{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T20:55:48Z","timestamp":1779396948317,"version":"3.53.1"},"reference-count":36,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2012,10,1]],"date-time":"2012-10-01T00:00:00Z","timestamp":1349049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Visceral leishmaniasis is an emerging neglected tropical disease (NTD) caused by the protozoan\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania infantum<\/jats:named-content>\n            in the countries bordering the Mediterranean Basin. Currently there is no effective vaccine against this disease, and the therapeutic approach is based on toxic derivatives of Sb\n            <jats:sup>V<\/jats:sup>\n            . Therefore, the discovery of new therapeutic targets and the development of drugs designed to inhibit them comprise an extremely important approach to fighting this disease. DNA topoisomerases (Top) have been identified as promising targets for therapy against leishmaniasis. These enzymes are involved in solving topological problems generated during replication, transcription, and recombination of DNA. Being unlike that of the mammalian host, type IB DNA topoisomerase (TopIB) from\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania<\/jats:named-content>\n            spp. is a unique bisubunit protein, which makes it very interesting as a selective drug target. In the present investigation, we studied the effect of two TopIB poisons with indenoisoquinoline structure, indotecan and AM13-55, on a murine BALB\/c model of infected splenocytes with\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. infantum<\/jats:named-content>\n            , comparing their effectiveness with that of the clinically tested leishmanicidal drug paromomycin. Both compounds have high selectivity indexes compared with uninfected splenocytes. SDS-KCl-precipitable DNA-protein complexes in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania<\/jats:named-content>\n            promastigotes and\n            <jats:italic>in vitro<\/jats:italic>\n            cleaving assays confirmed that these drugs are Top poisons. The inhibitory potency of both indenoisoquinolines on\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. infantum<\/jats:named-content>\n            recombinant TopIB was assessed\n            <jats:italic>in vitro<\/jats:italic>\n            , with results showing that indotecan was the most active compound, preventing the relaxation of supercoiled DNA. Experimental infections in susceptible BALB\/c mice treated with 2.5 mg\/kg body weight\/day once every other day for a total of 15 days showed that indotecan cleared more than 80% of the parasite burden of the spleen and liver, indicating promising activity against visceral leishmaniasis.\n          <\/jats:p>","DOI":"10.1128\/aac.00499-12","type":"journal-article","created":{"date-parts":[[2012,7,31]],"date-time":"2012-07-31T07:47:26Z","timestamp":1343720846000},"page":"5264-5270","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":47,"title":["Indotecan (LMP400) and AM13-55: Two Novel Indenoisoquinolines Show Potential for Treating Visceral Leishmaniasis"],"prefix":"10.1128","volume":"56","author":[{"given":"Rafael","family":"Bala\u00f1a-Fouce","sequence":"first","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Universidad de Le\u00f3n, Campus de Vegazana, Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher F.","family":"Prada","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Universidad de Le\u00f3n, Campus de Vegazana, Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Mar\u00eda","family":"Requena","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Centro de Biolog\u00eda Molecular Severo Ochoa, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Cushman","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Pommier","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"\u00c1lvarez-Velilla","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Universidad de Le\u00f3n, Campus de Vegazana, Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Miguel","family":"Escudero-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Universidad de Le\u00f3n, Campus de Vegazana, Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Calvo-\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Universidad de Le\u00f3n, Campus de Vegazana, Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"P\u00e9rez-Pertejo","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Universidad de Le\u00f3n, Campus de Vegazana, Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa M.","family":"Reguera","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Universidad de Le\u00f3n, Campus de Vegazana, Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1007\/s00436-011-2555-5","article-title":"Leishmania antimony resistance: what we know what we can learn from the field","volume":"109","author":"A\u00eft-Oudhia K","year":"2011","unstructured":"A\u00eft-OudhiaK GazanionE VergnesB OuryB SerenoD. 2011. 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Pharmacol."},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/519690"},{"key":"e_1_3_3_10_2","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1517\/14656566.6.8.1381","article-title":"Miltefosine to treat leishmaniasis","volume":"6","author":"Berman J","year":"2005","unstructured":"BermanJ. 2005. Miltefosine to treat leishmaniasis. Expert Opin. Pharmacother. 6:1381\u20131388.","journal-title":"Expert Opin. Pharmacother."},{"key":"e_1_3_3_11_2","doi-asserted-by":"crossref","first-page":"3726","DOI":"10.1073\/pnas.92.9.3726","article-title":"Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania","volume":"92","author":"Bodley AL","year":"1995","unstructured":"BodleyAL ShapiroTA. 1995. Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania. Proc. Natl. Acad. Sci. U. S. A. 92:3726\u20133730.","journal-title":"Proc. Natl. Acad. Sci. U. S. 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