Effect of MEN 10755, a new disaccharide analogue of doxorubicin, on sarcoplasmic reticulum Ca 2+ handling and contractile function in rat heart

The use of anthraquinone antineoplastic agents is limited by their cardiac toxicity, which is largely due to activation of the sarcoplasmic reticulum (SR) Ca 2+ release channel (ryanodine receptor). MEN 10755 is a new disaccharide analogue of doxorubicin. We have evaluated its effects on SR function and its toxicity in isolated working rat hearts. In rat SR vesicles, doxorubicin stimulated [ 3 H]‐ryanodine binding by increasing its Ca 2+ ‐sensitivity. At 1 μ M Ca 2+ , ryanodine binding increased by 15.3±2.5 fold, with EC 50 =20.6 μ M . Epirubicin produced a similar effect, i.e. 9.7±0.6 fold stimulation with EC 50 =11.1 μ M . MEN 10755 increased ryanodine binding by 1.9±0.3 fold ( P <0.01 vs doxorubicin and epirubicin), with EC 50 =38.9 μ M . Ca 2+ ‐induced Ca 2+ release experiments were performed by quick filtration technique, after SR loading with 45 Ca 2+ . At 2 μ M Ca 2+ , doxorubicin (50 μ M ) increased the rate constant of Ca 2+ release to 82±5 s −1 vs a control value of 22±2 s −1 ( P <0.01), whereas 50 μ M MEN 10755 did not produce any significant effect (24±3 s −1 ). Ca 2+ ‐ATPase activity and 45 Ca 2+ ‐uptake were not significantly affected by doxorubicin, its 13‐dihydro‐derivative, epirubicin, MEN 10755 and the 13‐dihydro‐derivative of MEN 10755, at concentrations 100 μ M . In isolated heart experiments, administration of 30 μ M doxorubicin or epirubicin caused serious contractile impairment, whereas 30 μ M MEN 10755 produced only minor effects. In conclusion, in acute experiments MEN 10755 was much less cardiotoxic than equimolar doxorubicin or epirubicin. This result might be accounted for by reduced activation of SR Ca 2+ release.British Journal of Pharmacology (2000) 131 , 342–348; doi: 10.1038/sj.bjp.0703575