Comparative Hematopoietic Toxicity of Doxorubicin and 4'-Epirubicin

4′-Epirubicin is an anthracycline analog of doxorubicin which has been shown to be similar to doxorubicin in its anti-tumor activity but significantly lower in its cardiotoxicity. Therefore, it has been proposed as a potential clinical substitute for doxorubicin. Using the hematopoietic colony-forming unit, spleen (CFU-S) assay technique, direct comparison was made of the hematopoietic toxicity of the two drugs in vivo in a mouse model, and 4′-epirubicin was found to be significantly (P < 0.01) less toxic than doxorubicin. On a milligram per kilogram basis, the dose of 4′-epirubicin required to achieve a given level of hematopoietic progenitor cell kill was approximately 50% larger than that required for doxorubicin. Early CFU-S recovery following 4′-epirubicin exposure was also stronger than that achieved following doxorubicin, as was short-term peripheral white blood cell recovery. These findings confirm previous clinical suggestions that the acute toxicity of 4′-epirubicin toward hematopoietic progenitor cells might be less than that of doxorubicin. At the same time, however, when given in doses near their lethal limit, both drugs were shown to induce a chronic hematopoietic suppression. This was evident in the depressed long-term CFU-S levels following high doses of either drug, as well as in chronically depressed white blood cell levels following high-dose 4′-epirubicin.