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 microM 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 approximately 40-50%, whereas MEN 10755 inhibited by approximately 6%. 3. One hundred microM EPI exhibited the same uptake as equimolar DOX, but formed approximately 50% less alcohol metabolite. One hundred microM MEN 10755 still exhibited the lowest uptake, forming approximately 60% less alcohol metabolite than EPI. Under these conditions DOX inhibited post-rest contractions by 88%. EPI and MEN 10755 were approximately 18% (P<0.05) or approximately 80% (P<0.001) less inhibitory than DOX, respectively. 4. The negative inotropism of 30-100 microM 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 approximately 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 not 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.
Minotti
G
G
Department of Drug Sciences, G. D'Annunzio University School of Pharmacy, Via dei Vestini, 66013 Chieti, Italy. gminotti@unich.it
Parlani
M
M
Salvatorelli
E
E
Menna
P
P
Cipollone
A
A
Animati
F
F
Maggi
C A
CA
Manzini
S
S
D000438:Alcohols / Q000378:metabolism; D000818:Animals; D018943:Anthracyclines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004187:Disaccharides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
D000438:Alcohols; D018943:Anthracyclines; D000970:Antineoplastic Agents; D004187:Disaccharides; C449241:MEN 11609; D004317:Doxorubicin; C107602:sabarubicin