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Titolo:
Reversal of mitomycin C resistance by overexpression of bioreductive enzymes in Chinese hamster ovary cells
Autore:
Baumann, RP; Hodnick, WF; Seow, HA; Belcourt, MF; Rockwell, S; Sherman, DH; Sartorelli, AC;
Indirizzi:
Yale Univ, Sch Med, Dept Pharmacol, Canc Ctr, New Haven, CT 06520 USA YaleUniv New Haven CT USA 06520 macol, Canc Ctr, New Haven, CT 06520 USA Yale Univ, Sch Med, Dept Therapeut Radiol, Canc Ctr, New Haven, CT 06520 USA Yale Univ New Haven CT USA 06520 adiol, Canc Ctr, New Haven, CT 06520 USA Yale Univ, Sch Med, Dev Therapeut Program, Canc Ctr, New Haven, CT 06520 USA Yale Univ New Haven CT USA 06520 ogram, Canc Ctr, New Haven, CT 06520 USA Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 robiol, Minneapolis, MN 55455 USA Univ Minnesota, Biol Proc Technol Inst, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 l Inst, Minneapolis, MN 55455 USA
Titolo Testata:
CANCER RESEARCH
fascicolo: 21, volume: 61, anno: 2001,
pagine: 7770 - 7776
SICI:
0008-5472(20011101)61:21<7770:ROMCRB>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
COLON-CARCINOMA CELLS; DT-DIAPHORASE; HYPOXIC CONDITIONS; REDUCTIVE ACTIVATION; CANCER-CELLS; STREPTOMYCES-LAVENDULAE; DEFICIENT ACTIVATION; METABOLIC-ACTIVATION; P-450 REDUCTASE; CHO CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Sartorelli, AC Yale Univ, Sch Med, Dept Pharmacol, Canc Ctr, 333 Cedar St,New Haven, CT 06520 USA Yale Univ 333 Cedar St New Haven CT USA 06520 CT 06520 USA
Citazione:
R.P. Baumann et al., "Reversal of mitomycin C resistance by overexpression of bioreductive enzymes in Chinese hamster ovary cells", CANCER RES, 61(21), 2001, pp. 7770-7776

Abstract

The clinical utility of antineoplastic agents is limited by the development of drug resistance by tumors. Mitomycin C (MC) is a bacterial product that must be enzymatically reduced to exert anticancer activity. We have demonstrated that expression of the bacterial MC resistance-associated (MCRA) protein in Chinese hamster ovary (CHO) cells confers profound resistance to this antibiotic under aerobic conditions, but not under hypoxia. MCRA produces resistance to MC by redox cycling of the activated hydroquinone intermediate back to the prodrug form. A CHO cell line developed by stepwise exposure to increasing concentrations of MC likewise expressed high level resistance to MC in air, but not under hypoxia. The overexpression of DT-diaphorase and NADPH:cytochrome c (P-450) reductase, two enzymes known to activate MC, restored sensitivity to MC in both MCRA-transfected and drug-selected cell lines. The level of sensitization was proportional to the quantity of enzyme activity expressed, supporting the concept that the levels of these two activating enzymes are important for sensitivity to MC. The findings of resistance to MC in air but not under hypoxic conditions and of restoration of sensitivity to MC by increasing levels of DT-diaphorase activity, properties not adequately explained by other resistance mechanisms (i.e., decreases in MC activation, repair of DNA lesions, and/or drug efflux), support the hypothesis that a functional mammalian homologue of MCRA may be involved in producing resistance to MC.

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Documento generato il 27/10/20 alle ore 04:45:54