Misonidazole: inter-related factors affecting cytotoxicity.

A detailed investigation was undertaken of reported modifiers of the toxicity towards hypoxic cells of misonidazole. The modifiers tested were medium type, cell type, cell density, concentration of misonidazole, addition of serum, addition of sulfhydryl, addition of oxygen and pH. The latter 5 modifiers were found to be most important and were studied in many of the possible combinations. Serum has its greatest protective effect at low concentration (e.g. 0.5 mM) of misonidazole. In the absence of serum, the (log10) survival curve for misonidazole toxicity can be described mathematically as a function of time by a shoulder (DQ) inversely related to misonidazole concentration, and a slope (1/D0) related directly to log10 misonidazole concentration. Sulfhydryl's (cysteamine) protective effect dominates at high concentrations of misonidazole. The protective action of SH can change to potentiative in the absence of serum or at high pH. Addition of oxygen results in overall protection but no relative changes in the effect of the other modifiers. Drugs like ascorbate and disulfide may only potentiate toxicity to the level found in the absence of serum.