A Comparison of the Intracellular Uptake and Radiosensitization Efficiency in Different Media of Uncharged 2-nitroimidazoles of Varying Lipophilicity

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Abstract
The effect of varying octanol: water partition coefficients, P, (range 0.026-260) on the uptake of uncharged 2-nitroimidazoles into Chinese hamster V79 379A cells has been studied. Average intracellular concentrations were measured by high performance liquid chromatography after centrifuging cells through oil or an aqueous medium. The ratio of intracellular concentration of radiosensitizer to extracellular concentration (Ci/Ce) for misonidazole (P=0.43) was 0.85 for the oil method and 0.68 for the aqueous method. For values of P less than about 0.05 uptake was initially very slow and Ci was always less than Ce. When P .gtoreq. 0.1 uptake was rapid and then remained unchanged for times up to 3 h; for P .gtoreq. 10, Ci/Ce increased rapidly as P increased, Ro 31-1405 (P=260) concentrated by a factor of 7 inside the cell. Although uptake was identical for cells suspended in full growth medium and PBS, radiosensitization was greater for cells in PBS: 1 mmol dm-3 misonidazole produced an enhancement ratio of 1.6 in full growth medium and 1.9 in PBS. This increase in radiosensitization could not be accounted for by protein binding. However, measurements on cellular non-protein sulphydryl (NPSH) demonstrated the levels to be reduced to about 60 per cent for cells in PBS. Similar reductions in NPSH levels have previously been shown not to increase the radiosensitivity of control cells but to increase greatly the effectiveness of nitroimidazole radiosensitizers.