Dexrazoxane (Dex) is an iron chelator and a potent catalytic topoisomerase II inhibitor. Clinically, it prevents and reduces anthracycline induced cardiotoxicity; preclinically, it rescues experimental animals from high doses of various topoisomerase II poisons, such as daunorubicin (Dau) and etoposide. Dex has been suggested to protect against Dau induced GI-tract toxicity, but the effect on the hematological tissue is not well investigated. In mice, we have shown that Dex reduces myelosuppression from Dau as well as etoposide. Here we show that Dex also reduces myelosuppression from Dau in dogs.


3 groups of 4 male beagle dogs received Dau 2.0, 2.5 and 2.7 mg/kg as a single intravenous dose. In each group, 2 dogs received Dau + pretreatment with Dex 25 mg/kg and 2 received Dau plus saline only. Automated analysis of the complete blood cell counts (on an ABX Pentra 120) were obtained pretreatment and every 2nd day post-dosing. Statistical analysis was by two-way analysis of variance.


The leukocytes (WBC), neutrophils (ANC), platelets (PLT) and red blood cells (RBC) on nadir compared to the pretreatment values were significantly higher after Dau + Dex compared to Dau alone; dex pretreatment also reduced general clinical signs of toxicity.


In addition to its activity against cardiotoxicity, Dex is suggested to also antagonize one of the major acute toxic side effects from daunorubicin, i.e. the myelosuppression. This reduction of toxicity may possibly be used to improve the therapeutic indices of the topoisomerase II poisons. One possible use of such protection is the safe use of escalated doses of cytotoxics against for example brain tumors, while at the same time reducing systemic side effects. How this interaction may possibly affect Dau anticancer efficacy against systemic disease is not known, and would need to be determined in appropriate clinical trials.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA