Preclinical models of cardiac protection and testing for effects of dexrazoxane on doxorubicin antitumor effects

The ability of dexrazoxane (DEX) to protect against doxorubicin (DOX)-induced cardiomyopathy has been demonstrated in mice, normotensive and hypertensive rats, rabbits, dogs, swine, and humans. These animal models of DOX-induced cardiomyopathy were found to be highly predictive of DEX activity clinically. In mice administered maximally tolerated doses of DOX over a period of 7 weeks, the optimum dose of DEX was from 10:1 to 20:1 (DEX:DOX) given from 30 minutes before to 15 minutes after DOX. The dose ratio required to reduce the incidence of moderate to severe cardiomyopathy by 90% in the mouse was more than 20:1 for DOX and 10:1, 5:1, and 5:1 for epirubicin, daunorubicin, and idarubicin, respectively. Dexrazoxane was most effective in rats when treatment commenced with the first and third doses of DOX, but also provided cardioprotection when started with the sixth of 10 doses of DOX. The cardioprotective activity of DEX in rats was evident for more than 6 months after completion of DOX dosing. Results of antitumor studies in several experimental tumor models indicate that DEX does not interfere with the antineoplastic activity of DOX or other antitumor drugs. In some case, especially cyclophosphamide, there was a markedly synergistic antitumor effect when combined with DEX.