DEVELOPMENT OF THE MODEL OF RAT ISOLATED-PERFUSED HEART FOR THE EVALUATION OF ANTHRACYCLINE CARDIOTOXICITY AND ITS CIRCUMVENTION

1 In order to develop a predictive model for the preclinical evaluatio n of anthracycline cardiotoxicity and the means of preventing it, we h ave studied the functional parameters of perfused hearts isolated From rats receiving repeated doses of several anthracyclines. 2 The anthra cyclines studied were doxorubicin, epirubicin, pirarubicin and daunoru bicin. and we also studied a liposomal formulation of daunorubicin (Da unoXome) and the co-administration of dexrazoxane (ICRF-187) and doxor ubicin. 3 Anthracyclines were administered i.p. at equimolar doses cor responding to 3 mg kg(-1) per injection of doxorubicin, every other da y for a total of six doses. Dexrazoxane was used at the dose of 30 mg kg(-1) per injection and was administered either 30 min before or 30 m in after doxorubicin. We evaluated any general toxicity towards the an imals as well as alterations of left ventricular contractility and rel axation es vivo. 4 Epirubicin and daunorubicin were significantly less cardiotoxic than doxorubicin, and neither pirarubicin nor DaunoXome c aused significant alterations in cardiac function. There was a direct relationship between the decrease in cardiac contractility or relaxati on and anthracycline accumulation in the heart, evaluated after the sa me treatment schedule. 5 Dexrazoxane induced a significant protection against doxorubicin-induced cardiac toxicity when administered 30 min before doxorubicin, whereas this protection was ineffective when admin istered 30 min after doxorubicin. Direct perfusion of DaunoXome in iso lated hearts of untreated animals resulted in a 12-fold reduction of t he accumulation of daunorubicin in heart tissue as compared to the per fusion of free daunorubicin, and did not cause alterations in cardiac function at a dosage for which free daunorubicin induced major alterat ions. 6 The isolated perfused rat heart appears to be a valuable model for screening of new anthracyclines and of strategies for circumventi ng anthracycline cardiotoxicity.