Enhanced radiation-sensitivity by preincubation with nitroimidazoles: effect of glutathione depletion

The mechanism of enhanced radiosensitization by nitroheterocyclics after a preincubation period under hypoxic conditions was investigated. The hypothesis that this phenomenon was caused by glutathione depletion was tested.

The phenomenon of enhanced radiosensitization by nitroheterocyclics after a preincubation period under hypoxic conditions is potentially of importance therapeutically because essentially nonlethal preradiation exposures to the electron 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 test various hypotheses about maximizing its possible therapeutic benefit. In view of many observations that thiols are depleted by incubation of cells with nitroimidazoles under hypoxic conditions, we have specifically investigated this aspect of the preincubation effect. Depletion of glutathione was either enhanced by an overnight incubation with buthionine sulfoximine or minimized by preincubation with a 2-nitroimidazole which is sterically inhibited from causing thiol depletion.

When conditions were chosen which minimized variations in cellular glutathione content during the preincubation period, no preincubation effect was observed. At low, therapeutically relevant radiation doses, where 2-nitroimidazoles are less efficient sensitizers, the preincubation effect may be even more important, but thiol depletion still minimizes its impact in this region of the dose-response curve.

These results suggest that the preincubation effect is caused by a "self-sensitization" involving the known enhancement of radiation sensitization by thiol depletion.