Roles of Oxygen and Oxygen Substitutes in DNA Sugar Damage by Antitumor Antibiotics
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.
KeywordsStrand Break Peroxyl Radical Base Release Abasic Site Strand Breakage
Unable to display preview. Download preview PDF.
- 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
- 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
- 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.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
- 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.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