Towards a Role for Promutagenic Lesions in Carcinogenesis

  • Peter J. O’Connor
Part of the NATO ASI Series book series (NSSA, volume 182)


The reactions of alkylating agents with DNA are now widely considered to be major determinants in the toxic, mutagenic, carcinogenic and other biological properties of these compounds. Until recently, it has not been possible to begin to confirm the relevance of such observations for human disease, but techniques now permit preliminary studies of these potentially initiating events in human tissues.


Positive Nucleus Target Cell Population Uninvolved Tissue Sister Chromatid Exchange Induction Repair Deficient Cell 
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. Adamkiewicz, J., Drosdziok, W., Eberhardt, W., Langenberg, H., and Rajewski, M. F., 1982. High-affinity monoclonal antibodies specific for DNA components structurally modified by alkylating agents, In: Banbury report No. 13; Indicators of Genetic Exposure, p.37, B.A. Bridges, D. E. Butterworth and I. B. Weinstein, eds. Cold Sring Harbor Laboratory, New York.Google Scholar
  2. Bartsch, H. and Montesano, R. 1984. Relevance of nitrosamines to human cancer. Carcinogenesis, 5: 1381.PubMedCrossRefGoogle Scholar
  3. Brennand, J. and Margison, G. P. 1986a. Reduction of the toxicity and mutagenicity of alkylating agents in mammalian cells harbouring the Escherichia coli alkyltransferase gene. Proc. Natl. Acad. Sci. USA, 83: 6292.PubMedCrossRefGoogle Scholar
  4. Brennand, J. and Margison, G. P. 1986b. Expression in mammalian cells of a truncated Escherichia coli gene coding for O6-alkylguanine alkyltransferase reduced the toxic effects of alkylating agents. Carcinogenesis, 7: 2081.PubMedCrossRefGoogle Scholar
  5. Demple, B., Sedgwick, B., Robins, P., Totty, N., Waterfield, M.D., and Lindahl, T. 1985. Active site and complete sequence of the suicidal methyltransferase that counters alkylation mutagenesis. Proc. Natl. Acad. Sci. USA, 82: 2688.PubMedCrossRefGoogle Scholar
  6. Driver, H. E., White, I.N.H., and Butler, W.H. 1987. Dose response relationships in chemical carcinogensis: renal mesenchymal tumors induced in the rat by single dose dimethylnitrosamine. Br. J. Exp. Path. 68: 133.Google Scholar
  7. Evarts, R. P., Marsden, E. R., and Thorgiersson, S. S. 1985. Modulation of asialoglycoprotein receptor levels in rat liver by phenobarbital treatment. Carcinogenesis, 6: 1767.PubMedCrossRefGoogle Scholar
  8. Fan, C.Y., Butler, W. H., and O’Connor, P. J. Data in preparation.Google Scholar
  9. Fox, M. and Margison, G. P., 1988. Expression of an E. coli O6-alkylguanine alkyltransferase gene in Chinese hamster cells protects against N-methyl-and N-ethyl-nitrosourea-induced reverse mutation at the hypoxanthine phosphoribosyl transferase locus. Mutagenesis, 3: 409.PubMedCrossRefGoogle Scholar
  10. Hall, C.N., Saffhill, R., Badawi, A. G. and O Connor, P.J. Data in preparation.Google Scholar
  11. Jelinek, J., Keible, K., Dexter, T.M., and Margison, G. P. 1988. Transfection of murine multipotent haemopoietic stem cells with an E. coli DNA alkyltransferase gene confers resistance to the toxic effects of alkylating agents. Carcinogenesis, 9: 81.PubMedCrossRefGoogle Scholar
  12. Kataoka, M., Mali, J., and Karran, P. 1986. Complementation of sensitivity to alkylating agents in E. coli and Chinese hamster ovary cells by expression of a cloned bacterial repair gene. EMBO Journal, 5:3195.PubMedGoogle Scholar
  13. Margison, G. P., Butler, J., and Hoey, B. 1985. O 6-Methyl-guanine methyltransferase activity is increased in rat tissues by ionizing radiation. Carcinogenesis, 6:1699.PubMedCrossRefGoogle Scholar
  14. Nicoll, J.W., Swann, P.F., and Pegg, A.E. 1975. Effect of dimethylnitrosamine on persistence of methylated guanines in rat liver and kidney DNA. Nature, 2 54:261.CrossRefGoogle Scholar
  15. O’Connor, P. J., Fida, S., Fan, C.Y., Bromley, M. and Saffhill, R. 1988. Phenobarbital: a non-genotoxic agent which induces the repair of O 6-methylguanine from hepatic DNA. Carcinogenesis, 9:2033.PubMedCrossRefGoogle Scholar
  16. O’Connor, P.J., Saffhill, R., and Margison, G.P. 1979. N-Nitroso compounds: biochemical mechanisms of action, In: Environmental Carcinogenesis. p.73. P. Emmelot and E. Kriek, eds., Elsevier/North Holland Biomedical Press, Amsterdam.Google Scholar
  17. Saffhill, R., Badawi, A.F., and Hall, C.N. 1988a. Detection of O 6-methylguanine in human DNA, In: Methods for Detecting DNA Damaging Agents in Humans: Applications for Cancer Epidemiology and Prevention, p.301. H. Bartsch, K. Hemminki, and I.K. O’Neill, eds., IARC Sci. Pub. No. 89, Lyon.Google Scholar
  18. Saffhill, R., Fida, S., Bromley, M., and O’Connor, P.J. 1988b. Promutagenic alkyl lesions are induced in the tissue DNA of animals treated with Isoniazid, Human Toxicol. 7: 311.CrossRefGoogle Scholar
  19. Saffhill, R., Margison, G. P., and O’Connor, P. J. 1985. Mechanism of carcinogenesis induced by alkylating agents. Biochim. Biophys. Acta, 823:111.PubMedGoogle Scholar
  20. Schmerold, I. and Wiestier, O.D. 1986. Induction of rat liver O 6-alkylguanine-DNA alkyltransferase following whole body X-irradiation. Cancer Res. 46:245.PubMedGoogle Scholar
  21. Scbwartz, M., Peres, P., Buchmaun, A., Friedberg, T., Waxman, D. J., and Kunz, W. 1987. Phenobarbital induction of cytochrome p450 in normal and preneoplastic liver: comparison of enzyme and mRNA expression as detected by immunohistochemistry and in situ hybridization. Carcinogenesis, 8:1355.CrossRefGoogle Scholar
  22. Swann, P. F., Kaufman, D. G., Magee, P.N., and Mace, R. 1980. Induction of kidney tumors by a single dose of dimethylnitrosamine: Dose reponse and influence of diet and benzo(a)pyrene treatment. Br. J. Cancer, 41:285.PubMedCrossRefGoogle Scholar
  23. Umbenhauer, D., Wild, C. P., Montesano, R., Saffhill, R., Boyle, J.M., Huh, N., Kirstein, N., Thomale, J., Rajewski, M.F., and Lu, S.H., 1985. O 6-methyldeoxyguanosine in oesophageal DNA among individuals at high risk of oesophageal cancer. Int. J. Cancer, 36:661.PubMedCrossRefGoogle Scholar
  24. White, G.R.M., Ockey, C. H., Brennand, J., and Margison, G. P. 1986. Chinese Hamster cells harbouring the Escherichia coli O 6-alkylguanine alkyltransferase gene are less susceptible to sister chromatid exchange induction and chromosome damage by methylating agents. Carcinogenesis, 7:2077.PubMedCrossRefGoogle Scholar
  25. Wild, C.P., Smart, G., Saffhill, R., and Boyle, J.M. 1983. Radioimunoassay of O 6-methyldeoxyguanosine in DNA of cells alkylated in vitro and in vivo. Carcinogenesis, 4: 1605.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Peter J. O’Connor
    • 1
  1. 1.CRC Section of Carcinogenesis, Paterson Institute for Cancer ResearchChristie Hospital and Holt Radium InstituteManchesterUK

Personalised recommendations