PIII-12.

Background/aims: Anthracyclines, such as doxorubicin and daunorubicin, can cause chronic, cumulative dose-related cardiotoxicity. This can be prevented by dexrazoxane, a putative iron chelator. Disorders of iron metabolism, including altered IRP1-IRE binding may be an important mechanism of anthracycline cardiotoxicity. This study was designed to examine the role of IRP1-IRE binding in a chronic model of daunorubicin cardiotoxicity and whether dexrazoxane could prevent such changes in IRP1-IRE binding due to daunorubicin.Methods: Young adult, Fischer 344 rats received daunorubicin 2.5 mg/kg iv once per week for 6 weeks with (N, 9) and without(N, 11) pretreatment with ip dexrazoxane 50 mg/kg. Other groups received saline (controls; N, 8) or dexrazoxane alone (N, 9). Rats were sacrificed either 4h (for IRP1/IRE binding) or 2 weeks (for IRP1/IRE binding and atrial functional studies) after the last dose of daunorubicin.Results: Contractility (dF/dt) in atrial tissue was significantly reduced in daunorubicin-treated compared to control rats (dF/dt 10.1 +/− 1.0 vs. 32.9 +/− 3.1 g/sec; P < 0.001). dF/dt was unchanged in rats given daunorubicin with dexrazoxane pretreatment (dF/dt 26.9 +/− 2.9 g/sec). Left ventricular IRP1/IRE binding was not significantly affected by daunorubicin treatment either 4h or 2 weeks after treatment.Conclusions: IRP1/IRE binding may not be altered in chronic anthracycline cardiotoxicity. Dexrazoxane protects against chronic anthracycline cardiotoxicity in the rat.Clinical Pharmacology & Therapeutics (2005) 79, P61–P61; doi: 10.1016/j.clpt.2005.12.220 [ABSTRACT FROM AUTHOR]