EFFECT OF G-CSF AND M-CSF ON THE IN-VITRO TOXICITY ASSOCIATED WITH ZIDOVUDINE IN NORMAL HUMAN BONE-MARROW HEMATOPOIETIC PROGENITOR STEM-CELLS

Zidovudine, the antiviral drug used in the treatment of acquired immun odeficiency syndrome (AIDS), causes toxicity to the haematopoietic sys tem. Although use of the haematopoietic growth factors, GM-CSF and ery thropoietin have been investigated in clinical trials to modulate anti viral toxicity, there is scant data which supports their ability to am eliorate zidovudine induced toxicity on haematopoietic progenitor cell s when combined in vitro. We describe here the results of studies desi gned to evaluate the capacity of additional haematopoietic factors suc h as granulocyte-colony stimulating factor (G-CSF) and macrophage-colo ny stimulating factor (M-CSF) to modulate zidovudine-induced toxicity on G-CSF and M-CSF dependent-colony formation in the presence or absen ce of zidovudine in vitro. These factors were also studied combined wi th erythropoietin in culture for the early erythroid progenitor BFU-E using adherent, T-cell, depleted normal human bone marrow cells in the presence or absence of zidovudine. In the presence of zidovudine at t he concentration producing 50% inhibition of G- and M-CSF dependent co lony formation, (5 x 10(-5) M), dose-escalation of either G-CSF or M-C SF failed to ameliorate zidovudine toxicity. However, in the Presence of zidovudine at the concentration that produces 50% inhibition of BFU -E (5 x 10(-9) m), and optimal erythropoietin (1 unit ml-1), G-CSF ame liorated zidovudine inhibition of BFU-E, which was not observed with M -CSF. In the presence of erythropoietin, G-CSF increased significantly normal BFU-E. These studies indicate that G-CSF may be useful in amel iorating zidovudine-induced anaemia and suggest G-CSF may act as a syn ergistic factor to enhance erythropoietin to support the growth of ery throid progenitors in conditions where erythropoitin is ineffective.