Molecular targeting of mitomycin C chemotherapy.
In 10 human cancer cell lines, the activity of mitomycin C (MMC) was found to be determined by an interplay between activation by DT-diaphorase (DTD) and inactivation by glutathione S-transferase (GST). NADPH/cytochrome P-450 reductase was not responsible for MMC activation and expression of MDRI (Mr 170,000 P-glycoprotein), and MRP (multidrug resistance-associated protein) genes did not relate to MMC resistance. Gene expression analysis for NQO1 (DTD gene) and GSTpi predicted which enzyme activity predominated in a cell line, except K562 and K562/DOX. For tumors with DTD activity only, MMC given by itself was most active. In cell lines in which DTD action was predominant, tumor selectivity was achieved by enhancing DTD-mediated activation with m-iodobenzylguanidine and hyperglycemia, which reduced the intra-tumoral pH. KW2149, a novel MMC analogue activated by glutathione, was most active against tumors in which GSTpi predominated. These various enzyme-specific effects could be observed even in cell lines derived from tumors with multidrug resistance. Such MMC treatment based on cell enzymology may enhance significantly MMC efficacy, helping to overcome multidrug resistance.
Nishiyama
M
M
Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan. yamacho@mcai.med.hiroshima-u.ac.jp
Suzuki
K
K
Kumazaki
T
T
Yamamoto
W
W
Toge
T
T
Okamura
T
T
Kurisu
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D016685:Mitomycin; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D005978:Glutathione