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 hu man beings, Among the pathogenic protozoa, Trypanosoma brucei, Trypano soma cruzi, and Leishmania donovani are hemoflagellates that cause par ticularly serious diseases (sleeping sickness, Chagas disease, and lei shmaniasis, respectively), The drugs currently available to treat thes e infections are limited by marginal efficacy, severe toxicity, and sp reading 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 the n lysed with SDS, both nuclear and mitochondrial DNA are cleaved and c ovalently linked to protein, This is consistent with the existence of drug-sensitive topoisomerase I activity in both compartments, Camptoth ecin also inhibits the incorporation of [H-3]thymidine in these parasi tes, These molecular effects are cytotoxic to cells in vitro, with EC( 50) values for T. brucei, T. cruzi, and L. donovani, of 1.5, 1.6, and 3.2 mu M, respectively, For these parasites, camptothecin is an import ant lead for much-needed new chemotherapy, as well as a valuable tool for studying topoisomerase I activity.