Hicks, K. O., Siim, B. G., Pruijn, F. B. and Wilson, W. R. Oxygen Dependence of the Metabolic Activation and Cytotoxicity of Tirapazamine: Implications for Extravascular Transport and Activity in Tumors. Radiat. Res. 161, 656–666 (2004).

The hypoxic cytotoxin tirapazamine (TPZ) is currently in phase III clinical trial and appears to have clinical activity. One hypothesis as to why TPZ has been used more successfully in the clinic than most other bioreductive drugs is that its unusual O2 dependence allows killing of radioresistant cells at “intermediate” O2 concentrations. We have determined the O2 dependence of the metabolism of TPZ to its reduction product SR 4317, and its cytotoxicity, in stirred suspensions of HT29 colon carcinoma cells while monitoring O2 in solution with an Oxylite™ probe. The O2 dependence of the cytotoxicity of TPZ is entirely accounted for by its inhibition of the metabolism of TPZ, with a KO2 value (O2 concentration for 50% inhibition) of 1.21 ± 0.09 (SEM) μM. We used this experimental O2 dependence to extend a recent (Hicks et al., Cancer Res. 63, 5970–5977, 2003) pharmacokinetic/pharmacodynamic model for the cytotoxicity of TPZ in anoxic HT29 multicellular layers to model cell killing in tumors. The model indicates that the O2 dependence of killing by TPZ complements that of radiation well during fractionated radiotherapy. It predicts that lowering KO2 would decrease killing in radioresistant cells at intermediate O2 concentrations, while higher KO2 values would exacerbate metabolic consumption of TPZ and thus further impede its penetration into hypoxic regions. Raising KO2 would also increase metabolic activation at physiological O2 concentrations, thereby compromising hypoxic selectivity. We conclude that the KO2 value of TPZ is indeed close to the optimum for a bioreductive drug of this class (i.e. one that kills only cells in which it is reduced).

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