M., Jacobs J. B., Friedell G. H. Promoting effect of saccharin and DL-tryptophan in urinary bladder carcinogenesis. Cancer Res. 1979 Apr;39(4):1207–1217. [PubMed] [Google Scholar]
  6. Cox R., Irving C. C. Effect of N-methyl-N-nitrosourea on the DNA of rat bladder epithelium. Cancer Res. 1976 Nov;36(11 Pt 1):4114–4118. [PubMed] [Google Scholar]
  7. Festing M. F. A case for using inbred strains of labroatory animals in evaluating the safety of drugs. Food Cosmet Toxicol. 1975 Jun;13(3):369–375. doi: 10.1016/s0015-6264(75)80302-6. [DOI] [PubMed] [Google Scholar]
  8. Frei J. V., Lawley P. D. Methylation of DNA in various organs of C57B1 mice by a carcinogenic dose of N-methyl-N-nitrosourea and stabiltty of some methylation products up to 18 hours. Chem Biol Interact. 1975 Jun;10(6):413–427. doi: 10.1016/0009-2797(75)90072-1. [DOI] [PubMed] [Google Scholar]
  9. Fukushima S., Cohen S. M., Arai M., Jacobs J. B., Friedell G. H. Scanning electron microscopic examination of reversible hyperplasia of the rat urinary bladder. Am J Pathol. 1981 Mar;102(3):373–380. [PMC free article] [PubMed] [Google Scholar]
  10. Hicks R. M., Chowaniec J. Experimental induction, histology, and ultrastructure of hyperplasia and neoplasia of the urinary bladder epithelium. Int Rev Exp Pathol. 1978;18:199–280. [PubMed] [Google Scholar]
  11. Hicks R. M., Chowaniec J. The importance of synergy between weak carcinogens in the induction of bladder cancer in experimental animals and humans. Cancer Res. 1977 Aug;37(8 Pt 2):2943–2949. [PubMed] [Google Scholar]
  12. Hicks R. M. Multistage carcinogenesis in the urinary bladder. Br Med Bull. 1980 Jan;36(1):39–46. doi: 10.1093/oxfordjournals.bmb.a071611. [DOI] [PubMed] [Google Scholar]
  13. Hicks R. M., Wakefield J. J. Membrane changes during urothelial hyperplasia and neoplasia. Cancer Res. 1976 Jul;36(7 Pt 2):2502–2507. [PubMed] [Google Scholar]
  14. Hicks R. M., Wakefield J. S. Rapid induction of bladder cancer in rats with N-methyl-N-nitrosourea. I. Histology. Chem Biol Interact. 1972 Jul;5(2):139–152. doi: 10.1016/0009-2797(72)90040-3. [DOI] [PubMed] [Google Scholar]
  15. Hicks R. M., Wakefield J., Chowaniec J. Evaluation of a new model to detect bladder carcinogens or co-carcinogens; results obtained with saccharin, cyclamate and cyclophosphamide. Chem Biol Interact. 1975 Sep;11(3):225–233. doi: 10.1016/0009-2797(75)90101-5. [DOI] [PubMed] [Google Scholar]
  16. Hooson J., Hicks R. M., Grasso P., Chowaniec J. Ortho-toluene sulphonamide and saccharin in the promotion of bladder cancer in the rat. Br J Cancer. 1980 Jul;42(1):129–147. doi: 10.1038/bjc.1980.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jacobs J. B., Arai M., Cohen S. M., Friedell G. H. A long-term study of reversible and progressive urinary bladder cancer lesions in rats fed N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide. Cancer Res. 1977 Aug;37(8 Pt 2):2817–2821. [PubMed] [Google Scholar]
  18. Koss L. G., Lavin P. Effects of a single dose of cyclophosphamide on various organs in the rat. II. Response of urinary bladder epithelium according to strain and sex. J Natl Cancer Inst. 1970 May;44(5):1195–1200. [PubMed] [Google Scholar]
  19. Kunze E., Schauer A., Schatt S. Stages of transformation in the development of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced transitional cell carcinomas in the urinary bladder of rats. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol. 1976;87(2):139–160. doi: 10.1007/BF00284372. [DOI] [PubMed] [Google Scholar]
  20. Newman J., Hicks R. M. Detection of neoplastic and preneoplastic urothelia by combined scanning and transmission electron microscopy of urinary surface of human and rat bladders. Histopathology. 1977 Mar;1(2):125–135. doi: 10.1111/j.1365-2559.1977.tb01651.x. [DOI] [PubMed] [Google Scholar]
  21. Pamukcu A. M., Ertürk E., Yalçiner S., Bryan G. T. Histogenesis of urinary bladder cancer induced in rats by bracken fern. Invest Urol. 1976 Nov;14(3):213–218. [PubMed] [Google Scholar]
  22. Peraino C., Fry R. J., Staffeldt E., Kisieleski W. E. Effects of varying the exposure to phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Cancer Res. 1973 Nov;33(11):2701–2705. [PubMed] [Google Scholar]
  23. Shirai T., Cohen S. M., Fukushima S., Hananouchi M., Ito N. Reversible papillary hyperplasia of the rat urinary bladder. Am J Pathol. 1978 Apr;91(1):33–48. [PMC free article] [PubMed] [Google Scholar]
  24. Swann P. F. The rate of breakdown of methyl methanesulphonate, dimethyl sulphate and N-methyl-N-nitrosourea in the rat. Biochem J. 1968 Nov;110(1):49–52. doi: 10.1042/bj1100049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tiltman A. J., Friedell G. H. The histogenesis of experimental bladder cancer. Invest Urol. 1971 Nov;9(3):218–226. [PubMed] [Google Scholar]

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