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Experimental Biology and Medicine 232:1414-1424 (2007)
doi: 10.3181/0705-RM-138
© 2007 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Effects of Dexrazoxane and Amifostine on Evolution of Doxorubicin Cardiomyopathy In Vivo

Snezana K. Bjelogrlic*,1, Jelena Radic{dagger}, Sinisa Radulovic*, Milan Jokanovic{ddagger} and Viktor Jovic§

* Department of Experimental Oncology and {dagger} Department of Medical Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia; {ddagger} Department of Pharmacy, School of Medicine, Nis, Serbia; and § Department of Pathology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia

To whom requests for reprints should be addressed at 1 Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, Belgrade, Serbia. E-mail: zanab{at}bitsyu.net

Doxorubicin is one of the most active drugs in oncology, with cardiotoxicity as a serious side effect of its application. The aim of this study was to investigate dexrazoxane and amifostine impact on the evolution of myocardial changes induced by doxorubicin. BalbC female mice were treated with doxorubicin only (10 mg/kg, single intravenous push), or with dexrazoxane (200 mg/kg, intraperitoneal [ip]) or amifostine (200 mg/kg, ip) 60 mins or 30 mins prior to treatment with doxorubicin, respectively. Blood sampling for determination of conventional serum-marker activity was performed 48 hrs later. The grade of histopathology changes was evaluated by light microscopy 1.5 and 3 months after treatments using the Billingham scoring method. Control groups consisted of nontreated mice. After doxorubicin-only treatment, the grade of heart tissue damage was found to increase in the period between 1.5 and 3 months. A similar but less intense progression was also detected in amifostine-pretreated animals, with significant difference among median Billingham scores between the two time points. The pretreatment with dexrazoxane suspended expansion of tissue lesions in time. Changes in serum enzyme activity revealed two correlations: the greater reduction in alpha-hydroxybutyrate dehydrogenase ({alpha}-HBDH) leakage is associated with a lower percentage of damaged tissue, and the creatine kinase to {alpha}-HBDH percent of difference ratio being greater than one is correlated with limited spreading of pathological lesions. Our results indicate that the development of doxorubicin-induced heart failure is based on a slow and persistent expansion of pathological process even long after the completion of the treatment. Dexrazoxane has proved to be successful and superior over amifostine against such an evolution of doxorubicin cardiomyopathy.

Key Words: evolution of doxorubicin cardiomyopathy • dexrazoxane • amifostine • in vivo






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