DT-diaphorase as a target enzyme for biochemical modulation of mitomycin C.
We studied a selective enhancement of the mitomycin C (MMC)-induced antitumor effect focusing on the intracellular metabolism by NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD). The level of cellular DTD activity related well to the degree of MMC-induced DNA total cross links and cell growth inhibition in human cancer cell lines, KB, PH101, SH101 and K562. A DTD inhibitor, dicoumarol (DIC) or flavin adenine dinucleotide (FAD), inhibited the MMC-induced DNA damage and cytotoxicity at a non-toxic concentration. The DTD-mediated MMC activation was pH-dependent, and highest at pH 6 and lowest at pH 8. Although an inverse relationship appeared to exist between DTD activity and MMC efficacy in human xenografts implanted into nude mice and 9 fresh human tumor specimens, the investigation in 3 culture cells, HEC-46, HCC-48 and HCC-50, established from those xenografts, showed that DTD activated MMC in a pH-dependent manner as well as the other cell lines. Significant tumor pH reduction from 7.1 to 6.7 by continuous glucose infusion also increased the MMC-induced tumor growth inhibition in the human tumor xenografts. Thus, we conclude that bioreductive activation by DTD in a pH-dependent manner may be of key importance in the MMC-induced antitumor effect and that an increased MMC efficacy at a reduced pH caused by hyperglycemia may be applied to clinical use as a new manipulation for a biochemical modulation of MMC.
Saeki
S
S
Department of Surgical Oncology, Hiroshima University, Japan.
Nishiyama
M
M
Toge
T
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D016685:Mitomycin; D016660:NAD(P)H Dehydrogenase (Quinone)