Thiol Reactive Nitroimidazoles: Radiosensitization Studiesin Vitroandin Vivo

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Abstract
Using Chinese hamster V79 cells in vitro, a study was made of the radiosensitizing porperties of 4- or 5-nitroimidazoles substituted in the 2, 5 or 4 position with various halo, sulfur ether, sulfonamide, sulfonate, ether or nitro groups. Values of .**GRAPHIC**. ( the 1-electron reduction potential measured vs. the normal hydrogen electrode at pH7) vary in the range -178 to -565 mV. All the compounds, with 1 exception, are more efficient radiosensitizers than would be predicted from their redox potentials, and the factor, .**GRAPHIC**. by which a compound is more efficient was calculated. The 2nd-order rate constants, k2, for reaction of these nitroimidazoles with glutathione and/or dithiothreitol were determined. Within each class of nitroimidazole there is a trend for k2 to increase with increasing redox potential. However, there is no clear trend between k2 and .**GRAPHIC**. The concentration required to cause a 50% depletion of intracellular glutathione was determined for selected compounds, as was the ability of glutathione-S-tranferase to catalyse reaction with thiols. The relative thiol reactivity measured under chemically controlled conditions evidently does not necessarily indicate thiol reactivity intracellularly. Studies using the MT tumor in mice showed that the high levels of radiosensitization seen in vitro could not be duplicated in vivo. This was attributed to thiol reactivity, resulting in low metabolic stability and rapid depletion of sensitizer in vivo.