Mechanism-Based Engineering Against Anthracycline Cardiotoxicity

Since their first discovery nearly 50 years ago1, anthracyclines, including doxorubicin (Adriamycin), daunorubicin (Cerubidine), epirubicin (Ellence) and idarubicin (Idamycin PFS) have been successfully developed as potent anti-cancer 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 since the agents acutely produce arrhythmias, LV dysfunction, and pericarditis, and chronically lead to LV dysfunction and heart failure2. The toxicity is clearly dose-related with sharp rises in LV dysfunction with cumulative doses above 400-450 mg/m2 for doxorubicin.3 When cardiac imaging was employed, the incidence of HF was 5%, 26%, and 48% in patients receiving 400, 550, and 700 mg/m2 of doxorubicin. As a result, most oncologists typically limit the dose to 450-500 mg/m2. Children are especially vulnerable with rates of significant LV dysfunction of 5% at 15 yrs 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 children5. 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 cancers, oncologists would like to use higher doses.