The role of reductive enzymes in cancer cell resistance to mitomycin C.

Mitomycin C (MMC) is bioreductively activated to DNA binding species via complex chemical pathways involving a common hydroquinone intermediate. A recent publication by Belcourt et al. (1999) has revealed that the bacterial mitomycin C resistance protein (MCRA) acts as a unique hydroquinone oxidase converting this reactive intermediate back to the parent drug in the presence of molecular oxygen, preventing the formation of cytotoxic interstrand DNA crosslinks. It was argued that a mechanism analogous to MCRA may be responsible for the often observed phenomenon of aerobic drug resistance that develops in vitro to MMC in human cancer cell lines. Altered expression of activating reductase enzymes, which usually accompanies aerobic drug resistance, was claimed to be of lesser importance. Therefore, the role of reductases in MMC drug resistance has been reviewed. While it is clear from numerous studies that lowered reductase expression can in certain situations produce drug resistance, simple correlations between a specific enzyme and chemosensitivity generally do not hold due to the complex functional and regulatory interplay that exists among the different activating enzymes and detoxification systems. Copyright 2000 Harcourt Publishers Ltd.