Comparative toxicity of mitoxantrone and doxorubicin on hematopoietic stem cells

Mitoxantrone (DHAD) is a recently developed cancer chemotherapeutic drug proposed as a possible substitute for the older established chemotherapeutic, doxorubicin (adriamycin, or ADR). We have directly compared the toxicity of DHAD and ADR against normal hematopoietic progenitors in a mouse model. Using doses that produced equal depressions in spleen weight, we examined the recovery patterns for pluripotent hematopoietic stem cells (CFU-S), myeloid cell progenitors (CFU-GM), and reticulocyte (Retic) production. The spleen weight depression assay indicated that, on a mg/kg basis, DHAD was more toxic to the organ than ADR, with 17.5 mg of ADR required to produce the same level of effect as 10 mg of DHAD. Recovery of splenic mass after exposure to these doses was also poorer in the DHAD-treated mice. CFU-S studies showed that the initial direct killing effects of pluripotent stem cells by the two drugs were equivalent, but that CFU-S recovery was better after ADR exposure than after DHAD exposure. By 12 days after exposure to ADR, the number of CFU-S per spleen had not only regained normal levels, but exceeded the normal by a factor of 2. In contrast, in the DHAD-treated mice the number was only half normal at this same time. The results suggest that there is a delay in recovery of the pluripotent stem cell compartment after DHAD exposure that may be due to some type of unrepaired damage to the support tissue in the spleen on which the CFU-S are dependent. Analysis of the effects of DHAD and ADR on CFU-GM indicated an initial toxic effect that was roughly equivalent for the two drugs at the doses used. However, the timing of the points of maximum suppression were different--earlier after exposure to DHAD than after ADR. Subsequently, the recovery patterns were quite similar for both drugs, and at 14 days the CFU-GM numbers were virtually normal. Reticulocyte assay indicated that both ADR and DHAD severely depressed red blood cell production. Recovery was rapid and complete by nine days, however, with significant overshoots, especially in the case of ADR exposure. Serial white blood cell (WBC) counts were also carried out. Reduction in total WBC number was evident between two and 11 days after exposure and more severe with DHAD than with ADR. However, neither the extent of suppression nor its duration accurately reflected the events occurring in the CFU-S or CFU-GM progenitor compartments.(ABSTRACT TRUNCATED AT 400 WORDS)