ACUTE TOXIC EFFECTS OF 3'-AZIDO-3'-DEOXYTHYMIDINE (AZT) ON NORMAL ANDREGENERATING MURINE HEMATOPOIESIS

The immediate hematopoietic response to 3'-azido-3'-deoxythymidine (AZ T) was characterized in an unperturbed and regenerating mouse marrow m odel to identify the in vivo hematopoietic targets of AZT and test whe ther AZT toxicity is dependent on the proliferative activity of the he matopoietic targets. B6D2F1 mice received intravenous (IV) bolus injec tions of 30, 60, 120, and 240 mg/kg AZT. None of the doses induced con sistent changes in the number of hematopoietic stem and progenitor cel ls. 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-ery throid (BFU-E) and colony-forming units-erythroid (CFUE) were substant ially reduced to about 15 to 35% at the two highest doses, whereas the femoral content of colony-forming units-granulocyte/macrophage (CFU-G M) and colony-forming units-megakaryocyte (CFU-Meg) was unchanged. Whe n administered to mice whose marrow was regenerating from total-body i rradiation (TBI) and subsequent bone marrow transplantation (high prol iferative fraction), 240 mg/kg AZT caused considerable reductions of a ll 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 sensi tive to AZT toxicity; and (3) hematotoxicity increases with increasing proliferative activity.