Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel

Purpose: Results of several clinical studies suggest that the combination o f doxorubicin (DOX) and paclitaxel (PTS) is highly active against solid tum ors. Both drugs are known to cause adverse cardiac effects, cardiomyopathy in the case of DOX and acute changes in cardiac rhythm in the case of PTX. It has been suggested that the addition of dexrazoxane (DZR) to this regime n may reduce the risk of cardiotoxicity. A model of chronic cardiomyopathy in the rat was used to determine whether DZR was tolerated and cardioprotec tive in a DOX + PTX combination. Methods: Male rats were treated once weekl y for 7 weeks with one of the following vehicle and/or drug sequences: Grou p A, M/6 sodium lactate/saline/Cremophor EL (CEL); Group B, lactate/DOX/CEL ; Group C, DZR/DOX/CEL; Group D, lactate/DOX/PTX; and Group E, DZR/DOX/PTX. DZR and DOX or their respective vehicles were given i.v. whilst PTX or CEL were given i.p. DZR, DOX and PTX were administered at 16 mg/kg, 0.8 mg/kg and 2.4 mg/kg, respectively, doses which caused minimal noncardiac toxiciti es. The hearts were examined histologically 5 weeks following the last trea tment. Results: There were no deaths and no signs of overt toxicity during the 12 weeks of study. There was a significant decrease (P < 0.01) in white blood cell count in rats treated with DZR + DOX, DOX + PTX or DZR + DOX PTX but not in those given DOX alone. Liver and kidney weights were increas ed in rats given DOS (P < 0.05) but not in those given DZR + DOS. PTS had n o effect on the DOS-induced liver and kidney changes and did not interfere with the protective effect of DZR on the kidney. The severity and extent of cardiomyopathy expressed as the mean total score (MTS) for each treatment group, was similar for DOX and DOX + PTX (3.6 and 4.2, respectively). DZR p rovided significant cardioprotection (P < 0.01) when added to either DOS (M TS 2.0) or to DOX + PTX (MTS 2.1). Conclusions: The results suggest that PT X does not exacerbate the chronic cardiomyopathy caused by DOX and when add ed to the DON + PTX combination, DZR retains its protective activity agains t DOS-induced cardiotoxicity without increasing noncardiac toxicity.