Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies Karlijn A. Wouters, 1,3 Leontien C. M. Kremer, 2 Tracie L. Miller, 3,5 Eugene H. Herman 4 and Steven E. Lipshultz 5 1 Division of Paediatrics, Vrije Universiteit Medical Centre, Amsterdam, the Netherlands, 2 Department of Paediatric Oncology, Academic Medical Centre, Emma Children’s Hospital, Amsterdam, the Netherlands, 3 Division of Pediatric Clinical Research, University of Miami, Miller School of Medicine, Miami, FL, USA, 4 Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration (HFD-910), Silver Spring, MD, USA, and 5 Department of Pediatrics, University of Miami, Miller School of Medicine, Holtz Children’s Hospital of the University of Miami-Jackson Memorial Medical Centre, and the Sylvester Comprehensive Cancer Center, Miami, FL, USA Summary Over the last 40 years, great progress has been made in treating childhood and adult cancers. However, this progress has come at an unforeseen cost, in the form of emerging long-term effects of anthracycline treatment. A major complication of anthracycline therapy is its adverse cardiovascular effects. If these cardiac complications could be reduced or prevented, higher doses of anthracyclines could potentially be used, thereby further increasing cancer cure rates. Moreover, as the incidence of cardiac toxicity resulting in congestive heart failure or even heart transplantation dropped, the quality and extent of life for cancer survivors would improve. We review the proposed mechanisms of action of anthracyclines and the consequences associated with anthracycline treatment in children and adults. We summarise the most promising current strategies to limit or prevent anthracycline-induced cardiotoxicity, as well as possible strategies to prevent existing cardiomyopathy from worsening. Keywords: cancer, anthracyclines, myocardial damage, cardi- oprotective agents, prevention. The discovery of doxorubicin (Adriamycin), an anthracycline antitumour antibiotic, in the early 1960s was a major advance in the fight against cancer. As a result of the introduction of anthracyclines, together with other improvements of treatment, cancer survival has improved markedly, particularly among children, where survival rates have increased from 30% in the 1960s to 70% currently (Bleyer, 1990; Gatta et al, 2002). Anthracyclines are effective antineoplastic agents with a very broad antitumour spectrum that includes many solid tumours and leukaemia. However, the use of anthracyclines is limited by a dose-dependent cardiotoxicity (Lefrak et al, 1973). Cardiotoxicity may be the dose-limiting factor in cancer treatment. Furthermore, cardiotoxicity can lead to long-term side-effects and severe morbidity (Grenier & Lipshultz, 1998; Lipshultz et al, 2005a). In a study on childhood leukaemia, nearly 60% of the 115 survivors had echocardiographic abnormalities in heart function (Lipshultz et al, 1991). Con- sidering that more than 50% of long-term survivors of childhood cancer alone were treated with doxorubicin or another anthracycline (Krischer et al, 1997), anthracycline- induced cardiotoxicity is a widely prevalent problem that cannot be ignored. Several strategies for detecting and preventing cardiotoxicity have been developed, some of which are more effective than others. Although this is not a systematic review of all available evidence, we will review in detail the current and emerging preventive strategies against anthracycline-induced myocardial damage (Table I). Mechanisms of anthracycline-induced cardiotoxicity Despite the wide use of anthracyclines in cancer treatment, their mechanisms of action, both in treating cancer and in their toxicity on the heart and other organs, are still not well understood. The majority of evidence shows that myocyte toxicity involves the generation of free radicals, through an enzymatic mechanism using the mitochondrial respiratory chain, as well as through a non-enzymatic pathway, which incorporates iron (Gianni et al, 1985; Olson & Mushlin, 1990). Free radicals and iron can damage cell membranes or macromolecules and increase cell membrane permeability (Olson & Mushlin, 1990). Compared with cells of other organs, Correspondence: Steven E. Lipshultz MD, Department of Pediatrics, University of Miami, Miller School of Medicine, Medical Campus- MCCD-D820, 1601 NW 12th Avenue, 9th Floor, Miami, FL 33136, USA. E-mail: slipshultz@med.miami.edu review ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131, 561–578 doi:10.1111/j.1365-2141.2005.05759.x