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 fac tor (GM-CSF) on the suppression of hematopoiesis associated with the u se of the antiviral drug zidovudine (AZT) administered in vivo to norm al mice, as determined by measuring peripheral blood indices, and assa ys of hematopoietic progenitors, i.e. erythroid (CFU-E/BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) from bone marrow and spleen. Pr evious studies from this laboratory have established that dose-escalat ion zidovudine induced a dose-dependent decrease in hematocrit, WBC, a nd platelets with altered populations of bone marrow and splenic eryth roid, myeloid and megakaryocyte progenitors when administered to norma l mice. Daily administration of GRM-CSF (10 mu g/kg/bw) was associated with altered peripheral blood indices and progenitor cells. Dose-esca lation AZT, i.e. 0.1, 1.0 and 2.5 mg/ml,,vas associated with a compara ble reduction in all indices, i.e. hematocrit, WBC, and platelets duri ng the 6-meek examination period. GM-CSF reduced zidovudine-induced my eloid 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 R-CSF induced a reduction in circulating platelets following zidovudin e treatment at weeks 2 and 4 with the 1.0 mg/ml and 2.5 mg/ml treatmen t group respectively, compared to a persistent decrease in platelets i n the presence of zidovudine alone. GM-CSF failed to reverse or minimi ze the development of anemia. No reversal in reduced CFU-E was observe d, however BFU-E were elevated indicating the restriction in erythoid differentiation was still present. These studies demonstrate GM-CSF in fluences myeloid and megakaryocyte recovery, but not the erythoid supp ression associated with the antiviral drug zidovudine.