Long-lasting effect of dexrazoxane against anthracycline cardiotoxicity in rats.
The long-lasting protective effect of dexrazoxane (ADR-529) against doxorubicin- and epirubicin-induced cardiotoxicity was evaluated in the multiple-dose 35-wk rat model. Groups of 36 male Sprague-Dawley rats were given ADR-529 30 min before administration of cardiotoxic doses of doxorubicin (1 mg/kg/wk) or epirubicin (1.13 mg/kg/wk). The compounds were intravenously injected once weekly for 7 consecutive wk at ADR-529; anthracycline ratios ranging from 5:1 to 20:1. These ratios covered the entire chemotherapeutic range in humans and allowed studying the chronic progressive cardiomyopathy in our rat model. Animals were observed for up to 35 wk to follow the time course of the well-characterized cardiomyopathy, which was evaluated through the well-established qualitative/quantitative morphological grading. It was clearly demonstrated in this rat model that ADR-529, at the ratios administered, provided ample cardioprotection for a duration of 35 wk, which corresponds to 25 yr of equivalent human time.
Della Torre
P
P
Toxicology and Safety Assessment, Pharmacia, Milan, Italy.
Podesta
A
A
Pinciroli
G
G
Iatropoulos
M J
MJ
Mazué
G
G
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity; D015251:Epirubicin / Q000037:antagonists & inhibitors / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D015251:Epirubicin; D011929:Razoxane; D004317:Doxorubicin