Key result
Liposomal doxorubicin resulted in less reduction of ventricular systolic function and myocardial fibrosis than standard doxorubicin, associated with upregulation of interferon-stimulated genes.
Why the study?
Clinical use of doxorubicin is limited by cardiotoxicity, prompting evaluation of transcriptomic responses to anthracyclines with differing cardiotoxicity profiles in a large animal model to identify potential alleviation strategies.
Does liposomal doxorubicin reduce cardiotoxicity compared to standard doxorubicin in a large animal model?
Does liposomal doxorubicin reduce cardiotoxicity compared to standard doxorubicin in a large animal model?
Liposomal doxorubicin mitigates cardiotoxicity compared to standard doxorubicin in a porcine model, potentially via upregulation of interferon-stimulated genes.
Animal transcriptomics may identify cardioprotective targets; leaves open clinical translation of anthracycline strategies.
AIMS: The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies. METHODS AND RESULTS: We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups. CONCLUSIONS: All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.
No takes yet. Share an insight, caveat, or question.
Gyöngyösi et al. (2019) studied Anthracycline-induced cardiomyopathy. Liposomal doxorubicin vs. Standard doxorubicin, epirubicin, and saline was evaluated on Cardiotoxicity and transcriptomic responses. Liposomal doxorubicin resulted in less reduction of ventricular systolic function and myocardial fibrosis than standard doxorubicin, associated with upregulation of interferon-stimulated genes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: