DNA Modification and Repair in Vivo: Towards a Biochemical Basis of Organ-Specific Carcinogenesis by Methylating Agents

  • Paul Kleihues
  • Ruth M. Hodgson
  • Christof Veit
  • Fritz Schweinsberg
  • Manfred Wiessler
Part of the Basic Life Sciences book series


The elucidation of the biological basis of organ-specific tumor induction by chemicals is a major objective of cancer research. For many carcinogens, the principal site of tumor induction has been shown to vary with species, dose, route of administration, and age or developmental stage. Some species also exhibit marked differences in their overall susceptibility to certain classes of chemical carcinogens. Accordingly, to accurately predict the adverse effects of genotoxic agents in humans, the basic mechanisms underlying organ and species specificity must first be understood.


Tumor Induction Esophageal Tumor Meriones Unguiculatus Selective Induction Methylating Agent 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hathway, D.E., and G.F. Kolar. 1980. Mechanisms of reaction between ultimate chemical carcinogens and nucleic acid. Chem. Society Rev. 9: 241–264.Google Scholar
  2. 2.
    Pegg, A.E. 1977. Formation and metabolism of alkylated nucleosides: Possible role in carcinogenesis by nitroso compounds and alkylating agents. Adv. Cancer Res. 25: 195–269.Google Scholar
  3. 3.
    Kleihues, P., G. Doerjer, L.K. Keefer, J.M. Rice, P.P. Roller, and R.M. Hodgson. 1979. Correlation of DNA methylation by methyl(acetoxymethyl)nitrosamine with organ-specific carcinogenicity in rats. Cancer Res. 39: 5136–5140.PubMedGoogle Scholar
  4. 4.
    O’Connor, P.J. 1981. Interaction of chemical carcinogens with macromolecules. J. Cancer Res. Clinic. Oncol. 99: 167–186.Google Scholar
  5. 5.
    Singer, B., W.J. Bodell, J.E. Cleaver, G.H. Thomas, M.F. Rajewsky, and W. Thon. 1978. Oxygens in DNA are main targets for ethylnitrosourea in normal and xeroderma pigmentosum fibroblasts and fetal rat brain cells. Nature 276: 85–88.PubMedCrossRefGoogle Scholar
  6. 6.
    Joshi, S.R., J.M. Rice, M.L. Wenk, P.P. Roller, and L.K. Keefer. 1977. Selective induction of intestinal tumors in rats by methyl(acetoxymethyl)nitrosamine, an ester of the presumed reactive metabolite of dimethylnitrosamine. J. Natl. Cancer Inst. 58: 1531–1535.Google Scholar
  7. 7.
    Ward, J.M., J.M. Rice, P.P. Roller, and M.L. Wenk. 1977. Natural history of intestinal neoplasms induced in rats by a single injection of methyl(acetoxymethyl)nitrosamine. Cancer Res. 37: 3046–3052.PubMedGoogle Scholar
  8. 8.
    Berman, J.J., J.M. Rice, M.L. Wenk, and P.P. Roller. 1979. Dependence on route of administration of tumor spectrum in Sprague-Dawley rats resulting from single or multiple injections of methyl(acetoxymethyl)nitrosamine. J. Natl. Cancer Inst. 63: 93–100.Google Scholar
  9. 9.
    Habs, M., D. Schmähl, and M. Wiessler. 1978. Carcinogenicity of acetoxymethyl-methyl-nitrosamine after subcutaneous, intravenous, and intrarectal application in rats. Z. Krebsforsch. 91: 217–221.Google Scholar
  10. 10.
    Stekar, J., and J. Gimmy. 1980. Induction of lung tumours in rats by i.v. injection of N-methyl-N’-nitro-N-nitrosoguanidine. Eur. J. Cancer 16: 395–400.Google Scholar
  11. 11.
    Druckrey, H., R. Preussman, S. Ivankovic, and D. Schmähl. 1967. Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z. Krebsforsch. 69: 103–201.PubMedCrossRefGoogle Scholar
  12. 12.
    Stekar, J. 1977. Pulmotropic carcinogenic activity of N-methyl-N-nitrosopropionamide. Eur. J. Cancer 13: 1183–1189.Google Scholar
  13. 13.
    Diaz Gomez, M.I., P.F. Swann, and P.N. Magee. 1977. The absorption and metabolism in rats of small oral doses of dimethylnitrosamine. Biochem. J. 164: 497–500.Google Scholar
  14. 14.
    Pegg, A.E. 1980. Formation and subsequent repair of alkylation lesions in tissues of rodents treated with nitrosamines. Arch. Toxicol. Suppl. 3: 55–68.Google Scholar
  15. 15.
    Stinson, S.F., R.A. Squire, and M.B. Sporn. 1978. Pathology of esophageal neoplasms and associated proliferative lesions induced in rats by N-methyl-N-benzylnitrosamine. J. Natl. Cancer Inst. 61: 1471–1475.Google Scholar
  16. 16.
    Hodgson, R.M., M. Wiessler, and P. Kleihues. 1980. Preferential methylation of target organ DNA by the oesophageal carcinogen N-nitrosomethylbenzylamine. Carcinogenesis 1: 861–865.PubMedCrossRefGoogle Scholar
  17. 17.
    Hodgson, R.M., F. Schweinsberg, M. Wiessler, and P. Kleihues. 1982. Mechanism of esophageal tumor induction by N-nitrosomethylbenzylamine and its ring-methylated analog N-nitrosomethyl(4-methylbenzyl)amine. Submitted for publication.Google Scholar
  18. 18.
    Kleihues, P., Ch. Veit, M. Wiessler, and R.M. Hodgson. 1981. DNA alkylation by N-Nitrosomethylbenzylamine in target and non-target tissues of NMRI mice. Carcinogenesis 2: 897–899.PubMedCrossRefGoogle Scholar
  19. 19.
    Schweinsberg, F., and M. Kouros. 1979. Reactions of N-methyl-N-nitrosobenzylamine and related substrates with enzyme-containing cell fractions isolated from various organs of rats and mice. Cancer Lett. 7: 115–120.PubMedCrossRefGoogle Scholar
  20. 20.
    Schweinsberg, F., P. Schott-Kollat, and G. Bürkle. 1977. Veränderung der Toxizität und Carcinogenität von N-Methyl-N-Nitrosobenzylamin durch Methylsubstitution am Phenylrest bei Ratten. Z. Krebsforsch. 88: 231–236.CrossRefGoogle Scholar
  21. 21.
    Schweinsberg, F., G. Döring, and M. Kouros. 1979. Metabolism of isomeric N-methyl-N-nitroso-(methylphenyl)-methylamines. Cancer Lett. 8: 125–132.PubMedCrossRefGoogle Scholar
  22. 22.
    Sander, J., and F. Schweinsberg. 1973. Tumorinduktion bei Mäusen durch N-Methylbenzyl-nitrosamin in niedriger Dosierung. Z. Krebsforsch. 79: 157–161.Google Scholar
  23. 23.
    Rogers, K.J., and A.E. Pegg. 1977. Formation of 06-methylguanine by alkylation of rat liver, colon, and kidney DNA following administration of 1,2-dimethylhydrazine. Cancer Res. 37: 4082–4088.PubMedGoogle Scholar
  24. 24.
    Swenberg, J.A., H.K. Cooper, J. Bücheler, and P. Kleihues. 1979. 1,2-Dimethylhydrazine-induced methylation of DNA bases in various rat organs and the effect of pretreatment with disulfiram. Cancer Res. 39: 465–467.Google Scholar
  25. 25.
    Swenburg, J.A., M.A. Bendell, K.C. Billings, and J.G. Lewis. 1982. Cell specificity in DNA Damage and Repair. In: Organ and Species Specificity in Chemical Carcinogenesis. R. Langenbach, S. Nesnow, and J. Rice, eds. Plenum Press: New York. pp. 605–617.Google Scholar
  26. 26.
    Cooper, H.K., J. Bücheler, and P. Kleihues. 1978. DNA alkylation in mice with genetically different susceptibility to 1,2-dimethylhydrazine-induced colon carcinogenesis. Cancer Res. 38: 3063–3065.PubMedGoogle Scholar
  27. 27.
    Olsson, M., and T. Lindahl. 1980. Repair of alkylated DNA in Escherichia cola. Methyl group transfer from 06-methylguanine to a protein cysteine residue. J. Biol. Chem. 22: 10569–10571.Google Scholar
  28. 28.
    Foote, R.S., S. Mitra, and B.C. Pal. 1980. Demethylation of 06-methylguanine in a synthetic DNA polymer by an inducible activity in Escherichia cola. Biochem. Biophys. Res. Comm. 2: 654–659.Google Scholar
  29. 29.
    Goth, R., and M.F. Rajewsky. 1974. Persistence of 06-ethylguanine in rat-brain DNA: Correlation with nervous system-specific carcinogenesis by ethylnitrosourea. Proc. Natl. Acad. Sci. USA 71: 639–643.Google Scholar
  30. 30.
    Kleihues, P., and G.P. Margison. 1974. Carcinogenicity of N-methyl-N-nitrosourea: Possible role of repair excision of 06-methylguanine from DNA. J. Natl. Cancer Inst. 53: 1839–1842.Google Scholar
  31. 31.
    Kleihues, P., and J. Bücheler. 1977. Long-term persistence of 0 Lmethylguanine in rat brain DNA. Nature 269: 625–626.PubMedCrossRefGoogle Scholar
  32. 32.
    Margison, G.P., and P. Kleihues. 1975. Chemical carcinogenesis in the nervous system. Preferential accumulation of 06methylguanine in rat brain deoxyribonucleic acid during repetitive administration of N-methyl-N-nitrosourea. Biochem. J. 148: 521–525.Google Scholar
  33. 33.
    Kleihues, P., H.K. Cooper, J. Bucheler, and G.F. Kolar. 1979. Investigations on the mechanism of perinatal tumor induction by neuro-oncogenic alkylnitrosoureas and dialkyl-aryltriazenes. Natl. Cancer Inst. Monogr. 51: 227–231.Google Scholar
  34. 34.
    Kleihues, P. G. Doerjer, J.A. Swenberg, E. Hauenstein, J. Bucheler, and H.K. Cooper. 1979. DNA repair as a regulatory factor in the organotropy of alkylating carcinogens. Arch. Toxicol. Suppl. 2: 253–261.Google Scholar
  35. 35.
    Kleihues, P., St. Bamborschke, and G. Doerjer. 1980. Persistence of alkylated DNA bases in the Mongolian gerbil ( Meriones unguiculatus) following a single dose of methylnitrosourea. Carcinogenesis 1: 111–113.Google Scholar
  36. 36.
    Lewis, J.G., and J.A. Swenberg. 1980. Differential repair of O6-methylguanine in DNA of rat hepatocytes and nonparenchymal cells. Nature 288: 185–187.PubMedCrossRefGoogle Scholar
  37. 37.
    Frei, J.V., D.H. Swenson, W. Warren, and P.D. Lawley. 1978. Alkylation of deoxyribonucleic acid in vivo in various organs of C57BL mice by the carcinogens N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea and ethyl methanesulphonate in relation to induction of thymic lymphoma. Biochem. J. 174: 1031–1044.Google Scholar
  38. 38.
    Frank, N., C. Janzowski, and M. Wiessler. 1980. Stability of Nitrosoacetoxymethylmethylamine in in vitro systems and in vivo and its excretion by the rat organism. Biochem. Pharmacol. 29: 383–387.Google Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Paul Kleihues
    • 1
  • Ruth M. Hodgson
    • 1
  • Christof Veit
    • 1
  • Fritz Schweinsberg
    • 2
  • Manfred Wiessler
    • 3
  1. 1.Abteilung Neuropathologie, Pathologisches InstitutUniversitat FreiburgFreiburgFederal Republic of Germany
  2. 2.Hygiene InstitutUniversitat TubingenTubingenFederal Republic of Germany
  3. 3.Deutsches KrebsforschungszentrumHeidelbergFederal Republic of Germany

Personalised recommendations