The role of DT-diaphorase in determining the sensitivity of human tumor cells to tirapazamine (SR 4233).
Patterson AV., Robertson N., Houlbrook S., Stephens MA., Adams GE., Harris AL., Stratford IJ., Carmichael J.
PURPOSE: To determine the dependency of the aerobic and hypoxic toxicity of tirapazamine on the intracellular activity of DT-diaphorase. METHODS AND MATERIALS: A panel of 18 human cell lines comprising predominantly small cell and nonsmall cell lung cancer and breast cancer lines were used. The activity of DT-diaphorase was determined in cytosolic preparations from cell lysates. The toxicity of tirapazamine was determined using the MTT assay after either 96 or 3 h aerobic exposure or 3 h treatment in hypoxia. RESULTS: The cell lines exhibited a 5000-fold range in DT-diaphorase activity. In toxicity experiments, values of IC50 range from 10.2-120 microM and from 155-1230 for 96 and 3 h aerobic exposures, respectively. In N2, IC50s ranged from 8-55 microM. None of the toxicity values correlate with activity of DT-diaphorase, neither did the ratio of aerobic:hypoxic toxicity (differential toxicity). CONCLUSION: The expression of DT-diaphorase in human tumor cells does not affect the toxicity of tirapazamine.