Molecular targeting of mitomycin C chemotherapy

✍ Scribed by Masahiko Nishiyama; Katsuyuki Suzuki; Tsutomu Kumazaki; Wataru Yamamoto; Tetsuya Toge; Tatsunori Okamura; Kaoru Kurisu

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: French
• Weight: 190 KB
• Volume: 72
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19970807)72:4<649::aid-ijc17>3.0.co;2-6

✦ Synopsis

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 MDR1 (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 GSTp 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 miodobenzylguanidine and hyperglycemia, which reduced the intra-tumoral pH. KW2149, a novel MMC analogue activated by glutathione, was most active against tumors in which GSTp 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.