PROTECTION AND RESCUE FROM 2',3'-DIDEOXYPYRIMIDINE NUCLEOSIDE ANALOG TOXICITY BY HEMIN IN HUMAN BONE-MARROW PROGENITOR CELLS

Long-term therapy of AIDS patients with 3'-azido-3'-deoxythymidine (AZ T) remains of concern because of resulting hematopoietic toxicity, Whi le the mechanism(s) of this toxicity remains elusive, alternative stra tegies are being developed to reduce these toxic effects, including co mbination therapy with nonmyelotoxic antihuman immunodeficiency virus drugs and/or administration of protective oi rescue agents, including cytokines and growth factors. By using a particularly relevant human C D34(+) liquid culture system, the unique profiles of dideoxynucleoside (ddN) toxicities to both proliferation and differentiation were demon strated, with decreased potencies in the order of 3'-fluoro-3'-deoxyth ymidine (FLT) = 3'-amino-3'-deoxythymidine (AMT) 2',3'-dideoxycytidine > AZT for inhibition of proliferation and in the order of FLT = AMT > AZT much greater than 2',3'-dideoxycytidine for inhibition of hemoglo bin synthesis, Hemin selectively protected erythroid-lineage human bur st-forming unit-erythroid cells from AZT- and AMT-induced inhibition b ut had no effect on FLT toxicity under similar conditions, Myeloid-lin eage human CFU-granulocyte-macrophages were also not protected by hemi n against all three ddN analogs, The simultaneous exposure of cells to hemin and AZT resulted in a complete protection of both cell prolifer ation and hemoglobin synthesis, In contrast, in reversal studies only the inhibition of the percentage of hemoglobin-synthesizing cells retu rned to control levels, but the inhibition of proliferation of cells p reviously exposed to AZT was not reversed by hemin, These studies furt her define the unique and multifactorial mechanism(s) of ddN-induced t oxic effects during hematopoietic development of pluripotent stem cell s and suggest that the use of hemin could be beneficial in alleviating the toxicity of certain ddN analogs.