The reduced antitumor antibiotic mitomycin C in aqueous solution exposed to air gives a 36-line electron spin resonance spectrum of the semiquinone identified by computer simulation. Incubation of this radical with the spin trap N-tert-butyl-alpha-phenylnitrone (PBN) gives the PBN.OH nitroxide radical identified by independent generation. This nitroxide radical is also formed from similar treatment of a DNA to which mitomycin C is covalently attached. Incubation of the semiquinone from mitomycin C, mitomycin B, or streptonigrin (SN) with catalase or with superoxide dismutase inhibits the generation of OH, implying the intermediacy of H2O2 and O2 in its formation. The formation of the spin-trapped nitroxide radical is similarly inhibited by EDTA, suggesting the intermediacy of trace metal ions in the generation of hydroxyl radicals from SN. The results are consistent with the generation by the aminoquinone antibiotics in vivo of OH. already implicated in the degradation of DNA.
This paper is dedicated to Prof. Raymond U . Lemieux on the occasion of his 60th birthday J. WILLIAM LOWN and HSIAO-HSIUNG CHEN. Can. J. Chem. 59,390 (1981). The nature of the reactive oxygen species generated from certain quinone antitumor antibiotics upon reductive activation in aqueous solution was investigated. A kinetic criterion was employed involving the relative rate of trapping of hydroxyl and formate radicals by the spin-trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) in conjunction with epr spectroscopy. By comparison with a system involving the photolysis of hydrogen peroxide as a standard free hydroxyl system it was concluded that at pH 7 and at 37'C reductive activation of adriamycin, daunorubicin, mitomycin B, mitomycin C, and streptonigrin gives rise to free hydroxyl radicals in direct contrast with, for example, the photolysis of quinones in solution.
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