Acute toxic effects of 3'-azido-3'-deoxythymidine (AZT) on normal and regenerating murine hematopoiesis.
The immediate hematopoietic response to 3'-azido-3'-deoxythymidine (AZT) was characterized in an unperturbed and regenerating mouse marrow model to identify the in vivo hematopoietic targets of AZT and test whether AZT toxicity is dependent on the proliferative activity of the hematopoietic targets. B6D2F1 mice received intravenous (IV) bolus injections of 30, 60, 120, and 240 mg/kg AZT. None of the doses induced consistent changes in the number of hematopoietic stem and progenitor cells. However, identical cumulative doses administered as an intravenous 24-hour infusion led to marked changes. Spleen colony-forming units (CFU-S) per femur were diminished to about 60%. Burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E) were substantially reduced to about 15 to 35% at the two highest doses, whereas the femoral content of colony-forming units-granulocyte/macrophage (CFU-GM) and colony-forming units-megakaryocyte (CFU-Meg) was unchanged. When administered to mice whose marrow was regenerating from total-body irradiation (TBI) and subsequent bone marrow transplantation (high proliferative fraction), 240 mg/kg AZT caused considerable reductions of all hematopoietic cell stages even when given as a single IV injection. The results indicate that (1) the mode of application is critical for AZT hematotoxicity; (2) erythropoietic progenitors are the most sensitive to AZT toxicity; and (3) hematotoxicity increases with increasing proliferative activity.
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Division of Hematology and Oncology, Wayne State University, School of Medicine, Detroit, MI 48201.
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Nakeff
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D000818:Animals; D001853:Bone Marrow / Q000502:physiology* / Q000528:radiation effects; D001854:Bone Marrow Cells; D001855:Bone Marrow Diseases / Q000139:chemically induced; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004920:Erythropoiesis / Q000502:physiology; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012038:Regeneration / Q000187:drug effects*; D013997:Time Factors; D014916:Whole-Body Irradiation; D015215:Zidovudine / Q000008:administration & dosage / Q000633:toxicity*
D015215:Zidovudine