Suppression of murine hematopoiesis in vivo after chronic administration of zidovudine: evidence that zidovudine-induced anemia is the result of decreased bone marrow-derived, erythropoietin-responsive progenitor cells.
We studied the long-term effect of continued zidovudine exposure in mice on hematopoiesis, as determined by peripheral blood indices, assays of erythroid (colony-forming unit-erythroid [CFU-E] and burst-forming unit-erythroid [BFU-E]), myeloid (CFU-granulocyte-macrophage [GM]), megakaryocyte (CFU-Meg), and plasma titers of erythropoietin, granulocyte-macrophage colony-stimulating factor, megakaryocyte colony-stimulating factor, and tumor necrosis factor-alpha. Dose-escalation of zidovudine (0.1, 1.0, and 2.5 mg/ml) induced a dose-dependent decrease in hematocrit, white blood cells, and platelets. High-dose drug, i.e., greater than 1.0 mg/ml, reduced marrow CFU-E; splenic CFU-E was increased after 1 week, then declined. BFU-E was increased at Weeks 1 and 2, then declined to control levels. Splenic BFU-E rose during the examination period that was dose-dependent. Femoral CFU-GM was cyclic, i.e., low-dose drug, 0.1 mg/ml, was increased gradually, the declined; higher doses of 1.0 and 2.5 mg/ml were lower until Week 5, then were above controls. Splenic CFU-GM was increased initially at Week 2 (1.0 mg/ml), then declined; the higher dose (2.5 mg/ml) increased initially, then declined below controls (Week 6). Femoral CFU-Meg was increased after low-dose drug and inhibited after high dose (2.5 mg/ml). Splenic CFU-Meg was reduced initially, followed by an increase at Week 4. Plasma titer of erythropoietin was elevated, proportional to dose escalation of drug, and inversely proportional to the hematocrit. No difference was observed in plasma levels of granulocyte-macrophage colony-stimulating factor, megakaryocyte colony-stimulating factor, or tumor necrosis factor-alpha. This study demonstrates that zidovudine-induced anemia results from: (i) inadequate numbers of bone marrow-derived, erythropoietin-dependent hematopoietic progenitors, i.e., CFU-E; and (ii) a shift in erythropoietin-responsive progenitors from bone marrow to spleen capable of responding to obligatory growth factors.
Gallicchio
V S
VS
Department of Medicine, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, Lexington 40536-0084.
Hughes
N K
NK
D000740:Anemia / Q000139:chemically induced*; D000818:Animals; D001854:Bone Marrow Cells; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000032:analysis / Q000502:physiology*; D005260:Female; D058851:GPI-Linked Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008562:Membrane Glycoproteins; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000032:analysis; D015215:Zidovudine / Q000633:toxicity*
D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D004921:Erythropoietin; D015215:Zidovudine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000090204:Mesothelin