DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C.
A role of DTD in the bioreductive activation of mitomycin C was supported by indirect evidence utilizing enzyme inhibitors in cellular systems. Using a cell-free system, we have confirmed that DTD can bioactivate mitomycin C using both purified rat and human DTD. Metabolism and bioactivation of mitomycin C by DTD is pH-dependent. At pH 7.8 alkylation of DTD leading to enzyme inhibition and DTD crosslinking occurs whereas at pH values of 7.4 and below metabolite formation, preservation of catalytic activity of DTD and sequence-selective DNA crosslinking occurs. Bioactivation of mitomycin C by DTD and the cytotoxicity of this drug in DTD-rich cell lines is oxygen-independent. Mitomycin C induces greater DNA crosslinking, even after chemical reduction, at lower pH values. This suggests that if mitomycin C is used in tumors with elevated DTD activity, greater therapeutic activity may be obtained by lowering intratumoral pH. Human NSCLC has elevated DTD activity relative to SCLC and normal lung and may be a target for the development of drugs which can be efficiently bioactivated by DTD. Because of the pH-dependent inactivation of DTD by mitomycin C, however, other drugs which are efficiently metabolized and bioactivated by DTD may be better candidates for the therapy of tumors high in DTD such as NSCLC.
Ross
D
D
School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262.
Siegel
D
D
Beall
H
H
Prakash
A S
AS
Mulcahy
R T
RT
Gibson
N W
NW
D000818:Animals; D002460:Cell Line; D006801:Humans; D008658:Inactivation, Metabolic; D016685:Mitomycin / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011809:Quinones / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D011809:Quinones; D016685:Mitomycin; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone)