Virchows Archiv B

, 27:119 | Cite as

Cell kinetics of mouse urinary bladder epithelium

VII. Changes in proliferation and nuclear DNA content after repeated doses of dibutylnitrosamine
  • Tore Farsund
  • Olav Hilmar Iversen


The effect of repeated subcutaneous injections of 0.01 ml of the bladder carcinogen dibutylnitrosamine dissolved in 0.2 ml propylene glycol on the cell kinetics of the mouse (hr/hr strain) urinary bladder epithelium was studied by several methods in two groups of animals. Group 1 received injections three times a week and were followed up for three months; Group 2 received injections once a week and were followed up for six months, when several bladder carcinomas had occurred. In the first group there was a high mortality, but in the second there was none. In both experimental groups DNA synthesis in tetraploid cells was inhibited from an early stage, and thereafter first the octoploid and finally the tetraploid cells disappeared. In the diploid cells, however, the LI and the proportion of cells in S phase increased and there was a high mean grain count and a high mitotic rate. Thus, repeated injections of dibutylnitrosamine led to a hyperplasia of the diploid cells due to both a high rate of diploid cell proliferation and a block in the mechanism of repeated DNA synthesis. Finally, in Group 2 malignant transformation occurred after five to six months’ treatment. When compared with previously published results, these findings show that the kinetic disturbances in urothelial cell turnover induced by repeated injections of dibutylnitrosamine are qulitatively similar to, but quantitatively far more pronounced than those provoked by repeated injections of cyclophosphamide or propylene glycol. Thus, no qualitative change specific for the carcinogen was observed, but it cannot be excluded that the early and strong effect of the bladder carcinogen on the urothelial cell DNA is in some way related to its carcinogenic potency. The results support the theory that the diploid basal cells in the bladder mucosa are the target cells for the specific effect of the carcinogen, and that tumor cell aneuploidy is different from the normal polyploidy in urothelium.

Key words

Bladder mucosa Carcinogenesis Dibutylnitrosamine Polyploidy Repeated DNA synthesis Urothelium 


  1. Althoff, J., Krüger, F.W., Mohr, U., Schmähl, D.: Dibutylnitrosamine carcinogenesis in Syrian Golden and Chinese hamsters. Proc. Soc. Exp. Biol. Med.136, 168–173 (1971)PubMedGoogle Scholar
  2. Althoff, J., Mohr, U., Page, N., Reznik, G.: Carcinogenic effect of dibutylnitrosamine in European hamsters (Cricetus cricetus). J. Natl. Cancer Inst.53, 795–800 (1974)PubMedGoogle Scholar
  3. Bergkvist, A., Ljungqvist, A., Moberger, G.: Classification of bladder tumours based on the cellular pattern: Preliminary report of a clinical-pathological study of 300 cases with a minimum follow up of eight years. Acta Chir. Scand.130, 371–378 (1965)PubMedGoogle Scholar
  4. Bertram, J.S., Craig, A.W.: Induction of bladder tumours in mice with dibutylnitrosamine. Br. J. Cancer24, 352–359 (1970)PubMedGoogle Scholar
  5. Clayson, D.B., Cooper, E.G.: The immediate response of bladder epithelium to injury by chemical carcinogens. Br. J. Urol.41, 710–713 (1969)PubMedCrossRefGoogle Scholar
  6. Cooper, E.G.: Biologie cellulaire du cancer de la vessie. Rev. Franc. Étud. Clin. Biol.14, 806–814 (1969)PubMedGoogle Scholar
  7. Cooper, E.H., Levi, P.E., Anderson, C.K., Williams, R.E.: The evolution of tumour cell populations in human cancer. Br. J. Urol.41, 714–717 (1969)PubMedGoogle Scholar
  8. Druckrey, H., Preussmann, R., Ivankovic, S., Schmidt, C.H., Mennel, H.D., Stahl, K.W.: Selektive Erzeugung von Blasenkrebs an Ratten durch Dibutyl- und N-Butyl-N-butanol(4)-nitrosamin. Z. Krebsforsch.66, 280–290 (1964)PubMedCrossRefGoogle Scholar
  9. Druckrey, H., Preussmann, R., Ivankovic, S., Schmähl, D.: Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z. Krebsforsch.69, 103–201 (1967)PubMedCrossRefGoogle Scholar
  10. Farsund, T.: Preparation of bladder mucosa cells for micro-flow fluorometry. Virchows Arch. B Cell Path.16, 35–42 (1974)Google Scholar
  11. Farsund, T.: Cell kinetics of mouse urinary bladder epithelium. I. Circadian and age variations in cell proliferation and nuclear DNA content. Virchows Arch. B Cell Path.18, 35–49 (1975)Google Scholar
  12. Farsund, T.: Cell kinetics of mouse urinary bladder epithelium. II. Changes in proliferation and nuclear DNA content during necrosis, regeneration, and hyperplasia caused by a single dose of cyclophosphamide. Virchows Arch. B Cell Path.21, 279–298 (1976)Google Scholar
  13. Farsund, T.: Cell kinetics of mouse urinary bladder epithelium. IV. Changes in cell proliferation, nuclear DNA content, and number of diploid, tetraploid and octoploid cells after a single dose of dibutylnitrosamine. Virchows Arch. B Cell Path.25, 179–189 (1977)Google Scholar
  14. Farsund, T.: Cell kinetics of mouse urinary bladder epithelium. V. Changes in the proportion of cells with various nuclear DNA content after repeated doses of cyclophosphamide. Virchows Arch. B Cell Path. (1978a) (in press)Google Scholar
  15. Farsund, T.: Cell kinetics of mouse urinary bladder epithelium. VI. Changes in the proportion of cells with various nuclear DNA content after repeated doses of propylene glycol (1,2 propanediol). Virchows Arch. B Cell Path. (1978 b) (in press)Google Scholar
  16. Fosså, S.D.: Feulgen-DNA-values in transitional cell carcinoma of the human urinary bladder. Beitr. Pathol.155, 44–55 (1975)PubMedGoogle Scholar
  17. Ivankovic, S., Bücheier, J.: Leber- und Blasen-Carcinome beim Meerschweinchen nach Di-n-butylnitrosamin. Z. Krebsforsch.71, 183–185 (1968)PubMedCrossRefGoogle Scholar
  18. Levi, P.E., Cooper, E.H., Anderson, C.K., Path, M.C., Williams, R.E.: Analyses of DNA content, nuclear size and cell proliferation of transitional cell carcinoma in man. Cancer23, 1074–1085 (1969)PubMedCrossRefGoogle Scholar
  19. Mohr, U., Althoff, J., Schmähl, D., Krüger, F.W.: The carcinogenic effect of dibutylnitrosamine in Syrian and Chinese hamsters. Z. Krebsforsch.74, 112–113 (1970)PubMedCrossRefGoogle Scholar
  20. Wakefield, J.St. J., Hicks, R.M.: Pre-neoplastic changes in bladder epithelial cells of rats treated with dibutylnitrosamine. J. Pathol.103, XII-XIV (1971)Google Scholar
  21. Walker, B.E.: Polyploidy and differentiation in the transitional epithelium of mouse urinary bladder. Chromosoma9, 105–118 (1958)PubMedCrossRefGoogle Scholar
  22. Wood, M., Flaks, A., Clayson, D.B.: The carcinogenic activity of dibutylnitrosamine in IF × C57 mice. Eur. J. Cancer6, 433–440 (1970)PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • Tore Farsund
    • 1
  • Olav Hilmar Iversen
    • 1
  1. 1.Institute of PathologyUniversity of Oslo RikshospitaletOslo 1Norway

Personalised recommendations