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Titolo:
Inhibition of DNA cross-linking by mitomycin C by peroxidase-mediated oxidation of mitomycin C hydroquinone
Autore:
Penketh, PG; Hodnick, WF; Belcourt, MF; Shyam, K; Sherman, DH; Sartorelli, AC;
Indirizzi:
Yale Univ, Sch Med, Ctr Canc, Dept Pharmacol, New Haven, CT 06520 USA YaleUniv New Haven CT USA 06520 Dept Pharmacol, New Haven, CT 06520 USA Yale Univ, Sch Med, Ctr Canc, Dev Therapeut Program, New Haven, CT 06520 USA Yale Univ New Haven CT USA 06520 erapeut Program, New Haven, CT 06520 USA Univ Minnesota, Dept Microbiol, St Paul, MN 55108 USA Univ Minnesota St Paul MN USA 55108 Dept Microbiol, St Paul, MN 55108 USA Univ Minnesota, Biol Proc Technol Inst, St Paul, MN 55108 USA Univ Minnesota St Paul MN USA 55108 c Technol Inst, St Paul, MN 55108 USA Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 t Chem, Minneapolis, MN 55455 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 37, volume: 276, anno: 2001,
pagine: 34445 - 34452
SICI:
0021-9258(20010914)276:37<34445:IODCBM>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
SQUAMOUS-CELL CARCINOMA; ASSAY; RESISTANCE; REDUCTASE; ADJUNCT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Sartorelli, AC Yale Univ, Sch Med, Ctr Canc, Dept Pharmacol, 333 Cedar St,New Haven, CT 06520 USA Yale Univ 333 Cedar St New Haven CT USA 06520 CT 06520 USA
Citazione:
P.G. Penketh et al., "Inhibition of DNA cross-linking by mitomycin C by peroxidase-mediated oxidation of mitomycin C hydroquinone", J BIOL CHEM, 276(37), 2001, pp. 34445-34452

Abstract

Mitomycin C requires reductive activation to crosslink DNA and express anticancer activity. Reduction of mitomycin C (40 muM) by sodium borohydride (200 muM) in 20 nM Tris-HCl, 1 mM EDTA at 37 degreesC, pH 7.4, gives a 50-60% yield of the reactive intermediate mitomycin C hydroquinone. The hydroquinone decays with first order kinetics or pseudo first order kinetics with at(1/2) of similar to 15 s under these conditions. The cross-linking of T7 DNA in this system followed matching kinetics, with the conversion of mitomycin C hydroquinone to leuco-aziri-dinomitosene appearing to be the rate-determining step. Several peroxidases were found to oxidize mitomycin C hydroquinone to mitomycin C and to block DNA cross-linking to various degrees. Concentrations of the various peroxidases that largely blocked DNA crosslinking, regenerated 10-70% mitomycin C from the reduced material. Thus, significant quantities of products other than mitomycin C were produced by the peroxidase-mediated oxidation of mitomycin C hydroquinone or products derivedtherefrom. Variations in the sensitivity of cells to mitomycin C have beenattributed to differing levels of activating enzymes, export pumps, and DNA repair. Mitomycin C hydroquinone-oxidizing enzymes give rise to a new mechanism by which oxic/hypoxic toxicity differentials and resistance can occur.

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Documento generato il 27/11/20 alle ore 02:25:48