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 agents (SbVs), the report of inhibition of purified topoisomerase I of Leishmania donovani by sodium stibogluconate (Pentostam), and the uncertain mechanism of action of antimonial drugs prompted an evaluation of SbVs in the stabilization of cleavable complexes in promastigotes of Leishmania (Viannia). The effect of camptothecin, an inhibitor of topoisomerase, and additive-free meglumine antimoniate (Glucantime) on the stabilization of cleavable DNA-protein complexes associated with the inhibition of topoisomerase was assessed in the human promonocytic cell line U-937, promastigotes of L. (Viannia) panamensis selected for SbV resistance in vitro, and the corresponding wild-type strain. The stabilization of cleavable complexes and the 50% effective dose (ED50) of SbVs for parasites isolated from patients with relapses were also evaluated. The median ED50 for the wild-type strain was 16. 7 microg of SbV/ml, while that of the line selected for resistance was 209.5 microg of SbV/ml. Treatment with both meglumine antimoniate and sodium stibogluconate (20 to 200 microg of SbV/ml) stabilized DNA-protein complexes in the wild-type strain but not the resistant line. The ED50s of the SbVs 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. Cleavable complexes were observed in all Leishmania strains treated with camptothecin. Camptothecin stabilized cleavable complexes in U-937 cells; SbVs did not. The selective effect of the SbVs on the stabilization of DNA-protein complexes in Leishmania and the loss of this effect in naturally resistant or experimentally derived SbV-resistant Leishmania suggest that topoisomerase may be a target of antimonial drugs.
Facultad de Salud, Universidad del Valle, Cali, Colombia AA 5445.
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Lucumi
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Robledo
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Gama
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Saravia
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D016054:DNA, Protozoan / Q000378:metabolism*; D006801:Humans; D018334:Leishmania guyanensis / Q000187:drug effects*; D008536:Meglumine / Q000494:pharmacology*; D000077485:Meglumine Antimoniate; D009942:Organometallic Compounds / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000378:metabolism*
D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D009942:Organometallic Compounds; D015800:Protozoan Proteins; D008536:Meglumine; D000077485:Meglumine Antimoniate; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin