ENHANCED RADIATION-SENSITIVITY BY PREINCUBATION WITH NITROIMIDAZOLES - EFFECT OF GLUTATHIONE DEPLETION

Purpose: The mechanism of enhanced radiosensitization by nitroheterocy clics after a preincubation period under hypoxic conditions was invest igated. The hypothesis that this phenomenon was caused by glutilthione depletion was tested. Methods and Materials: The phenomenon of enhanc ed radiosensitization by nitroheterocyclics after a preincubation peri od under hypoxic conditions is potentially of importance therapeutical ly because essentially nonlethal preradiation exposures to the electro n affinic drugs cause a much larger radiation sensitization than would otherwise be expected. We have investigated this interesting property of several 2-nitroimidazoles to determine its possible cause and to t est various hypotheses about maximizing its possible therapeutic benef it. In view of many observations that thiols are depleted by incubatio n of cells with nitroimidazoles under hypoxic conditions, we have spec ifically investigated this aspect of the preincubation effect. Depleti on of glutathione was either enhanced by an overnight incubation with buthionine sulfoximine or minimized by preincubation with a 2-nitroimi dazole which is sterically inhibited from causing thiol depletion. Res ults: When conditions were chosen which minimized variations in cellul ar glutathione content during the preincubation period, no preincubati on effect was observed. At low, therapeutically relevant radiation dos es, where 2-nitroimidazoles are less efficient sensitizers, the preinc ubation effect may be even more important, but thiol depletion still m inimizes its impact in this region of the dose-response curve. Conclus ion: These results suggest that the preincubation effect is caused by a ''self-sensitization'' involving the known enhancement of radiation sensitization by thiol depletion.