Tumor-specific synergistic therapy of mitomycin C: modulation of bioreductive activation.
The bioreductive activation of mitomycin C (MMC) has been investigated using 10 human cancer cell lines. Except for 2 lines (COLO201 and COLO320DM), the cellular NAD(P)H: quinone oxidoreductase (DTD) activities correlated well with MMC-induced DNA damage and cytotoxicity. In addition, when the DTD activity was inhibited with 50 mM dicoumarol, the MMC activity decreased significantly. On the other hand, no correlation between the NADPH cytochrome P450 reductase (P450) activity and MMC efficacy was observed. We postulate that two electron reduction by DTD may be more important in MMC activation than one electron reduction by P450. The DTD-mediated metabolism was pH-dependent. In a nude mouse experimental model, the pH in the tumor decreased under hyperglycemic conditions due to unique glycolysis. The administration of m-iodobenzyl-guanidine (MIBG) enhanced the decrease in the pH of the tumor without affecting the pH of normal tissue (liver). It also significantly increased the antitumor activity of MMC. However, this biochemical modulation had no effect in the COLO201 and COLO320DM cells. Other mechanisms may be involved in the regulation of MMC activity in these cells. In conclusion, DTD may be an important target of MMC. Biochemical modulation using MIBG and glucose may selectively enhance the activity of MMC within cancer cells.
Sakamoto
N
N
Department of Surgical Oncology, Hiroshima University, Japan.
Toge
T
T
Nishiyama
M
M
D019797:3-Iodobenzylguanidine; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D001728:Dicumarol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007462:Iodobenzenes / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000378:metabolism / Q000627:therapeutic use*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D007462:Iodobenzenes; D019797:3-Iodobenzylguanidine; D016685:Mitomycin; D001728:Dicumarol; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone)