DOXORUBICIN AND EPIRUBICIN CARDIOTOXICITY - EXPERIMENTAL AND CLINICAL ASPECTS

Abstract

Epirubicin (EpiDx) belongs to the class of anthracycline antibiotics. It is an analog of doxorubicin (Dx) modified in the sugar moiety and in which the stereochemistry at the hydroxyl group bearing C-4'' has been inverted. The purpose of this study was to evaluate in an experimental model and in a clinical trial the cardiotoxic effects of EpiDx vs Dx. Cellular oxygen uptake was measured in vitro for equal concentration of Dx and EpiDx with a Warburg manometric apparatus and ATP intracellular concentration by high-pressure liquid chromatography. Dx inhibits cellular endogenous respiration of rat heart slices by 34% vs control, while EpiDx reduces oxygen uptake by 18%. ATP intracellular concentration was significantly reduced by both anthracycline derivates. The same results were obtained after Dx administration in vivo which enabled us to correlate the biochemical parameter (QO2) with the histological cardiac damages shown by light microscopy. For the clinical trial, we studied a total of 22 patients undergoing chemotherapy for solid tumors in an advanced stage. Nine of these were treated with Dx for a total of 66 therapeutic cycles and reached a maximal cumulative dose of 540 mg/m2. Thirteen were treated with EpiDx for a total of 121 cycles (maximal dose reached 720 mg/m2). The dosage of both agents was equal, 60 mg/m2 every 3 weeks. Acute cardiotoxicity was evaluated, measuring creatine-kinase isoenzyme MB (CK-MB) serum level before and 15 h after anthracyclines administration. In the group of Dx-treated patients, we observed significant isoenzyme increases, after therapy, of more than 8 U/I in 31 out of a total of 66 cycles (47%), while in the EpiDx-treated group, only 13% of their CK-MB measures (16 out of 121 treatment cycles) turned out to be significantly higher. Chronic cardiotoxicity was monitored, before every therapeutic cycle, the left ventricular performance by computerized M-Mode echocardiography. We measured the maximal velocity of circumferential fiber shortening (Vcfmax) which is considered a reliable and sensitive non-invasive parameter to evaluate myocardial contractility. The results of Vcfmax showed a significant impairment of the systolic function in 44% of the patients treated with Dx. By comparison, only 13% of the EpiDx treated patients exhibited a significant reduction of their systolic function. In conclusion, on the basis of our experimental and clinical findings, EpiDx-related cardiotoxicity is 40% less than that produced by Dx.