Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.
BACKGROUND
Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions.


METHODS
Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg(-1) weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection.


RESULTS
Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.


CONCLUSIONS
This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.
Popelová
O
O
Department of Pharmacology, Faculty of Medicine, Charles University in Prague, Simkova 870, Hradec Králové 500 38, Czech Republic.
Sterba
M
M
Hasková
P
P
Simůnek
T
T
Hroch
M
M
Guncová
I
I
Nachtigal
P
P
Adamcová
M
M
Gersl
V
V
Mazurová
Y
Y
D000818:Animals; D018943:Anthracyclines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054715:Cardiotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D011817:Rabbits; D011929:Razoxane / Q000494:pharmacology*
D018943:Anthracyclines; D002316:Cardiotonic Agents; D054715:Cardiotoxins; D011929:Razoxane