Mitomycin C (MC) is a naturally occurring
anticancer agent which has been shown to be more cytotoxic to hypoxic
tumor cells than to their aerobic counterparts. The mechanism of action of this agent is thought to involve
biological reductive activation, to a species that alkylates
DNA. A comparison of the cytotoxicity of MC to EMT6
tumor cells with that of the structural analogues
porfiromycin (PM), N-(N',N'-dimethylaminomethylene)
amine analogue of
mitomycin C (BMY-25282), and N-(N',N'-dimethylaminomethylene)
amine analogue of
porfiromycin (BL-6783) has demonstrated that PM is considerably less cytotoxic to aerobic EMT6 cells than MC, whereas
BMY-25282 and
BL-6783 are significantly more toxic. The relative abilities of each of these compounds to generate
oxygen free radicals following
biological activation were measured.
Tumor cell sonicates, reduced
nicotinamide adenine dinucleotide phosphate-
cytochrome c reductase,
xanthine oxidase, and mitochondria were used as the
biological reducing systems. All four
mitomycin antibiotics produced
oxygen radicals following
biological reduction, a process that may account for the aerobic cytotoxicity of agents of this class. The generation of relative amounts of
superoxide and
hydroxyl radical were also measured in EMT6 cell sonicates.
BMY-25282 and
BL-6783 produced significantly greater quantities of
oxygen free radicals with the EMT6 cell sonicate, reduced
nicotinamide adenine dinucleotide phosphate-
cytochrome c reductase, and mitochondria than did MC and PM. In contrast,
BMY-25282 and
BL-6783 did not generate detectable levels of
free radicals in the presence of
xanthine oxidase, whereas this
enzyme was capable of generating
free radicals with MC and PM as substrates. MC consistently produced greater amounts of
free radicals than PM with all of the reducing systems.
BMY-25282,
BL-6783, and MC all generated
hydroxyl radicals, while PM did not appear to form these radicals. The findings indicate that a correlation exists between the ability of the
mitomycin antibiotics to generate
oxygen radicals and their cytotoxicity to aerobic EMT6
tumor cells.