Selective protection of toxicity of 2',3'-dideoxypyrimidine nucleoside analogs by beta-D-uridine in human granulocyte-macrophage progenitor cells.
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'-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, beta-D-uridine also protected human CFU-GM against toxicity of the in vivo AZT metabolite, 3'-amino-3'-deoxythymidine (AMT). Beta-L-uridine and alpha-D-uridine, two stereoisomers of the natural form, and the base uracil, were unable to protect cells against either AZT or FLT toxicity, whereas beta-D-uridine-5'-bis(SATE)phosphotriester, a prodrug of beta-D-uridine-5'-monophosphate, successfully protected cells against AZT toxic effects, suggesting that beta-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.
Faraj
A
A
Department of Pharmacology, Center for AIDS Research, University of Alabama at Birmingham 35294, USA.
Schinazi
R F
RF
Xie
M Y
MY
Gosselin
G
G
Perigaud
C
C
Imbach
J L
JL
Sommadossi
J P
JP
D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects*; D006678:HIV / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D015394:Molecular Structure; D014529:Uridine / Q000494:pharmacology*; D015215:Zidovudine / Q000037:antagonists & inhibitors / Q000633:toxicity*
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D015215:Zidovudine; C019252:3'-aminothymidine; C002854:alovudine; D014529:Uridine