Key result
Dexrazoxane co-treatment completely prevented daunorubicin-induced mortality (0% vs 18%) and left ventricular dysfunction, and significantly suppressed cardiomyocyte apoptosis in vivo.
Why the study?
Does dexrazoxane co-treatment prevent cardiomyocyte apoptosis and cardiotoxicity in rabbits treated with chronic daunorubicin?
Does dexrazoxane co-treatment prevent cardiomyocyte apoptosis and cardiotoxicity in rabbits treated with chronic daunorubicin?
Absolute Event Rate: 0% vs 18%
p-value: p=<0.05
Dexrazoxane protects against chronic anthracycline cardiotoxicity in vivo primarily by inhibiting apoptosis rather than preventing lipoperoxidation.
DEX may inhibit apoptosis in vivo; leaves open clinical mechanism relevance.
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. CONCLUSION: 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.
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Popelová et al. (2009) studied Chronic anthracycline cardiotoxicity (n=27). Dexrazoxane vs. Daunorubicin alone (3 mg/kg i.v. weekly) and Saline was evaluated on Mortality and left ventricular systolic function (p=<0.05). Dexrazoxane co-treatment completely prevented daunorubicin-induced mortality (0% vs 18%) and left ventricular dysfunction, and significantly suppressed cardiomyocyte apoptosis in vivo.
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