Antibodies Specific for DNA Components Modified by Chemical Carcinogens and Their Binding Efficiency to DNA Modified in Vivo and in Vitro with the Corresponding Carcinogens

  • Erik Kriek
  • Frederik J. van Schooten
  • Michel J. X. Hillebrand
  • Maarten C. Welling


It is now well established that almost all carcinogens form a variety of reaction products with DNA, involving covalent binding to the various nucleophilic sites on all four DNA bases as well as the phosphate groups of DNA. Thus, even qualitative determination of all DNA adducts, even from a single carcinogen, presents a formidable analytical task. Although the major reaction products of many carcinogens have been characterized (reviewed by Singer and Grunberger1), the structures of a large number of carcinogen-DNA adducts, particularly those of minor products, have not yet been identified. The quantitative determination is further complicated by the extremely low levels usually found in vivo, the removal of adducts from DNA by repair processes at different rates, and the formation of secondary lesions from chemically unstable adducts. Also, unstable adducts may be released spontaneously, leaving apurinic sites. Despite these shortcomings, measurement of DNA adducts is important, since these are thought to represent initiating events leading to mutations and/or malignant transformation. Measurement of DNA adducts in situ in the DNA of cells should give the most direct evidence of genotoxic exposure. The potential value of measuring carcinogen-DNA adducts as a dosimeter of human exposure has been discussed in a number of recent reviews2,3.


Competitive ELISA Polycyclic Hydrocarbon Major Reaction Product Bovine Serum Albumin Conjugate Diol Epoxide 
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.
    B. Singer and D. Grunberger, “Molecular Biology of Mutagens and Carcinogens”, Plenum Press, New York (1983).CrossRefGoogle Scholar
  2. 2.
    G. N. Wogan and N. J. Gorelick, Chemical and biochemical dosimetry of exposure to genotoxic chemicals, Environ. Health Perspect. 62:5 (1985).PubMedCrossRefGoogle Scholar
  3. 3.
    F. P. Perera, R. M. Santella and M. C. Poirier, Biomonitoring of workers exposed to carcinogens: immunoassays to benzo(a)pyrene-DNA adducts as a prototype, J Qccup Med. 28:1117 (1986).CrossRefGoogle Scholar
  4. 4.
    P. T. Strickland and J. M. Boyle, Immunoassay of carcinogen-modified DNA, in: “Progr. Nucleic Acid Res. Mol. Biol.”, Vol. 31, W. E. Cohn and K. Moldave, eds., Academic Press, New York (1984).Google Scholar
  5. 5.
    J. Adamkiewicz, P. Nehls and M. F. Rajewski, Immunological methods for detection of carcinogen-DNA adducts, in: “Monitoring Human Exposure to Carcinogenic and Mutagenic Agents”, A. Berlin, M. Draper, K. Hemminki and H. Vainio, eds., International Agency for Research on Cancer, Lyon (1984).Google Scholar
  6. 6.
    G. J. Menkveld, C. J. Van Der Laken, G. Hermsen, E. Kriek, E. Scherer and L. Den Engelse, Immunohistochemical localization of O6-ethyl-deoxyguanosine and deoxyguanosin-8-yl-(acetyl)aminofluorene in liver sections of rats treated with diethylnitrosamine, ethylnitrosourea or N-acetylaminofluorene, Carcinogenesis 6:263 (1985).PubMedCrossRefGoogle Scholar
  7. 7.
    M. C. Poirier and F. A. Beland, eds., “Carcinogenesis and Adducts in Animals and Humans” (Progress in Experimental Tumor Research Vol. 31), Karger, Basel (1987).Google Scholar
  8. 8.
    I. C. Hsu, M. C. Poirier, S. H. Yuspa, R. J. Yolken and C. C. Harris, Ultrasensitive enzymatic radioimmunoassay (USERIA) detects femtomoles of acetylaminofluorene-DNA adducts, Carcinogenesis 1:455 (1980).PubMedCrossRefGoogle Scholar
  9. 9.
    C. J. Van Der Laken, A. M. Hagenaars, G. Hermsen, E. Kriek, A. C. Kuipers, J. Nagel, E. Scherer and M. C. Welling, Measurement of O — ethyl-deoxyguanosine and N-(deoxyguanosin-8-yl)-N-acetyl-2-amino-fluorene in DNA by high-sensitive enzyme immunoassays, Carcinogenesis 3:569 (1982).CrossRefGoogle Scholar
  10. 10.
    E. Kriek, Reactive forms of aromatic amines and amides: chemical and structural features in relation to carcinogenesis, in: “13th International Cancer Congress, Part B, Biology of Cancer (1)”, E. A. Mirand, W. B. Hutchinson and E. Mihich, eds., Alan R. Liss, Inc., New York (1983).Google Scholar
  11. 11.
    F. F. Kadlubar and F. A. Beland, Chemical properties of ultimate carcinogenic metabolites of arylamines and arylamides, in: “Polycyclic Hydrocarbons and Carcinogenesis” (ACS Symposium Series 283), R. G. Harvey, ed., American Chemical Society, Washington, D.C. (1985).Google Scholar
  12. 12.
    F. A. Beland, R. H. Heflich, P. C. Howard and P. P. Fu, The in vitro metabolic activation of nitro polycyclic aromatic hydrocarbons, in: “Polycyclic Hydrocarbons and Carcinogenesis”, (ACS Symposium Series 283) R. G. Harvey, ed., American Chemical Society, Washington, D.C. (1985).Google Scholar
  13. 13.
    P. C. Howard, R. H. Heflich, F. E. Evans and F. A. Beland, Formation of DNA adducts in vitro and in Salmonella typhimurium upon metabolic reduction of the environmental mutagen 1-nitropyrene, Cancer Res. 43:2052 (1983).PubMedGoogle Scholar
  14. 14.
    C. A. Stanton, F. L. Chow, D. H. Phillips, P. L. Grover, R. C. Garner and C. N. Martin, Evidence for N-(deoxyguanosin-8-yl)-l-aminopyrene as a major DNA adduct in female rats treated with 1-nitropyrene, Carcinogenesis 6:535 (1985).PubMedCrossRefGoogle Scholar
  15. 15.
    E. Kriek, M. C. Welling and C. J. Van Der Laken, Quantitation of carcinogen-DNA adducts by a standardized high-sensitive enzyme immunoassay, in: “Monitoring Human Exposure to Carcinogenic and Mutagenic Agents”, A. Berlin, M. Draper, K. Hemminki and H. Vainio, eds., International Agency for Research on Cancer, Lyon (1984).Google Scholar
  16. 16.
    E. Kriek and J. G. Westra, Structural identification of the pyrimidine derivatives formed from N-(deoxyguanosin-8-yl)-2-aminofluorene in aqueous solution at alkaline pH, Carcinogenesis 1:459 (1980).PubMedCrossRefGoogle Scholar
  17. 17.
    J. T. Lutgerink, J. Retèl, J. G. Westra, M. C. Welling, H. Loman and E. Kriek, The biological activity of single-stranded ØX174 DNA, modified with N-hydroxy-2-aminofluorene, is inhibited by guanine imidazole ring opening of the major, non-lethal aminofluorene-DNA adduct, Carcinogenesis 7:1359 (1986).PubMedCrossRefGoogle Scholar
  18. 18.
    R. G. Harvey, Activated metabolites of carcinogenic hydrocarbons, Acc Chem Res. 14:218 (1981).CrossRefGoogle Scholar
  19. 19.
    A. M. Jeffrey, Polycyclic aromatic hydrocarbon-DNA adducts: formation, detection and characterization, in: “Polycyclic Hydrocarbons and Carcinogenesis” (ACS Symposium Series 283), R. G. Harvey, ed., American Chemical Society, Washington D.C. (1985).Google Scholar
  20. 20.
    D. H. Phillips, A. Hewer and P. L. Grover, Formation of DNA adducts in mouse skin treated with metabolites of chrysene, Cancer Lett. 35:207 (1987).PubMedCrossRefGoogle Scholar
  21. 21.
    K. Hemminki, C. S. Cooper, O. Ribeiro, P. L. Grover and P. Sims, Reactions of “bay-region” and non-“bay-region” diol epoxides of benz(a)-anthracene with DNA: evidence indicating that the major products are hydrocarbon-N2-guanine adducts, Carcinogenesis 1:277 (1980).PubMedCrossRefGoogle Scholar
  22. 22.
    A. Dipple, M. A. Pigott, S. K. Agarwal, H. Yagi, J. M. Sayer and D. M. Jerina, Optically active benzo(c)phenanthrene diol epoxides bind extensively to adenine in DNA, Nature 327:535 (1987).PubMedCrossRefGoogle Scholar
  23. 23.
    R. G. Harvey, ed., “Polycyclic Hydrocarbons and Carcinogenesis”, (ACS Symposium Series 283), American Chemical Society, Washington, D.C. (1985).Google Scholar
  24. 24.
    F. J. Van Schooten, E. Kriek, M. J. S. T. Steenwinkel, H. P. J. M. Ncteborn, M. J. X. Hillebrand and F. E. Van Leeuwen, The binding efficiency of polyclonal and monoclonal antibodies to DNA modified with benzo(a)pyrene diol epoxide is dependent on the level of modification. Implications for quantification of benzo(a)pyrene DNA adducts in vivo, Carcinogenesis 8:1263 (1987).PubMedCrossRefGoogle Scholar
  25. 25.
    M. S. Kulkarni and M. W. Anderson, Persistence of benzo(a)pyrene metabolite-DNA adducts in lung and liver of mice, Cancer Res, 44:97 (1984).PubMedGoogle Scholar
  26. 26.
    A. Haugen, G. Becker, C. Benestad, K. Vähäkangas, G. E. Trivers, M. J. Newman and C. C. Harris, Determination of polycyclic aromatic hydrocarbons in the urine, benzo(a)pyrene diol epoxide-DNA adducts in lymphocyte DNA, and antibodies to the adducts in sera from coke oven workers exposed to measured amounts of polycyclic aromatic hydrocarbons in the work atmosphere, Cancer Res. 46:4178 (1986).PubMedGoogle Scholar
  27. 27.
    L. P. A. Van Houte, J. T. Bokma, J. T. Lutgerink, J. G. Westra, J. Retèl, R. Van Grondelle and J. Blok, An optical study of the conformation of the aminofluorene-DNA complex, Carcinogenesis 8:759 (1987a).PubMedCrossRefGoogle Scholar
  28. 28.
    L. P. A. Van Houte, J. G. Westra, J. Retèl, R. Van Grondelle and J. Blok, A spectroscopic study of the conformation of poly d(GC).poly d(GC) modified with the carcinogen 2-aminofluorene, Abstracts 9th International Biophysical Congress, Jerusalem, August 23–28, 88 (1987b).Google Scholar
  29. 29.
    F. M. Pohl, Polymorphism of a synthetic DNA in solution, Nature 260:365 (1976).PubMedCrossRefGoogle Scholar
  30. 30.
    A. H. J. Wang, G. J. Quigley, F. J. Kolpak, G. Van Der Marel, J. H. Van Boom and A. Rich, Left-handed double helical DNA: variations in the backbone conformation, Science 211:171 (1981).PubMedCrossRefGoogle Scholar
  31. 31.
    L. L. Hsieh, A. M. Jeffrey and R. M. Santella, Monoclonal antibodies to 1-aminopyrene-DNA, Carcinogenesis 6:1289 (1985).PubMedCrossRefGoogle Scholar
  32. 32.
    F. P. Perera, K. Hemminki, R. M. Santella, D. Brenner and G. Kelly, DNA adducts in white blood cells of foundry workers, Proc Amer Assoc Cancer Res. 28:373 (1987).Google Scholar
  33. 33.
    C. C. Harris, B. F. Trump, R. C. Grafstrom and H. Autrup, Differences in metabolism of chemical carcinogens in cultured human epithelial tissues and cells, J. Cell. Biochem. 18:285 (1982).PubMedCrossRefGoogle Scholar
  34. 34.
    D. W. Nebert, S. Kimura and F. J. Gonzalez, Cytochrome P-450 genes and their regulation, in: “Molecular Biology of Development”, E. H. Davidson and R. A. Firtel, eds., Alan R. Liss, Inc., New York (1984).Google Scholar
  35. 35.
    E. Scherer, A. A. J. Jenner and L. Den Engelse, Immunocytochemical studies on the formation and repair of O6-alkylguanine in rat tissues, in: “Relevance of N-Nitroso Compounds to Human Cancer: Exposures and Mechanisms”, H. Bartsch, I. K. O’Neill and R. Schulte-Hermann, eds., International Agency for Research on Cancer, Lyon (1987).Google Scholar
  36. 36.
    R. A. Baan, P. T. M. Van Den Berg, W. P. Watson and R. J. Smith, In situ detection of DNA adducts formed in cultured cells by benzo(a)-pyrene diol epoxide with monoclonal antibodies specific for the BP-deoxyguanosine adduct, Toxicol. Environ. Chem. 16:325 (1988).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Erik Kriek
    • 1
  • Frederik J. van Schooten
    • 1
  • Michel J. X. Hillebrand
    • 1
  • Maarten C. Welling
    • 1
  1. 1.Division of Chemical CarcinogenesisThe Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis)AmsterdamThe Netherlands

Personalised recommendations