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Dose-Response Relationship of Dexrazoxane for Prevention of Doxorubicin-induced Cardiotoxicity in Mice, Rats, and Dogs¹

Pharmacia and Upjohn, Inc., P. O. Box 16529, Columbus, Ohio 43216 [A. R. I., T. L. R., L. M. H.] and Nerviano, Italy [P. D. T., G. M., A. P., G. P.], and Health Division, Battelle Memorial Institute, Columbus, Ohio 43201-2693 [A. R. I., T. M. S.]

Dexrazoxane [(DZR), ADR 529, ICRF-187] ameliorates doxorubicin (DOX)-induced cardiotoxicity in animals, and is recommended as a cardioprotectant in patients receiving cumulative doses of DOX above 300 mg/m². A DZR:DOX dose ratio of 10:1 is recommended based on studies in patients receiving 50 mg/m². Since DOX may be 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 evaluated 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. Without DZR, the MTS 4 weeks after the last treatment was 3.7 with 4 mg/kg DOX and 1.3 with 2 mg/kg DOX. DZR at 5:1, 10:1, and 20:1 dose ratios caused a dose-dependent decrease in the MTS but was less efficacious with the higher, more cardiotoxic dose of DOX. 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. Cardiomyopathy was most severe with the highest dose of DOX in the absence of DZR, especially in males, and progressed during the 6 weeks following 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 amount 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 reduced the MTS significantly (P < 0.05) in males and females but cardiac lesions were still present in each of the DZR-treated dogs. The results indicate that although DZR is highly effective in attenuating the cardiomyopathy caused by DOX, dose ratios of DZR:DOX capable of providing total or nearly complete cardioprotection at low doses of DOX are less efficacious at higher doses of DOX. One possible explanation for this effect is the marked pharmacokinetic difference between DZR and DOX, with DZR undergoing a much more rapid rate of elimination from the body compared to DOX. These findings point to the need for further studies to optimize the dose scheduling of DZR before using it clinically with bolus doses of DOX above those currently recommended.

¹ This work was presented, in part, at the 87th Annual Meeting of the American Association for Cancer Research, Washington, DC, April 20–24, 1996.

² To whom requests for reprints should be addressed, at Health Division, Battelle Memorial Institute, 505 King Avenue, Columbus, OH 43201-2693.

Received 5/ 1/96. Accepted 7/17/96.

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