Selective protection of toxicity of 2′,3′-dideoxypyrimidine nucleoside analogs by β- d-uridine in human granulocyte-macrophage progenitor cells

Abstract

β- 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′-deoxythymidine (AZT), 3′-fluoro-3′-deoxythymidine (FLT) and a combination of AZT and FLT, without impairment of the activities of these respective drugs against human immunodeficiency virus (HIV) replication. In addition, β- d-uridine also protected human CFU-GM against toxicity of the in vivo AZT metabolite, 3′-amino-3′-deoxythymidine (AMT). β- l-uridine and α- d-uridine, two stereoisomers of the natural form, and the base uracil, were unable to protect cells against either AZT or FLT toxicity, whereas β- d-uridine-5′-bis(SATE)phosphotriester, a prodrug of β- d-uridine-5′-monophosphate, successfully protected cells against AZT toxic effects, suggesting that β- d-uridine needs to be metabolized to its nucleotides to exert a pharmacological effect. These data suggest in addition that AZT, FLT and AMT share a common target site(s) of toxicity involved in myelosuppression.