SELECTIVE PROTECTION OF TOXICITY OF 2',3'-DIDEOXYPYRIMIDINE NUCLEOSIDE ANALOGS BY BETA-D-URIDINE IN HUMAN GRANULOCYTE-MACROPHAGE PROGENITORCELLS

beta-D-Uridine protected human granulocyte-macrophage lineage cells in both semi-solid (granulocyte-macrophage colony-forming units, CFU-GM) and liquid cultures against the toxic effects of 3'-azido-3'-deoxythy midine (AZT), 3'-fluoro-3'-deoxythymidine (FLT) and a combination of A ZT and FLT, without impairment of the activities of these respective d rugs against human immunodeficiency virus (HIV) replication. In additi on, beta-D-uridine also protected human CFU-GM against toxicity of the in vivo AZT metabolite, 3'-amino-3'-deoxythymidine (AMT). beta-L-urid ine and alpha-D-uridine, two stereoisomers of the natural form, and th e base uracil, were unable to protect cells against either AZT or FLT toxicity, whereas beta-D-uridine-5'-bis(SATE)phosphotriester, a prodru g of beta-D-uridine-5'-monophosphate, successfully protected cells aga inst AZT toxic effects, suggesting that beta-D-uridine needs to be met abolized to its nucleotides to exert a pharmacological effect. These d ata suggest in addition that AZT, FLT and AMT share a common target si te(s) of toxicity involved in myelosuppression.