European Heart Journal Advance Access originally published online on April 12, 2006
European Heart Journal 2006 27(10):1137-1138; doi:10.1093/eurheartj/ehi702
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Anthracycline cardiotoxicity
1 Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, Northern Ireland, UK
2 Department of Haematology, Queen's University Belfast, Northern Ireland, UK
3 Department of Medicine, Institute of Clinical Science, Queen's University Belfast, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland, UK
* Corresponding author. Tel: +44 28 9063 4825; fax: +44 28 9031 2907. E-mail address: p.p.mckeown{at}qub.ac.uk
This editorial refers to ‘Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression’
by T.G. Neilan et al., on page 1251
Anthracycline drugs have been widely used as chemotherapeutic agents against a range of cancers, including sarcomas, carcinomas, leukaemias, and lymphomas. However, cardiotoxic effects, in particular the development of cardiomyopathy, have limited their clinical use. The observation of dose-dependent cardiotoxicity has resulted in a recommended empirical dose limit of 450 mg/m2 of body surface area. Age, gender, pre-existing heart disease, hypertension, and mediastinal irradiation have also been implicated as factors contributing to the development of doxorubicin-associated cardiomyopathy. However, cardiotoxicity may still occur at relatively low levels of drug administration, even in individuals with no additional risk factors, and the onset may be delayed by many years.1 More recently, the use of trastuzumab, a monoclonal antibody directed against the HER2 receptor, has been reported to cause cardiomyopathy, especially if co-administered with anthracyclines.2 Uncommonly, anthracyclines may also cause acute or subacute cardiotoxicity, manifest by arrhythmias or myopericarditis.1
Anthracyclines have been reported to have many different actions in cancer cells: intercalation into DNA (leading to inhibition of synthesis), direct effects on DNA binding, free-radical mediated DNA damage/lipid peroxidation, and inhibition of topoisomerase II.3 The pathological contributors to the development of cardiomyopathy include oxidative stress and intracellular iron, ultimately leading to apoptosis. Other potential mechanisms have also been suggested: these include activation of signal transduction pathways resulting in altered cardiac gene expression, and a role for doxorubicinol, a C-13 hydroxy metabolite, which has been shown to be an inhibitor of various pumps in the cell, thus affecting myocardial energy metabolism as well as ionic currents. Doxorubicin's chemical structure is susceptible to free-radical formation; in addition, its administration also causes a decrease in intracellular antioxidants normally responsible for preventing free-radical damage.3 Recently, Lebrecht et al.,4 in a rat model, have reported that doxorubicin-induced mitochondrial DNA alterations and subsequent respiratory chain dysfunction accumulate over time in the absence of continued administration of the drug. These findings may provide an explanation for the delayed onset of cardiomyopathy.
Careful monitoring of cardiac function, usually by echocardiography, is required. Recently, there has been renewed interest in the use of cardiac troponins as biomarkers of acute damage.5 As individuals may present many years after treatment with doxorubicin-associated cardiomyopathy (even with previously normal echocardiograms), long-term follow-up is required. Definitive diagnosis can usually be achieved by endomyocardial biopsy of the right ventricle, although the use of this test is limited by its invasive nature. The histopathological changes include myofibril loss and vacuolization of the cytoplasm.1
As anthracyclines have very potent anti-tumour effects, their widespread use will continue until effective and safer alternatives have been identified. There has been much interest in the use of cardioprotective agents during the administration of doxorubicin. However, a major concern regarding these agents is the possibility that, in attempting to reduce the cardiac toxicity, activity against tumour cells may be lost. To date, most research in this area has focused on anti-oxidant agents or iron chelators.3 Probucol and carvedilol have shown promise in animal studies, although other antioxidants, such as vitamin E, have been unsuccessful in clinical studies.3 Dexrazoxane, a derivative of EDTA, can offer protection against oxidative stress by chelating iron and diverting it from potential toxic interactions with anthracyclines; however, significant myelosuppressive effects have been reported with dexrazoxane and one study has raised the possibility that dexrazoxane may decrease tumour response in breast cancer patients treated with doxorubicin.3,5 Lipshultz et al.5 measured troponin T levels in 206 children with high-risk acute lymphoblastic leukaemia treated with doxorubicin with or without dexrazoxane. The troponin T levels were lower in the dexrazoxane group. Although no echocardiographic differences were seen, long-term follow-up will be required in order to establish if the diminution in acute injury may prevent long-term sequelae, with no increase in long-term relapse rate.
Neilan et al.6 report that iloprost attenuates doxorubicin-induced cardiac injury. This research group has previously reported data on doxorubicin-induced changes in cyclooxygenase (COX) expression and prostaglandin production in in vitro and in vivo animal models.7,8 COX, which catalyzes the conversion of arachidonic acid to prostaglandin H2, has two isoforms: the constitutively expressed COX-1 and an inducible COX-2. COX-2 expression is upregulated in many cancers and has been implicated in tumour growth and protection against apoptosis. COX-2 expression has been identified in human cardiomyocytes from patients with ischaemic myocardium and dilated cardiomyopathy but not in normal hearts, and the predominant product in cardiomyocytes is prostacyclin (PGI2).7–9
In experiments on neonatal rat cardiomyocytes, Adderley and Fitzgerald7 demonstrated that doxorubicin induced COX-2 expression, which was associated with activation of ERK1/2, and that this activation could be prevented by the use of free radical scavengers. Increased COX-2 expression was also associated with increased PGI2 production. The use of a COX-2 inhibitor appeared to enhance cell damage, as measured by the release of lactate dehydrogenase, and this injury was prevented by iloprost, an analogue of PGI2. Dowd et al.,8 using a rat model, reported that the degree of doxorubicin-induced injury, as detected by levels of troponin T, LDH, and cardiomyocyte apoptosis, was attenuated by iloprost administration.
Neilan et al.6 implanted Lewis lung carcinoma cells in mice and commenced doxorubicin when tumours became visible. Some mice were administered iloprost 4 days prior to doxorubicin treatment until sacrifice 5 days following completion of doxorubicin treatment. Echocardiography and invasive haemodynamics were performed. They report that doxorubicin-induced cardiac dysfunction was attenuated by iloprost. Iloprost also significantly reduced cardiomyocyte apoptosis but had no effect on tumour growth.
This article stimulates interest in the use of iloprost as a novel approach for the prevention of doxorubicin-associated cardiomyopathy. However, many questions remain unanswered. Results obtained in animal models require to be reproduced in human studies. The length of follow-up in these experiments, although appropriate for the hypotheses tested, was short. It is possible that the animals may have developed signs of cardiotoxicity had they lived longer. Likewise, the tumour relapse rates may have been higher when compared with animals treated with doxorubicin only. The mechanisms underlying the cardioprotective effect of iloprost require to be elucidated. Practical issues remain concerning the tolerability and safe administration of iloprost to patients, in particular, bleeding complications in those who may be thrombocytopenic.
Recently, Delgado et al.10 have reported that inhibition of COX-2 improved left ventricular function in mice with pre-existing doxorubicin-induced heart failure. This is at variance with the work reported by Neilan et al.6 A possible explanation for this is that COX-2 expression may be initially beneficial but prolonged expression is not. This is a similar situation to the activation of other neuro-humoral mechanisms in other types of heart failure.
Doxorubicin is a potent chemotherapeutic agent. As many tumours, particularly the commonest of all childhood tumours, acute lymphoblastic leukaemia, are curable, it is important to limit the degree of cardiotoxicity. Options include the development of tumour-targeted derivatives, such as liposomal anthracycline formulations or synthesis of anthracycline pro-drugs, which are activated by peptidases secreted by cancer cells, or novel anthracycline analogues.3 Prevention is better than cure. To this end, cardioprotective agents, which prevent myocardial damage without reducing the chemotherapeutic efficacy of the drug, need to be developed. Prostaglandin and cyclooxygenase research may provide an answer.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehl003 
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Related articles in EHJ:
- Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression
- Tomas G. Neilan, Davinder S. Jassal, Michael F. Scully, Gang Chen, Catherine Deflandre, Hester McAllister, Elaine Kay, Sandra C. Austin, Elkan F. Halpern, Judy H. Harmey, and Desmond J. Fitzgerald
EHJ 2006 27: 1251-1256.[Abstract] [FREE Full Text]
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