Oxygen Tension, Cellular Respiration, and Redox State as Variables Influencing the Cytotoxicity of the Radiosensitizer Misonidazole

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Abstract
The colony-forming ability of Chinese hamster ovary (CHO) cells that were incubated in the presence of 10 mM misonidazole [1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol(MIS)] at intermediate O2 levels was studied using stirred cell suspensions gassed with gas mixtures containing 0.1-2% O2. During the treatment, the O2 tension in solution was directly monitored using a Clark-type O2-sensing electrode. Survival studies were also done with KCN-inhibited CHO cells and a respiration-deficient cell line [Chinese hamster lung fibroblast respiration-deficient CL16-B2 res- cells]. In all cases, the O2 probe measurements indicated that substantially lower O2 levels were present in solution relative to the gas phase due to cellular O2 consumption. Very low levels of O2 were effective in inhibiting MIS toxicity. Less than 200 ppm (2 .times. 10-7 M) O2 was sufficient to reduce the maximal rate of killing by 50% for 10 mM MIS. With the respiration-deficient cell line, the O2 dependence of MIS toxicity could be investigated under conditions where a constant O2 level could be maintained throughout the incubation. KCN enhanced drug toxicity at all nonzero O2 levels. MIS toxicity probably is mediated by an interplay of O2 level, respiration rate and redox state of the cell. MIS caused a time-dependent decrease in cellular O2 utilization rates, after substantial cell killing, which appeared to be responsible for the rise in O2 tension and reduced rate of killing by MIS noted at longer incubation times (6-12 h). [The hypoxic cell radiosensitizer MIS Ras also been shown to preferentially kill hypoxic tumor cells in the absence of radiation.].

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