Formation and Enzymatic Repair of Specific Reaction Products of Alkylating N-Nitroso Carcinogens in Cellular DNA: Relevance to Malignant Transformation

  • Manfred F. Rajewsky
  • Juergen Thomale
  • Nam-ho Huh
  • Peter Nehls
  • Gertrud Eberle


Structural modifications of genomic DNA, with the ensuing qualitative and quantitative alterations in the patterns of gene expression in the respective target cells and their progeny, appear to be key elements in the process of malignant transformation and tumorigenesis caused by cellular interactions with chemical carcinogens, radiation, or viruses. It is likely that the specific DNA sequence alterations (mutations) recently observed in genes associated with the tumorigenic conversion of various types of human and animal cells, may, at least in part, be traced back to the formation of specific adducts in genomic DNA by DNA-reactive agents from our environment.1,2 Of particular relevance with respect to the probability (“risk”) of carcinogen-induced malignant conversion of individual cells are (i) their capacity for enzymatic bioactivation of “precarcinogens” to their reactive derivatives (if such derivatives are not generated without enzymatic catalysis, i.e., by spontaneous decomposition of the parent compound),3 and (ii) their capacity for repair of damaged DNA in critical gene sequences via the action of specific repair enzymes.4 It goes without saying that the varying capacity of cells for enzymatic repair of specific DNA adducts also plays an important role with regard to cancer therapy, inasmuch as repair proficiency increases the resistance of cells towards the cytotoxic effects of DNA-reactive therapeutic agents.5 The present chapter focuses on N-nitroso compounds as an example of a large class of DNA-reactive alkylating carcinogens, using as a model a particularly potent carcinogen and mutagen, N-ethyl-N-nitrosourea (EtNU).4,6,7 Some aspects of the formation and distribution of the different alkylation products in genomic DNA will be discussed as well as the current methodology for their sensitive detection by monoclonal antibodies. Moreover, we will briefly describe results of experiments aiming at an evaluation of the relative importance of the selective enzymatic repair of one of these DNA alkylation products, O6-ethylguanine (O6-EtGua), as a determinant reducing the cellular risk of malignant transformation.


Chemical Carcinogen 208F Cell Chromatin Fiber Alkylation Product Agar Coloni 
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Copyright information

© Springer Science+Business Media New York 1989

Authors and Affiliations

  • Manfred F. Rajewsky
    • 1
  • Juergen Thomale
    • 1
  • Nam-ho Huh
    • 1
  • Peter Nehls
    • 1
  • Gertrud Eberle
    • 1
  1. 1.Institut fuer Zellbiologie (Tumorforschung)Universitaet Essen (GH)Essen 1Federal Republic of Germany

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