Effect of IL-1, IL-6, GM-CSF and Erythropoietin on thein vitroToxicity Associated with AZT on Human Bone Marrow Haematopoietic Progenitor Stem Cells: CFU-GM and BFU-E

Abstract

The drug azidothymidine (AZT), a synthetic thymidine analogue, has been used in the treatment of acquired immunodeficiency syndrome (AIDS). Clinical use of AZT has induced haematopoietic toxicity manifested by anaemia, neutropenia, and overall bone marrow suppression. Cytokines/growth factors, such as erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-6 (IL-6), are agents responsible for the growth and regulation of normal haematopoiesis by influencing various classes of haematopoietic progenitors. We report the results of studies designed to investigate the capacity of these factors to influence the toxicity of AZT. Low density, ≤ 1.077 g/cm3, adherent and/or T-cell depleted normal human marrow cells were co-cultured in the presence or absence of AZT and the appropriate growth factor, i.e. EPO for the early erythroid haematopoietic colony-forming progenitor stem cell (BFU-E) and GM-CSF for the granulocyte–macrophage haematopoietic colony-forming progenitor stem cell (CFU-GM), in dose escalation studies. Additional experiments measured the effect of increasing doses of the cytokines IL-1 and IL-6, alone or in combination in the presence of increasing doses of either EPO or GM-CSF. When comparing the rate of AZT-induced inhibition of BFU-E in vitro, EPO alone (from 2 to 10 U/ml) did not reduce the magnitude of AZT toxicity on BFU-E. GM-CSF alone (up to 1000 U/ml) was ineffective in reversing AZT toxicity on CFU-GM; however, in the presence of either IL-1 and IL-6, AZT toxicity was decreased. These results indicate that certain cytokines/growth factors such as IL-1 or IL-6 in combination with EPO or GM-CSF, but not EPO or GM-CSF alone, may be effective in ameliorating AZT bone marrow toxicity; therefore the use of specific cytokines may be warranted as adjuvant therapy in AIDS.