Misonidazole and other hypoxia markers: metabolism and applications

A substantial effort is being devoted to developing markers for hypoxia in tumors. Most of the work to date has been performed on misonidazole (MISO), which is selectively metabolized by hypoxic cells to reactive products that bind covalently to cellular constituents. This paper attempts to review the metabolism of MISO as it relates to binding, to summarize several of the properties of the binding of MISO to cells and tissues which appear to be directly relevant to the characteristics of the reactive species involved, and to evaluate the potential of MISO and other nitroheterocycles as markers for hypoxia. Four roles for a hypoxic marker are considered. MISO labeled with 3H or 14C is a good marker for local radiobiological hypoxia in autoradiograms of tumor sections, but more work is required to investigate factors other than oxygen concentration that conceivably might affect the binding process. In quantitating hypoxic fraction in tumors using non-destructive techniques, which has been modelled by correlating surviving fraction with 14C-misonidazole uptake, non-specific binding to aerobic and necrotic tissue limits the accuracy of the estimate, but useful clinical applications can still be envisaged. For quantitation of a change in the hypoxic fraction of an individual tumor using serial assays, preliminary data suggest that MISO binding should be a sensitive assay. Fluorescent nitroheterocycles have a great deal of potential as markers to enable the sorting of tumor cell suspensions into portions derived from the hypoxic and aerobic regions, but better compounds are needed.