The ability of combination treatment with
erythropoietin (Epo) and
heme to rescue hematopoietic activity in mice from the suppressive effect of
azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked
anemia,
thrombocytopenia,
neutropenia, and
weight loss, whereas mice that received Epo and
heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT-treated animals and reduced the severe
anemia and
thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced
anemia, although, when combined with
heme, there was a great improvement in recovery of erythropoiesis. The combination of
heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with
heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as
body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received
heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of
heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus,
heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT
therapy.