Ascorbate anion potentiates cytotoxicity of nitro-aromatic compounds under hypoxic and anoxic conditions

Abstract

The nitro-aromatic radiosensitizing drugs are selectively toxic to hypoxic mammalian cells, and this toxicity can be greatly increased by the addition of ascorbate. The ascorbate itself is not toxic to either hypoxic or aerobic cells (as long as catalase is present to prevent the formation of significant concentrations of hydrogen peroxide) and the mixture of ascorbate plus radiosensitizer is not more toxic to aerobic cells. Sulphydryl reducing agents and dithionite have an effect opposite to ascorbate and decrease the toxicity of nitro-aromatic drugs under hypoxic conditions. Sulphydryl reducing agents are also reported to nullify the radiosensitizing properties of nitro-aromatic drugs, in contrast to ascorbate which has no effect on the radiosensitizing properties. The toxicity of nitro-aromatic drugs decreases rapidly with increasing O2 concentration. This decrease is much less rapid when ascorbate is present. The role of ascorbate in this case may be primarily as an O2 scavenger, although it is also possible that the toxic species produced by radiosensitizer-ascorbate mixtures is less easily removed or detoxified by O2.