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. Enz ymatic reduction of a side chain carbonyl group converts DOX to a secondary alcohol metabolite that has been implicated in cardiotoxicity. We therefor e monitored negative inotropism, assessed as inhibition of post-rest contra ctions, in rat right ventricle strips exposed to DOX or to analogues formin g fewer amounts of their alcohol metabolites (epirubicin, EPI, and the nove l disaccharide anthracycline MEN 10755). 2 Thirty mum EPI exhibited higher uptake than equimolar DOX, but formed com parable amounts of alcohol metabolite due to its resistance to carbonyl red uction. MEN 10755 exhibited also an impaired uptake, and consequently forme d the lowest levels of alcohol metabolite. Accordingly, DOX and EPI inhibit ed 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 forme d similar to 50% less alcohol metabolite. One hundred muM MEN 10755 still e xhibited 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 w ith cellular levels of both alcohol metabolites (r=0.88, P <0.0001) and car bonyl 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 ino tropism of MEN 10755 was therefore increased by chemical procedures, like s ide chain valeryl esterification, that facilitated its uptake and conversio n to alcohol metabolite but riot its retention in a carbonyl form. 5 These results demonstrate that secondary alcohol metabolites are importan t mediators of cardiotoxicity. A combination of reduced uptake and limited conversion to alcohol metabolite formation might therefore render MEN, 1075 5 more cardiac tolerable than DOX and EPI.