DOSE-RESPONSE RELATIONSHIP OF DEXRAZOXANE FOR PREVENTION OF DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE, RATS, AND DOGS

Dexrazoxane [(DZR), ADR 529, ICRF-187] ameliorates doxorubicin (DOX)-i nduced cardiotoxicity in animals, and is recommended as a cardioprotec tant in patients receiving cumulative doses of DOX above 300 mg/m(2), A DZR:DOX dose ratio of 10:1 is recommended based on studies in patien ts receiving 50 mg/m(2). Since DOX may he used at much higher doses in certain clinical settings, we evaluated the ability of DZR to protect against cardiomyopathy in animals given bolus doses of DOX at varying dose levels, The severity and extent of the cardiomyopathy were evalu ated histologically and expressed as the mean total score (MTS). Mice were given 10 doses of DOX (2 or 4 mg/kg) over a 7-week period, Withou t DZR, the MTS 4 weeks after the last treatment was 3.7 with 4 mg/kg D OX and 1.3 with 2 mg/kg DOX, DZR at 5:1, 10:1, and 20:1 dose ratios ca used a dose-dependent decrease in the MTS but was less efficacious wit h the higher, more cardiotoxic dose of DOS, Rats were given DOX at 0.2 , 0.4, and 0.8 mg/kg with a 20:1 ratio of DZR weekly for 13 weeks. Car diomyopathy was most severe with the highest dose of DOX in the absenc e of DZR, especially in males, and progressed during the 6 weeks follo wing the last treatment, DZR reduced the MTS in both sexes but in the males given the highest dose of DOX, there was still a significant amo unt of cardiac damage compared to vehicle-treated controls, Dogs were given 0.1, 0.3, and 0.8 mg/kg DOX with 20:1 DZR for 13 weeks, DZR redu ced the MTS significantly (P < 0.05) in males and females but cardiac lesions were still present in each of the DZR-treated dogs. The result s indicate that although DZR is highly effective in attenuating the ca rdiomyopathy caused by DOX, dose ratios of DZR:DOX capable of providin g total or nearly complete cardioprotection at low doses of DOX are le ss efficacious at higher doses of DOX. One possible explanation for th is effect is the marked pharmacokinetic difference between DZR and DOX , with DZR undergoing a much more rapid rate of elimination from the b ody compared to DOX, These findings point to the need for further stud ies to optimize the dose scheduling of DZR before using it clinically with bolus doses of DOX above those currently recommended.