title: The antileishmanial drug miltefosine (Impavido(®)) causes oxidation of DNA bases, apoptosis, and necrosis in mammalian cells.
abstract: Miltefosine was developed to treat skin cancer; further studies showed that the drug also has activity against Leishmania. Miltefosine is the first oral agent for treating leishmaniasis. However, its mechanism of action is not completely understood. We have evaluated the induction of DNA damage by miltefosine. Cytotoxicity and genotoxicity (comet assay) tests were performed on human leukocytes exposed to the drug in vitro. Apoptosis and necrosis were also evaluated. In vivo tests were conducted in Swiss male mice (Mus musculus) treated orally with miltefosine. Oxidation of DNA bases in peripheral blood cells was measured using the comet assay followed by digestion with formamidopyrimidine glycosylase (FPG), which removes oxidized guanine bases. The micronucleus test was performed on bone marrow erythrocytes. Miltefosine caused DNA damage, apoptosis, and necrosis in vitro. Mice treated with miltefosine showed an increase in the DNA damage score, which was further increased following FPG digestion. The micronucleus test was also positive.
authors.affiliation: Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, Cidade Universitária do Bacanga, São Luís, Maranhão, Brazil. Electronic address: ifepv@yahoo.com.br.
authors.forename: Patrícia Valéria
authors.initials: PV
authors.lastname: Castelo Branco
authors.affiliation: Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, Cidade Universitária do Bacanga, São Luís, Maranhão, Brazil.
authors.forename: Rossy-Eric Pereira
authors.initials: RE
authors.lastname: Soares
authors.affiliation: Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, Cidade Universitária do Bacanga, São Luís, Maranhão, Brazil.
authors.forename: Luís Cláudio Lima
authors.initials: LC
authors.lastname: de Jesus
authors.affiliation: Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, Cidade Universitária do Bacanga, São Luís, Maranhão, Brazil.
authors.forename: Vanessa Ribeiro
authors.initials: VR
authors.lastname: Moreira
authors.affiliation: Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, Cidade Universitária do Bacanga, São Luís, Maranhão, Brazil.
authors.forename: Hugo José
authors.initials: HJ
authors.lastname: Alves
authors.affiliation: Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, Cidade Universitária do Bacanga, São Luís, Maranhão, Brazil.
authors.forename: Marta Regina
authors.initials: MR
authors.lastname: de Castro Belfort
authors.affiliation: University of State of Maranhão, São Luís, Maranhão, Brazil.
authors.forename: Vera Lucia Maciel
authors.initials: VL
authors.lastname: Silva
authors.affiliation: Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, Cidade Universitária do Bacanga, São Luís, Maranhão, Brazil.
authors.forename: Silma Regina
authors.initials: SR
authors.lastname: Ferreira Pereira
mesh_terms: D000328:Adult; D000818:Animals; D000981:Antiprotozoal Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D010084:Oxidation-Reduction / Q000187:drug effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000633:toxicity; D055815:Young Adult
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine
keywords: Comet assay; Genotoxicity; Micronucleus test