Additive effect of erythropoietin and heme on murine hematopoietic recovery
after azidothymidine treatment [see comments]
J Harrison, A Kappas, RD Levere, JD Lutton, JL Chertkov, S Jiang and NG Abraham
Department of Medicine, New York Medical College, Valhalla 10595.
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.
Volume 82,
Issue 12,
pp. 3574-3579,
12/15/1993
Copyright © 1993 by The American Society of Hematology
