Cardioprotection of rat heart myocytes with amifostine (Ethyol) and its free thiol, WR-1065, in vitro.
Cultured neonatal rat heart myocytes form a synchronously-contracting cell syncytium from one to two days after isolation, plating on plastic and incubation at 37 degrees C. On day 3 after plating, myocytes were exposed to the anthracycline doxorubicin, 0.1-10 micrograms/ml, for 1 h with or without a 15-min pretreatment with the thiophosphate compound amifostine (WR-2721, Ethyol) or its dephosphorylated metabolite, WR-1065. The concentration of each WR-compound was limited to 2 micrograms/ml or 10% of the maximal achievable plasma concentration of amifostine after an intravenous dose of 740 mg/m2. Both amifostine and the free thiol significantly reduced doxorubicin-induced heart-cell toxicity, measured by adenosine triphosphate content normalised to total cellular protein. A concurrent 1-h exposure to these compounds and doxorubicin was also cardioprotective, but neither compound was effective when administered after doxorubicin. Although both amifostine and WR-1065 were approximately equipotent in preventing doxorubicin-induced cardiotoxicity, only amifostine significantly increased glutathione levels in the myocytes. These results complement prior in vitro and in vivo studies in rodents showing cardioprotectant activity for amifostine and its free thiol, WR-1065, when administered prior to doxurubicin.
Dorr
R T
RT
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, USA.
Lagel
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K
McLean
S
S
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004334:Drug Administration Schedule; D005260:Female; D006321:Heart / Q000187:drug effects*; D008297:Male; D008624:Mercaptoethylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D008624:Mercaptoethylamines; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004317:Doxorubicin; D004999:Amifostine