Mechanism-Based Engineering Against Anthracycline Cardiotoxicity

• Editorials
• DNA topoisomerases, type II
• doxorubicine
• ligands
• neoplasms
• neuregulin-beta
• stroke

Since their first discovery nearly 50 years ago,¹ anthracyclines, including doxorubicin (Adriamycin), daunorubicin (Cerubidine), epirubicin (Ellence), and idarubicin (Idamycin PFS), have been successfully developed as potent anticancer therapeutics with significant efficacy in lymphomas and many solid tumors. Particularly in patients with breast cancer, they are the primary choices of therapy. However, cardiotoxicity has been a central limiting complication in treating patients because the agents acutely produce arrhythmias, left ventricular dysfunction, and pericarditis and chronically lead to left ventricular dysfunction and heart failure.² The toxicity is clearly dose related, with sharp rises in left ventricular dysfunction with cumulative doses >400 to 450 mg/m² for doxorubicin.³ When cardiac imaging was used, the incidence of heart failure was 5%, 26%, and 48% in patients receiving 400, 550, and 700 mg/m² doxorubicin. As a result, most oncologists typically limit the dose to 450 to 500 mg/m². Children are especially vulnerable, with rates of significant left ventricular dysfunction of 5% at 15 years of follow-up, increasing to 10% for cumulative doses of ≥550 mg/m².⁴ Heart failure may present many years after treatment. Mediastinal irradiation is an additional risk factor that may also be particularly problematic in children.⁵ To date, our only proven protective measure is adherence to stopping guidelines for total dose. Unfortunately, this typically limits the total dose an individual patient could receive, and for particularly problematic …