3'-AZIDO-3'-DEOXYTHYMIDINE (AZT) INHIBITS PROLIFERATION INVITRO OF HUMAN HEMATOPOIETIC PROGENITOR CELLS

Peripheral blood cytopenias are a serious, dose-limiting toxicity of AZT therapy in patients infected by HIV. To evaluate the mechanism by which cytopenias develop AZT effects of haematopoietic differentiation and growth were measured in serum-free, nucleoside-depleted cultures of normal human bone marrow. In contrast to native thymidine, AZT suppressed the proliferation of erythroid, granuolcyte/macrophage and primitive haematopoietic stem cells in a dose-related and time-dependent fashion. Relative progenitor sensitivity varied, with half-maximal concentrations of 1-5 .mu.M and 20-40 .mu.M AZT for inhibition of erythroid and nonerythroid progenitor cell growth, respectively. Inhibition was observed over full ranges of concentrations of haematopoietic tissue-specific regulators (human erythropoietin, colony-stimulating activity, interleukin-3 and lymphocyte conditioned medium) and of platelet-derived growth factor (PDGF), an agent that enhances erythropoiesis in vitro via accessory marrow stromal elements. Furthermore, suppression was similar in cultures of marrow cells that were depleted of accessory populations, suggesting that its action is directed at progenitors. Finally, when deoxythymidine was added in increasing amounts to cultures with a half-maximal concentration of AXT, inhibition was abrogated. We concluded that AZT is a potent inhibitor of haematopoiesis in vitro, and that erythroid progenitors are particulary sensitive to its action. These results may explain the marrow hypoplasia that occurs during AZT administration in vivo.