Doxorubicin-induced cardiotoxicity model elaboration in rats and rabbits

E.V. Mazukina, Department of Experimental Pharmacology and Toxicology, researcher. ORCID 0000-0002-1448-921X

E.V. Shekunova, PhD, Department of Experimental Pharmacology and Toxicology, head. ORCID 0000-0002-2689-6891

Ya.A. Guschin, Department of laboratory diagnostics, head. ORCID 0000-0002-7656-991Х

N.M. Faustova, PhD, Laboratory for enzyme immunoassay, head. ORCID 0000-0002-6866-5741

Research and manufacturing company «Home оf Pharmacy»,
188663, Russia, Leningrad oblast, Vsevolozhskiy district, Kuzmolovskiy t.s., Zavodskaya st. 3-245

E-mail: mazukina.ev@doclinika.ru

Abstract

Doxorubicin (DOX) is commonly used in the treatment of many types of cancers but its cardiotoxicity is limiting its clinical use. The establishing approaches to prevent DOX-mediated cardiotoxicity are urgent task. Experimental studies are needed for testing the effectiveness of innovative drugs. There are many methods describing. The literature describes various methodological approaches to the experimental modeling of DOX-induced cardiotoxicity.

The aim of the study: to reproduce the methods of DOX-induce cardiotoxicity in rats and rabbits based on scientific literature for further evaluation of the effectiveness of the cardioprotective properties of drugs.

Methods: rats were treated with DOX 2.5–5.0 mg/kg, intraperitoneally twice a week for 4 weeks;  cumulative doses were 20–32.5 mg/kg. Rabbits were treated with DOX 1.0 mg/kg, intravenously twice a week for 4 or 6 weeks, cumulative doses were 8 and 12 mg/kg. Assessment of cardiovascular function was made using electrocardiography (ECG) and blood pressure (BP) recording. The markers of oxidative stress (malondialdehyde, reduced glutathione) were also evaluated. The effect of doxorubicin on the myocardium was investigated with histological analysis.

Results: DOX administration, 5 mg/kg, resulted in high mortality rate (90%) in rats. Thus, this dose should not be used for DOX cardiotoxicity assessment. The least dose used (2.5 mg/kg) caused mild parameters changes. The mortality rate was around 20%. The DOX at doses 3.0–3.5 mg/kg resulted in severe myocardium histology changes, cardiac dysfunction (assesses by ECG), changes of antioxidant system parameters. The mortality rate at these doses was lower than that at dose 5 mg/kg (30–40%). Thus, DOX administration schedule at doses 3.0–3.5 for 4 weeks may be used to assess DOX cardiotoxicity.

In the rabbit study repeated intravenous DOX administration at dose 1 mg/kg caused severe myocardium histology changes indicating cardiotoxicity. The animals did not demonstrate any sigh of clinical abnormalities. In spite of presense of DOX-induced myocardial lesions, oxidative stress markers (malondialdehyde), blood pressure, ECG did not change significantly. There was high individual variability of these parameters. It could be speculated that to induce severe changes in oxidative stress markers the more prolong DOX administration is needed (up to 8 weeks).

Full text avaliable in Russain only 

Acknowledgements

The study was performed without external funding.

Authors’ contributions

E.V.Mazukina – conducting experiments, collecting data, analyzing data, writing a manuscript.

E.V. Shekunova – development of the research concept, data analysis, participation in the writing of the manuscript, critical revision of the content of the article.

Ya.A. Gushchin – pathomorphological analysis, participation in the writing of the manuscript

N.M. Faustova – conducting biochemical research, participating in the writing of the manuscript.

Conflict of interest

The authors declare no conflicts of interest.

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