Effect of MEN 10755, a new disaccharide analogue of doxorubicin, on sarcoplasmic reticulum Ca2+ handling and contractile function in rat heart

1 The use of anthraquinone antineoplastic agents is limited by their cardia c toxicity, which is largely due to activation of the sarcoplasmic reticulu m (SR) Ca2+ release channel (ryanodine receptor). MEN 10755 is a new disacc haride analogue of doxorubicin. We have evaluated its effects on SR functio n and its toxicity in isolated working rat hearts. 2 In rat SR vesicles, doxorubicin stimulated [H-3]-ryanodine binding by inc reasing its Ca2+. sensitivity. At 1 mu M Ca2+, ryanodine binding increased by 15.3 +/- 2.5 fold, with EC50 = 20.6 mu M. Epirubicin produced a similar effect, i.e. 9.7 +/- 0.6 fold stimulation with EC50 = 11.1 mu M. MEN 10755 increased ryanodine binding by 1.9 +/- 0.3 fold (P < 0.01 vs doxorubicin an d epirubicin), with EC50 = 38.9 mu M. 3 Ca2+-induced Ca2+ release experiments were performed by quick filtration technique, after SR loading with Ca-45(2+). At 2 mu M Ca2+, doxorubicin (50 mu M) increased the rate constant of Ca2+ release to 82 +/- 5 s(-1) vs a c ontrol value of 22 +/- 2 s(-1) (P< 0.01), whereas 50 mu M MEN 10755 did not produce any significant effect (24 +/- 3 s(-1)). 4 Ca2+-ATPase activity and Ca-45(2) + -uptake were not significantly affect ed by doxorubicin, its 13-dihydro-derivative, epirubicin, MEN 10755 and the 13-dihydro-derivative of MEN 10755, at concentrations less than or equal t o 100 mu M. 5 In isolated heart experiments, administration of 30 mu M doxorubicin or e pirubicin caused serious contractile impairment, whereas 30 mu M MEN 10755 produced only minor effects. 6 In conclusion? in acute experiments MEN 10755 was much less cardiotoxic t han equimolar doxorubicin or epirubicin. This result might be accounted for by reduced activation of SR Ca2+ release.