Advertisement

Cell Growth Dynamics and DNA Alterations in Carcinogenesis

  • Samuel M. Cohen
  • Leon B. Ellwein

Abstract

A biological model of carcinogenesis has been developed based on a two event process. The frequency of each event is dependent on the number of target cells, the frequency of their cell division, and the probability of a critical genomic error occurring with each cell division. A chemical can increase the likelihood of cancer by affecting either the rate of genomic errors (genotoxicity) or the rate of cell division, or both. Using these parameters a more rationale approach to quantitative risk assessment is proposed. Three chemicals are presented as examples of how genotoxic effects (2-acetylaminofluorene in the mouse liver, the “megamouse,” ED01 study) and proliferative effects (sodium saccharin) influence carcinogenesis and how genotoxic and proliferation effects can interact (2-acetylaminof luorene in the mouse bladder and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide in the rat bladder). The influence of pharmacokinetics, metabolism, physiology, and cell kinetics on the carcinogenicity of specific compounds is illustrated, demonstrating the importance of mechanistic information in assessing potential risk.

Keywords

Urinary Bladder Bladder Tumor Genotoxic Effect Increase Cell Proliferation Cancer Risk Assessment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Beland, F.A. Metabolie activation of aromatic amine carcinogens in vitro and in vivo, J. Univ. Occupât. Environ. Hlth., in press.Google Scholar
  2. 2.
    Beland, F.A., Fullerton, N.F., Kinouchi, T., and Poirier, M.C. DNA adduet formation during continuous feeding of 2-acetylaminofluorene at multiple concentrations. In: Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention, H. Bartsch, K. Hemminki and I.K. O’Neill, Eds., IARC, Lyon, pp. 175–180, 1988.Google Scholar
  3. 3.
    Cohen, S.M., Arai, M., Jacobs, J.B., and Friedell, G.H. Promoting effect of saccharin and DL-tryptophan in urinary bladder carcinogenesis. Cancer Res. 39: 1207–1217, 1979.Google Scholar
  4. 4.
    Cohen, S.M., Cano, M., Garland, E.M., and Earl, R.A. Silicate crystals in the urine and bladder epithelium of male rats fed sodium saccharin. Proc. Am. Assoc. Cancer Res. 30: 205, 1989.Google Scholar
  5. 5.
    Cohen, S.M., and Ellwein, L.B. Cell growth dynamics in long-term bladder carcinogenesis. Toxicol. Lett. 43: 151–173, 1988.CrossRefGoogle Scholar
  6. 6.
    Cohen, S.M., Jacobs, J.B., Arai, M., Johansson, S., and Friedell, G.H. Early lesions in experimental bladder cancer: Experimental design and light microscopic findings. Cancer Res. 36: 2508–2511, 1976.Google Scholar
  7. 7.
    Cohen, S.M., Murasaki, G., Fukushima, S., and Greenfield, R.E. Effect of regenerative hyperplasia on the urinary bladder:Carcinogenicity of sodium saccharin and N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide. Cancer Res. 42: 65–71, 1982.Google Scholar
  8. 8.
    Ellwein, L.B., and Cohen, S.M. A cellular dynamics model of experimental bladder cancer: Analysis of the effect of sodium saccharin in the rat. Risk Analysis 8: 215–221, 1988.CrossRefGoogle Scholar
  9. 9.
    Ellwein, L.B., and Cohen, S.M. Comparative analyses of the timing and magnitude of genotoxic and nongenotoxic cellular effects in urinary bladder carcinogenesis. In: Biologically-Based Methods for Cancer Risk Assessment, C.C. Travis, Ed., Plenum Publ. Corp, pp. 181–192, 1989.Google Scholar
  10. 10.
    Ellwein, L.B., and Cohen, S.M. The health risks of saccharin revisited. In: CRC Reviews in Toxicology, in press.Google Scholar
  11. 11.
    Fukushima, S., and Cohen, S.M. Saccharin-induced hyperplasia of the rat urinary bladder. Cancer Res. 40: 734–736, 1980.Google Scholar
  12. 12.
    Greenfield, R.E., Ellwein, L.B., and Cohen, S.M. A general probabilistic model of carcinogenesis: Analysis of experimental urinary bladder cancer. Carcinogenesis 5: 437–445, 1984.CrossRefGoogle Scholar
  13. 13.
    Hasegawa, R., and Cohen, S.M. The effect of different salts of saccharin on the rat urinary bladder. Cancer Lett. 30: 261–268, 1986.CrossRefGoogle Scholar
  14. 14.
    Hasegawa, R., Cohen, S.M., St. John, M., Cano, M., and Ellwein, L.B. Effect of dose on the induction of urothelial proliferation by N-[4-(5-nitro-2-furyl) -2-thiazolyl]formamide and its relationship to bladder carcinogenesis in the rat. Carcinogenesis 7: 633–636, 1986.CrossRefGoogle Scholar
  15. 15.
    Huitfeldt, H.S., Hunt, J.M., Pitot, H.C., and Poirier, M.C. Lack of acetylaminofluorene-DNA adduct formation in enzyme-altered foci of rat liver. Carcinogenesis 9: 647–652, 1988.CrossRefGoogle Scholar
  16. 16.
    Jacobs, J.B., Arai, M., Cohen, S.M., and Friedeil, 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. 37:2817–2821, 1977.Google Scholar
  17. 17.
    Kadlubar, F.F., Miller, J.A., and Miller, E.C. Hepatic microsomal N-glucuronidation and nucleic acid binding of N-hydroxy arylamines in relation to urinary bladder carcinogenesis. Cancer Res. 37: 805–814, 1977.Google Scholar
  18. 18.
    Lai, C.-C, Miller, J.A., Miller, E.C, and Liem, A. N-Sulfooxy-2-aminofluorene is the major ultimate electrophilic and carcinogenic metabolite of N-hydroxy-2-acetylaminofluorene in the livers of infant male C57BL/6J x C3H/HeJ Fl (B6C3Fl)mice. Carcinogenesis 6:1037–1045, 1985.CrossRefGoogle Scholar
  19. 19.
    Moolgavkar, S.H. Biologically motivated two-stage model for cancer risk assessment. Toxicol. Lett. 43:139–150, 1988.CrossRefGoogle Scholar
  20. 20.
    Murasaki, G., and Cohen, S.M. Effect of dose of sodium saccharin on the induction of rat urinary bladder proliferation. Cancer Res. 41: 942–944, 1981.Google Scholar
  21. 21.
    Murasaki, G., and Cohen, S.M. Co-carcinogenicity of sodium saccharin and N-[4-(5-nitro-2—furyl)-2-thiazolyl]formamide for the urinary bladder. Carcinogenesis 4: 97–99, 1983.CrossRefGoogle Scholar
  22. 22.
    Schoenig, G.P., Goldenthal, E.I., Geil, R.G., Frith, C.H., Richter, W.R., and Carlborg, F.W. Evaluation of the dose response and in utero exposure to saccharin in the rat. Fd. Chem. Toxicol. 23: 475–490, 1985.Google Scholar
  23. 23.
    Schreier, C.J., and Emerick, R.J. Diet calcium carbonate, phosphorus and acidifying and alkalizing salts as factors influencing silica urolithiasis in rats fed tetraethylorthosilicate. J. Nutr. 116: 823–830, 1986.Google Scholar
  24. 24.
    Staffa, J.A., and Mehlman, M.A. (Eds.) Innovations in cancer risk assessment (ED01 Study). J. Environ. Path. Toxicol. 3: 1–246, 1980.Google Scholar
  25. 25.
    Swenberg, J.A., Short, B., Borghoff, S., Strasser, J., and Charbonneau, M. The comparative pathobiology of 2u-globulin nephropathy. Toxicol. Appl. Pharmacol. 97: 35–46, 1989.CrossRefGoogle Scholar
  26. 26.
    VanRyzin, J. The assessment of low-dose carcinogenicity: Discussion. Biometrics 38(Supplement): 130–139, 1982.CrossRefGoogle Scholar
  27. 27.
    Williamson, D.S., Nagel, D.L., Markin, R.S., and Cohen, S.M. Effect of pH and ions on the electronic structure of saccharin. Fd. Chem. Toxicol. 25: 211–218, 1987.CrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1990

Authors and Affiliations

  • Samuel M. Cohen
  • Leon B. Ellwein

There are no affiliations available

Personalised recommendations