EXPLOITING TUMOR HYPOXIA THROUGH BIOREDUCTIVE RELEASE OF DIFFUSIBLE CYTOTOXINS - THE COBALT(III)-NITROGEN MUSTARD COMPLEX SN-24771

Purpose: To assess the oxygen dependence of a novel cobalt-nitrogen mustard complex, SN 24771, designed to release a diffusible cytotoxic metabolite in hypoxic tumor microenvironments. Methods and Materials: Oxygen dependence of cell killing was assessing in well-stirred single cell suspensions obtained by enzymatic dissociation of EMT6 spheroids, using a sensitive oxygen electrode to measure oxygen concentrations in solution. Cell killing in intact EMT6 spheroids was also compared with that in single cell suspensions. Results: Cytotoxicity of SN 24771 in single cell suspensions was inhibited by very low concentrations of oxygen. The C-50 value (O-2 required for 50% inhibition of log cell kill) was ca. 0.02% O-2 at 1 h, and the K value (O-2 required to give a cytotoxic potency equal to the average of that at zero and infinite O-2) was of a similar order. However, intact spheroids were much more sensitive to SN 24771 than could be accounted for by the K curve for single cell suspensions, this estimate being based on published data for the oxygen concentration profile in these spheroids. Conclusion: The cytotoxicity of SN 24771 is inhibited appreciably at oxygen concentrations which are too low to provide radiosensitization. In this respect, SN 24771 resembles organic bioreductive drugs such as quinones and nitroaromatic compounds. However, the extensive killing observed in multicellular spheroids is consistent with release of a diffusible nitrogen mustard on reduction. Bioreductive drugs with a low K value for activation, but which release a diffusible cytotoxin, may have desirable properties as tumor radiosensitizers.