Roles of Oxygen and Oxygen Substitutes in DNA Sugar Damage by Antitumor Antibiotics

  • Irving H. Goldberg
  • Lizzy Kappen
  • Der-Hang Chin
Part of the Basic Life Sciences book series (BLSC, volume 49)


Oxidative damage to the deoxyribose backbone of DNA produced by ionizing radiation and antitumor antibiotics (e.g., bleomycin) generally involves oxygen at two stages in the damage process: 1) “reactive oxygen” (OH radical or its equivalent) as the hydrogen atom abstracting species, generating a carbon-centered radical on the deoxyribose, and 2) addition of dioxygen to the latter to “fix” the lesion in a form not readily repaired. By contrast, neocarzinostatin (NCS) is a member of a class of antitumor antibiotics that binds specifically to DNA and is itself converted to a radical species that directly attacks the DNA sugar. Dioxygen or its substitute is involved only after generation of the DNA damage intermediate. This review will focus on the roles of dioxygen and oxygen substitutes, the nitroaromatic radiation sensitizers, in the formation of novel types of oxidative DNA sugar damage by NCS.


Strand Break Peroxyl Radical Base Release Abasic Site Strand Breakage 
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.
    I. H. Goldberg, T. Hatayama, L.S. Kappen, M.A. Napier, and L.F. Povirk, Protein antibiotics as DNA damaging agents, in: “Molecular Actions and Targets for Cancer Chemotherapeutic Agents,” A.C. Sartorelli, J.R. Bertino and J.S. Lazo, eds., Second Annual Bristol-Myers Symposium in Cancer Research, Academic Press, New York, p. 163 (1981).Google Scholar
  2. 2.
    I.H. Goldberg, Free radical mechanisms in neocarzinostatin-induced DNA damage, Free Radical Biol. Med. 3:41 (1987).CrossRefGoogle Scholar
  3. 3.
    O.D. Hensens, R.S. Dewey, J.M. Liesch, M.A. Napier, R.A. Reamer, J.L. Smith, G. Albers-Schönberg, and I.H. Goldberg, Neorcarzinostatin chromophore: Presence of a highly strained ether ring and its reaction with mercaptan and sodium borohydride, Biochem. Biophys. Res. Commun. 113:538 (1983).PubMedCrossRefGoogle Scholar
  4. 4.
    M. Shibuya, K. Toyooka, and S. Kubota, Synthesis of the naphthalenecarboxylic acid derivative obtained from neocarzinostatin (NCS): a structure revision, Tetradedron Lett. 25:1171 (1984).CrossRefGoogle Scholar
  5. 5.
    K. Edo, M. Mizugaki, Y. Koide, H. Seto, K. Furikata, N. Otake, and N. Ishida, The structure of neocarzinostatin chromophore possessing a novel bicyclo[7,3,0]dodecadiyne system, Tetradedron Lett. 26:331 (1985).CrossRefGoogle Scholar
  6. 6.
    D. Dasgupta, D.S. Auld and, I.H. Goldberg, Cryospectrokinetic evidence for the mode of reversible binding of neocarzinostatin chromophore to poly(deoxyadenylic-deoxythymidylic acid), Biochemistry 24:7049 (1985).PubMedCrossRefGoogle Scholar
  7. 7.
    D. Dasgupta and I.H. Goldberg, Mode of reversible binding of neocarzinostatin chromophore to DNA: Evidence for binding via the minor groove, Biochemistry 24:6913 (1985).PubMedCrossRefGoogle Scholar
  8. 8.
    D. Dasgupta and I.H. Goldberg, Base sequence dependency of binding, Nucleic Acid Res. 14:1089 (1986).PubMedCrossRefGoogle Scholar
  9. 9.
    L.S. Kappen, I.H. Goldberg, and J.M. Liesch, Identification of thymidine 5′-aldehyde at DNA strand breaks induced by neocarzino-statin chromophore, Proc. Natl. Acad. Sci. USA 79:744 (1982).PubMedCrossRefGoogle Scholar
  10. 10.
    L.S. Kappen and I.H. Goldberg, DNA damage by neocarzinostatin chromophore: Strand breaks generated by selective oxidation of C-5 of deoxyribose, Biochemistry 22:4872 (1983).PubMedCrossRefGoogle Scholar
  11. 11.
    L.F. Povirk and I.H. Goldberg, Covalent adducts between DNA and the nonprotein chromophore of neocarzinostatin contain a modified deoxyribose, Proc. Natl. Acad. Sci. USA 79L 369 (1982).CrossRefGoogle Scholar
  12. 12.
    L.F. Povirk and I.H. Goldberg, Neocarzinostatin chromophore-DNA adducts: Evidence for a covalent linkage to the oxidized C-5′ of deoxyribose, Nucleic Acids Res. 10:6255 (1982).PubMedCrossRefGoogle Scholar
  13. 13.
    L.F. Povirk and I.H. Goldberg, Competition between anaerobic covalent linkage of neocarzinostatin chromophore to deoxyribose in DNA and oxygen-dependent strand breakage and base release, Biochemistry 23:6295 (1984).CrossRefGoogle Scholar
  14. 14.
    L.F. Povirk and I.H. Goldberg, Endonuclease-resistant apyrimidinic sites formed by neocarzinostatin at cytosine residues in DNA: Evidence for a possible role in mutagenesis, Proc. Natl. Acad. Sci. USA 82:3182 (1985).PubMedCrossRefGoogle Scholar
  15. 15.
    L.F. Povirk and I.H. Goldberg, Base substitution mutations induced in the cI gene of lambda phage by neocarzinostatin chromphore: Correlation with depyrimidination hotspots at the sequence AGC, Nucleic Acids Res. 14:1417 (1986).PubMedCrossRefGoogle Scholar
  16. 16.
    L.S. Kappen, T.E. Ellenberger, and I.H. Goldberg, Mechanism and base specificity of DNA breakage in intact cells by neocarzinostatin, Biochemistry 26:384 (1987).PubMedCrossRefGoogle Scholar
  17. 17.
    W.G. DeGraff and J.B. Mitchell, Glutathione dependence of neocarzinostatin cytotoxicity and mutagenicity in Chinese hamster V-79 cells, Cancer Res. 45:4760 (1985).PubMedGoogle Scholar
  18. 18.
    L.F. Povirk and I.H. Goldberg, Detection of neocarzinostatin chromophore-deoxyribose adducts as exonuclease-resistant site in defined-sequence DNA, Biochemistry 24:4035 (1985).PubMedCrossRefGoogle Scholar
  19. 19.
    A.F. Fuciarelli, G.G. Miller, and J.A. Raleigh, An immunochemical probe for 8,5′-cycloadenosine-5′-monophosphate and its deoxy analog in irradiated nucleic acids, Radiat. Res. 104:272 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    M. Dizdaroglu, M.L. Dirksen, M.G. Simic, and J.H. Robbins, Identification of the novel lesion 8,5′-cyclo-2′-deoxyguanosine in DNA isolated from Y-irradiated human cells, Fed. Proc. 45:1626 (1986).Google Scholar
  21. 21.
    L.F. Povirk and I.H. Goldberg, Stoichiometric uptake of molecular oxygen and consumption of sulfhydryls by neocarzinostatin chromophore bound to DNA, J. Biol. Chem. 258:11767 (1983)Google Scholar
  22. 22.
    D.-H. Chin, S.A. Carr, and I.H. Goldberg, Incorporation of 18O2 into thymidine 5′-aldehyde in neocarzinostatin chromophore-damaged DNA, J. Biol. Chem. 259:9975 (1984).PubMedGoogle Scholar
  23. 23.
    D.-H. Chin and I.H. Goldberg, Generation of superoxide free radical by neocarzinostatin and its possible role in DNA damage, Biochemistry 25:1009 (1986).PubMedCrossRefGoogle Scholar
  24. 24.
    R.L. Chamas and I.H. Goldberg, Neocarzinostatin abstracts a hydrogen during formation of nucleotide 5′-aldehyde on DNA, Biochem. Biophys. Res. Commun. 122:642 (1984).CrossRefGoogle Scholar
  25. 25.
    L.S. Kappen and I.H. Goldberg, Activation of neocarzinostatin chromophore and formation of nascent DNA damage do not require molecular oxygen, Nucleic Acids Res. 13:1637 (1985).PubMedCrossRefGoogle Scholar
  26. 26.
    V. Favaudon, R.L. Chamas, and I.H. Goldberg, Polydeoxyadenylic-deoxythymidylic acid damage by radiolytically activated neocarzino-statin, Biochemistry 24:250 (1985).PubMedCrossRefGoogle Scholar
  27. 27.
    L.S. Kappen and I.H. Goldberg, Nitroaromatic radiation sensitizers substitute for oxygen in neorcarzinostatin-induced DNA damage, Proc. Natl. Acad. Sci. USA 81:3312 (1984).PubMedCrossRefGoogle Scholar
  28. 28.
    D.-H. Chin, L.S. Kappen, and I.H. Goldberg, 3′-formylphosphate-ended DNA: a high-energy intermediate in antibiotic-induced DNA sugar damage, Proc. Natl. Acad. Sci. USA, in press.Google Scholar
  29. 29.
    C. von Sonntag, U. Hagen, A. Schon-Böpp, and D. Schulte-Frohlinde, Radiation-induced strand breaks in DNA: Chemical and enzymatic analysis of end groups and mechanistic aspects, Adv. Radiat. Bol. 9:109 (1981).Google Scholar
  30. 30.
    G. Scholes and J. Weiss, Formation of acetylphosphate in the action of X-rays on monoethyl phosphoric acid in aqueous solutiion, Nature 173:267 (1954).CrossRefGoogle Scholar
  31. 31.
    S. Nishimoto, H. Ide, T. Wada, and T. Kagiya, Radiation-induced hydroxylation of thymine promoted by electro-affinie compounds, Int. J. Radiat. Biol. 44:585 (1983).CrossRefGoogle Scholar
  32. 32.
    T. Honna, M. Kuwabara, and G. Yoshii, Effect of misonidazole on free radical formation and inorganic phosphate release in gamma-irradiated nucleotides, Int. J. Radiat. Biol. 39:457 (1981).CrossRefGoogle Scholar
  33. 33.
    J.F. Remsen, Effect of misonidazole on formation of thymine damage by gamma rays, Radiat. Res. 101:306 (1985).PubMedCrossRefGoogle Scholar
  34. 34.
    M.D. Lee, T.S. Dunne, C.C. Chang, G.A. Ellestad, M.M. Siegel, G.O. Morton, W.J. McGahren, and D.B. Borders, Calichemicins, a novel family of antitumor antibiotics. 2. Chemistry and structure of calichemicinyγ1, J. Am. Chem. Soc. 109:3466 (1987).CrossRefGoogle Scholar
  35. 35.
    J. Golik, G. Dubay, G. Groenewold, H. Kawaguchi, M. Konishi, B. Krishnan, H. Ohkuma, K. Saitoh, and T.W. Doyle, Esperamicins, a novel class of potent antitumor antibiotics. 3. Structures of esperamicins A1,A2, and A1B, J. Am. Chem. Soc. 109:3462 (1987).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Irving H. Goldberg
    • 1
  • Lizzy Kappen
    • 1
  • Der-Hang Chin
    • 1
  1. 1.Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBostonUSA

Personalised recommendations