Comparison of the Cardiotoxic Effect of Doxorubicin and Liposome-Encapsulation of Doxorubicin Under Experimental Condition

Abstract

Aim: The objective of the present experimental study was to compare the cardiotoxic effect of doxorubicin (DOX) with liposome–encapsulated doxorubicin–citrate complex (Myocet® MYO) exploring gene expression profile differences in pig hearts. Methods: Fifteen domestic pigs received either DOX (n=6) or MYO (n=9) in 3 cycles of cytostatic treatment of human dose, 5 pigs served as control. Cardiac magnetic resonance imaging (cMRI) with gadolinium late enhancement (LE) was performed at baseline and at the 3 months follow-up to measure the left (LV) and right (RV) ventricular systolic (ejection fraction, EF), and LV diastolic (peak filling rate, PFR) function and myocardial fibrosis. Routine blood parameter and liver, kidney function were controlled during the treatment. Gene expression profile of the LV, RV and left atrium (LA) was analyzed by next generation sequencing (NGS). Results: Both DOX and MYO treatment led to systolic and diastolic dysfunction, but animals receiving MYO showed significantly better LV EF (56.4±5.6% vs 41.9 ±13.5%, p=0.039) and RV EF (42.1±2.8% vs 28.9±8.9%, p=0.009) as compared with DOX, with better LV diastolic function in MYO group (PFR: 10.7±4.8 vs 7.9±2.5 ml/s, p<0.1). Trend towards less myocardial fibrosis was observed in MYO-treated animals vs DOX, confirmed by cMRI (5.8±4.1% vs 6.6±2.9% of LV mass; 6.2±1.9% vs 8.6±3.9% of RV mass). NGS revealed significantly downregulated mitochondrial and cell membrane genes in the LA (n=685 and n=611), LV (n=1602 and n=1006) and RV (n=1230 and n=778) in MYO and DOX groups, respectively, as compared to controls. Gene array analysis showed 16 and 21 significantly (p<0.05) up-regulated metabolic, cell cycle and energy and ion transporting genes (eg. respiratory chain, mitochondrial, oxidative phosphorylation or NADH activity genes) in MYO LV and RV myocytes, respectively, as compared to DOX, while no difference in gene expression profile was observed in the LA between the MYO and DOX groups. Conclusions: The liposomal-encapsulated doxorubicin-citrat (MYO) proved to be less cardiotoxic as compared with DOX, resulting in better LV and RV systolic and LV diastolic function in association with higher expression levels of oxidative, cell cycle and energy genes i na n experimental model of cardiotoxic cytostatic therapy. Disclosure: All authors have declared no conflicts of interest.