title: The age factor for mitoxantrone's cardiotoxicity: multiple doses render the adult mouse heart more susceptible to injury.
abstract: Age is a known susceptibility factor for the cardiotoxicity of several anticancer drugs, including mitoxantrone (MTX). The impact of anticancer drugs in young patients is underestimated, thus we aimed to evaluate the cardiotoxicity of MTX in juvenile and adult animals. Juvenile (3 week-old) and adult (8-10 week-old) male CD-1 mice were used. Each group was treated with a 9.0mg/kg cumulative dose of MTX or saline; they were maintained in a drug-free period for 3-weeks after the last administration to allow the development of late toxicity (protocol 1), or sacrificed 24h after the last MTX administration to evaluate early cardiotoxicity (protocol 2). In protocol 1, no adult mice survived, while 2 of the juveniles reached the end of the protocol. High plasma aspartate aminotransferase/alanine aminotransferase ratio and a high cardiac reduced/oxidized glutathione ratio were found in the surviving MTX-treated juvenile mice. In protocol 2, a significant decrease in plasma creatine-kinase MB in juveniles was found 24h after the last MTX-administration. Cardiac histology showed that both MTX-treated populations had significant damage, although higher in adults. However, MTX-treated juveniles had a significant increase in fibrotic tissue. The MTX-treated adults had higher values of cardiac GSSG and protein carbonylation, but lower cardiac noradrenaline levels. For the first time, mature adult animals were shown to be more susceptible to MTX as evidenced by several biomarkers, while young animals appear to better adjust to the MTX-induced cardiac injury. Even so, the higher level of fibrotic tissue and the histological damage showed that MTX also causes cardiac damage in the juvenile population.
authors.affiliation: UCBIO-REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. Electronic address: jldsousa@ff.up.pt.
authors.forename: José Luís
authors.initials: JL
authors.lastname: Dores-Sousa
authors.affiliation: CIAFEL, Faculdade de Desporto, Universidade do Porto, Porto, Portugal.
authors.forename: José Alberto
authors.initials: JA
authors.lastname: Duarte
authors.affiliation: Departamento de Ciências Farmacêuticas, CESPU, Instituto Superior de Ciências da Saúde do Norte, ISCS-N, Paredes, Portugal.
authors.forename: Vítor
authors.initials: V
authors.lastname: Seabra
authors.affiliation: UCBIO-REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Maria de Lourdes
authors.initials: Mde L
authors.lastname: Bastos
authors.affiliation: UCBIO-REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: UCBIO-REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. Electronic address: veramcosta@ff.up.pt.
authors.forename: Vera Marisa
authors.initials: VM
authors.lastname: Costa
mesh_terms: D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D066126:Cardiotoxicity / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D052279:Creatine Kinase, MB Form / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000378:metabolism; D005355:Fibrosis; D019803:Glutathione Disulfide / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008942:Mitoxantrone / Q000008:administration & dosage / Q000633:toxicity*; D009206:Myocardium / Q000473:pathology*; D009638:Norepinephrine / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010725:Phosphocreatine / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D010725:Phosphocreatine; D008942:Mitoxantrone; D001219:Aspartate Aminotransferases; D052279:Creatine Kinase, MB Form; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D003401:Creatine; D019803:Glutathione Disulfide; D009638:Norepinephrine; D004837:Epinephrine
keywords: Age; Glutathione; Mitoxantrone; Noradrenaline; Protein carbonylation