Prevention of hematopoietic myeloid and megakaryocyte toxicity associated with zidovudine in vivo in mice with recombinant GM-CSF.
We studied the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the suppression of hematopoiesis associated with the use of the antiviral drug zidovudine (AZT) administered in vivo to normal mice, as determined by measuring peripheral blood indices, and assays of hematopoietic progenitors, i.e. erythroid (CFU-E/BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) from bone marrow and spleen. Previous studies from this laboratory have established that dose-escalation zidovudine induced a dose-dependent decrease in hematocrit, WBC, and platelets with altered populations of bone marrow and splenic erythroid, myeloid and megakaryocyte progenitors when administered to normal mice. Daily administration of GM-CSF (10 micrograms/kg/bw) was associated with altered peripheral blood indices and progenitor cells. Dose-escalation AZT, i.e. 0.1, 1.0 and 2.5 mg/ml, was associated with a comparable reduction in all indices, i.e. hematocrit, WBC, and platelets during the 6-week examination period. GM-CSF reduced zidovudine-induced myeloid toxicity (concentration < 2.5 mg/ml) which was associated with an increase in bone marrow and splenic CFU-GM. High concentration, i.e. 2.5 mg/ml still produced myelosuppression irreversible with GM-CSF. GM-CSF induced a reduction in circulating platelets following zidovudine treatment at weeks 2 and 4 with the 1.0 mg/ml and 2.5 mg/ml treatment groups respectively, compared to a persistent decrease in platelets in the presence of zidovudine alone. GM-CSF BFU-E were elevated indicating the restriction in erythoid differentiation was still present. These studies demonstrate GM-CSF influences myeloid and megakaryocyte recovery, but not the erythoid suppression associated with the antiviral drug zidovudine.
Department of Internal Medicine, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, Lexington 40536-0084.
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Gallicchio
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Hughes
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D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006400:Hematocrit; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D015215:Zidovudine / Q000633:toxicity*
D007375:Interleukin-1; D007377:Interleukin-3; D015850:Interleukin-6; D011994:Recombinant Proteins; D015215:Zidovudine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor