Oxygen transfer from the nitro group of a nitroaromatic radiosensitizer to a DNA sugar damage product.
Mechanisms based on one-electron oxidation appear incomplete in explaining cellular radiosensitization by nitroaromatic compounds such as misonidazole. Evidence is presented for a novel mechanism that may be involved in enhancing DNA strand breakage due to a variety of agents, including ionizing radiation, that generate carbon-centered radicals on DNA deoxyribose. Under anaerobic conditions the carbon-centered radical generated selectively at C-5' of deoxyribose of thymidylate residues in DNA by the antitumor antibiotic neocarzinostatin reacts with misonidazole to produce a DNA damage product in the form of 3'-(formyl phosphate)-ended DNA. In an 18O-transfer experiment we find that the carbonyl oxygen of the activated formyl moiety (trapped as formyl-Tris) is derived from the nitro group oxygen of misonidazole. This result strongly supports a mechanism in which a nitroxide radical adduct, formed by the addition of misonidazole to the radical at C-5' of deoxyribose, cleaves between the N and O so as to form an oxy radical precursor of the formyl moiety and a two-electron reduction species of misonidazole.
Kappen
L S
LS
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Lee
T R
TR
Yang
C C
CC
Goldberg
I H
IH
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003855:Deoxyribose / Q000032:analysis; D004579:Electron Transport / Q000187:drug effects; D005609:Free Radicals; D008401:Gas Chromatography-Mass Spectrometry; D008920:Misonidazole / Q000494:pharmacology*; D009574:Nitro Compounds / Q000032:analysis; D010084:Oxidation-Reduction; D010100:Oxygen / Q000032:analysis; D009353:Zinostatin / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D009574:Nitro Compounds; D003855:Deoxyribose; D008920:Misonidazole; D004247:DNA; D009353:Zinostatin; D010100:Oxygen