SENSITIVITY OF LEISHMANIA-VIANNIA-PANAMENSIS TO PENTAVALENT ANTIMONY IS CORRELATED WITH THE FORMATION OF CLEAVABLE DNA-PROTEIN COMPLEXES

The emergence of Leishmania less sensitive to pentavalent antimonial a gents (SbVs), the report of inhibition of purified topoisomerase I of Leishmania donovani by sodium stibogluconate (Pentostam), and the unce rtain mechanism of action of antimonial drugs prompted an evaluation o f SbVs in the stabilization of cleavable complexes in promastigotes of Leishmania (Viannia). The effect of camptothecin, an inhibitor of top oisomerase, and additive-free meglumine antimoniate (Glucantime) on th e stabilization of cleavable DNA-protein complexes associated with the inhibition of topoisomerase was assessed in the human promonocytic ce ll line U-937, promastigotes of L. (Viannia) panamensis selected for S bV resistance in vitro, and the corresponding wild-type strain. The st abilization of cleavable complexes and the 50% effective dose (ED50) o f SbVs for parasites isolated from patients with relapses were also ev aluated. The median ED50 for the wild-type strain was 16.7 mu g of SbV /ml, while that of the line selected for resistance was 209.5 mu g of SbV/ml, Treatment with both meglumine antimoniate and sodium stibogluc onate (20 to 200 mu g of SbV/ml) stabilized DNA-protein complexes in t he wild-type strain but not the resistant line, The ED(50)s of the SbV s for Leishmania strains from patients with relapses was comparable to those for the line selected for in vitro resistance, and DNA-protein complexes were not stabilized by exposure to meglumine antimoniate, Cl eavable complexes were observed in all Leishmania strains treated with camptothecin, Camptothecin stabilized cleavable complexes in U-937 ce lls; SbVs did not. The selective effect of the SbVs on the stabilizati on of DNA-protein complexes in Leishmania and the loss of this effect in naturally resistant or experimentally derived SbV-resistant Leishma nia suggest that topoisomerase may be a target of antimonial drugs.