Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue

1 The anticancer anthracycline doxorubicin (DOX) causes cardiotoxicity. Enzymatic reduction of a side chain carbonyl group converts DOX to a secondary alcohol metabolite that has been implicated in cardiotoxicity. We therefore monitored negative inotropism, assessed as inhibition of post-rest contractions, in rat right ventricle strips exposed to DOX or to analogues forming fewer amounts of their alcohol metabolites (epirubicin, EPI, and the novel disaccharide anthracycline MEN 10755). 2 Thirty mum EPI exhibited higher uptake than equimolar DOX, but formed comparable amounts of alcohol metabolite due to its resistance to carbonyl reduction. MEN 10755 exhibited also an impaired uptake, and consequently formed the lowest levels of alcohol metabolite. Accordingly, DOX and EPI inhibited post-rest contractions by similar to 40-50%, whereas MEN 10755 inhibited by similar to6%. 3 One hundred mum EPI exhibited the same uptake as equimolar DOX, but formed similar to 50% less alcohol metabolite. One hundred muM MEN 10755 still exhibited the lowest uptake, forming similar to 60% less alcohol metabolite than EPI. Under these conditions DOX inhibited post-rest contractions by 88%. EPI and MEN 10755 were similar to 18% (P <0.05) or similar to 80% (P <0.001) less inhibitory than DOX, respectively. 4 The negative inotropism of 30-100 muM DOX, EPI, or MEN 10755 correlated with cellular levels of both alcohol metabolites (r=0.88, P <0.0001) and carbonyl anthracyclines (r=0.79, P <0.0001). Nonetheless, multiple comparisons showed that alcohol metabolites were similar to 20 40 times more effective than carbonyl anthracyclines in inhibiting contractility. The negative inotropism of MEN 10755 was therefore increased by chemical procedures, like side chain valeryl esterification, that facilitated its uptake and conversion to alcohol metabolite but riot its retention in a carbonyl form. 5 These results demonstrate that secondary alcohol metabolites are important mediators of cardiotoxicity. A combination of reduced uptake and limited conversion to alcohol metabolite formation might therefore render MEN, 10755 more cardiac tolerable than DOX and EPI.