Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania.
Parasites pose a threat to the health and lives of many millions of human beings. Among the pathogenic protozoa, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani are hemoflagellates that cause particularly serious diseases (sleeping sickness, Chagas disease, and leishmaniasis, respectively). The drugs currently available to treat these infections are limited by marginal efficacy, severe toxicity, and spreading drug resistance. Camptothecin is an established antitumor drug and a well-characterized inhibitor of eukaryotic DNA topoisomerase I. When trypanosomes or leishmania are treated with camptothecin and then lysed with SDS, both nuclear and mitochondrial DNA are cleaved and covalently linked to protein. This is consistent with the existence of drug-sensitive topoisomerase I activity in both compartments. Camptothecin also inhibits the incorporation of [3H]thymidine in these parasites. These molecular effects are cytotoxic to cells in vitro, with EC50 values for T. brucei, T. cruzi, and L. donovani, of 1.5, 1.6, and 3.2 microM, respectively. For these parasites, camptothecin is an important lead for much-needed new chemotherapy, as well as a valuable tool for studying topoisomerase I activity.
Bodley
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Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185, USA.
Shapiro
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D000818:Animals; D002166:Camptothecin / Q000494:pharmacology* / Q000633:toxicity; D004261:DNA Replication / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000187:drug effects*; D016054:DNA, Protozoan / Q000096:biosynthesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D059004:Topoisomerase I Inhibitors; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism
D004272:DNA, Mitochondrial; D016054:DNA, Protozoan; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin