Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo

Abstract

The technique of alkaline elution has been adapted for the study of drug-induced DNA cross-link formation in vivo. Pretreatment with misonidazole (MISO) enhances the number of cross-links formed in a fibrosarcoma and in the spleen and gut of mice for periods up to 48 h following a single injection of melphalan (MEL). The tumour was sensitized by a greater factor (2.05) than either of the normal tissues (enhancement factor 1.4-1.5). This enhancement did not appear to be related to inhibition of the repair of actual cross-links. Rather, the effect was explicable in terms of one of two alternative models. Firstly, MISO pretreatment could result in a greater amount of binding of MEL to DNA at early times after injection. This may be the result of altered pharmacokinetics of MEL, or of enhanced intracellular uptake of MEL due to MISO pretreatment. Secondly, MISO may exert its affect by inhibition of the repair of cross-links or monoadducts at early times post-injection, which would not be observed in this study. The possible involvement of glutathione depletion in chemosensitization by MISO was investigated by comparison with the effect of diethyl maleate (DEM), a known thiol-depleting reagent. Glutathione depletion, while perhaps being important, could not account for all of the effects observed.