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Published on: July 27, 2022
The age factor for mitoxantrone's cardiotoxicity: multiple doses render the adult mouse heart more susceptible to
José Luís Dores-Sousa1, José Alberto Duarte2, Vítor Seabra3
1UCBIO-REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
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.
Insights
Adult animals are more susceptible to mitoxantrone (MTX) cardiotoxicity than juveniles. While young mice showed some cardiac damage and fibrosis, adult mice experienced higher mortality and biomarker changes, indicating greater MTX susceptibility.
Area of Science:
- Pharmacology
- Toxicology
- Cardiology
Background:
- Age is a known factor influencing anticancer drug cardiotoxicity.
- The impact of cardiotoxic agents like mitoxantrone (MTX) in younger populations is often underestimated.
- Understanding age-related differences in drug-induced cardiotoxicity is crucial for patient safety.
Purpose of the Study:
- To evaluate and compare the cardiotoxicity of mitoxantrone (MTX) in juvenile and adult mice.
- To assess both early and late cardiotoxicity effects of MTX across different age groups.
- To identify age-specific biomarkers of MTX-induced cardiac injury.
Main Methods:
- Juvenile (3-week-old) and adult (8-10 week-old) male CD-1 mice were administered a cumulative dose of 9.0mg/kg MTX or saline.
- Two protocols were used: one for late toxicity (3-week drug-free period) and one for early toxicity (sacrifice 24h post-treatment).
- Cardiotoxicity was assessed through survival rates, plasma enzyme levels (AST/ALT, CK-MB), cardiac glutathione redox state, protein carbonylation, noradrenaline levels, and histological analysis.
Main Results:
- Adult mice exhibited higher mortality than juveniles in the late toxicity protocol.
- Juvenile mice showed increased plasma AST/ALT and cardiac reduced/oxidized glutathione ratios, alongside elevated fibrotic tissue.
- Adult mice displayed higher cardiac GSSG, protein carbonylation, and histological damage, but lower noradrenaline levels, suggesting greater susceptibility to MTX cardiotoxicity.
Conclusions:
- Mature adult animals are more susceptible to mitoxantrone-induced cardiotoxicity compared to juveniles, as indicated by multiple biomarkers and survival data.
- Juvenile animals, while showing signs of cardiac injury including fibrosis, appear to have a better capacity to adjust to MTX-induced cardiac damage.
- Mitoxantrone causes significant cardiac damage in both juvenile and adult mice, highlighting the need for careful monitoring across all age groups.
