Attempts to reduce the incidence of congestive heart failure following 
anthracycline therapy include the replacement of the parent compounds 
(especially doxorubicin) by less cardiotoxic analogs. Among these analogs, 
idarubicin (4-demethoxy-daunorubicin) was shown to be less cardiotoxic than 
doxorubicin in phase II clinical trials, but its actual cardiotoxicity has never 
been evaluated in large series and has never been compared to that of 
doxorubicin in relevant experimental models. Using the isolated perfused rat 
heart model, we compared the cardiac effects (developed pressure, contractility 
and relaxation of the left ventricle) induced by idarubicin to those induced by 
doxorubicin. Drugs were administered i.v. every other day for 11 days at doses 
of 1, 2, 2.5 and 3 mg/kg per injection for doxorubicin and 0.5, 0.75 and 1 mg/kg 
per injection for idarubicin. We confirmed that similar general toxicity 
symptoms were obtained for a dose ratio of 1:4 (idarubicin:doxorubicin). 
However, at the maximum tolerated doses of both drugs (3 mg/kg per injection for 
doxorubicin and 0.75 mg/kg per injection for idarubicin), the cardiac toxicity 
of idarubicin remained significantly lower than that of doxorubicin. 
Anthracycline cardiac accumulation was evaluated in parallel and revealed a 
lower cardiac accumulation of idarubicin, which could explain the reduced 
cardiac toxicity of this analog. Direct perfusion of the drugs in the isolated 
hearts of untreated animals revealed that idarubicin was taken up more readily 
than doxorubicin in the cardiac tissue, despite the fact that it had less 
deleterious effects on cardiac function. This indicates that idarubicin also had 
less intrinsic cardiotoxicity than doxorubicin in this model.