Increased cell killing by metronidazole and nitrofurazone of hypoxic compared to aerobic mammalian cells.

Nitromidazole and nitrofuran derivatives comprise a large family of compounds, some of which have been shown to be hypoxic cell specific radiosensitizers in vivo and in vitro. The effects of metronidazole (2-methyl-5-nitroimidazole-1-ethanol) and nitrofurazone (5-nitro-2-furaldehyde semicarbazone) were studied on cell viability in vitro in the presence of air or nitrogen in the absence of radiation. Exponential-phase Chinese hamster ovary cells were placed in suspension culture in complete medium in the presence of air, made hypoxic by flowing nitrogen (less then 0.001% oxygen), and exposed to various concentrations of these drugs. As a function of time, aliquots were removed and plated to determine cell viability. After 8 hr of incubation of Chinese hamster ovary cells in 29 mM metronidazole or 500 muM nitrofurazone, the absolute plating efficiency remains relatively constant (80 to 40%) in the presence of air. In contrast, under hypoxic conditions the plating efficiency of the cells dropped to 1% after 6 hr of incubation in 29 mM metronidazole or 500 muM nitrofurazone. This phenomenon of hypoxic cell specific toxicity was found to be dependent upon cell type, concentration of drug, temperature of incubation, and oxygen concentration. The results of these experiments indicate an increased toxicity of these drugs under hypoxic conditions and suggest that further investigation into the mechanism and specificity of these effects is warranted.