Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2',3'-dideoxynucleoside activities against replication of human immunodeficiency virus.
We and other groups have recently reported the potentiation by ribonucleotide reductase inhibitors such as hydroxyurea of the anti-human immunodeficiency virus type 1 (HIV-1) activity of purine and pyrimidine 2',3'-dideoxynucleosides in both resting and phytohemagglutinin-stimulated peripheral blood mononuclear cells. Little agreement prevails, however, as to the mechanism of the synergistic effects described. We report here that in phytohemagglutinin-stimulated peripheral blood mononuclear cells, two mechanisms exist for the potentiation of the anti-HIV-1 activity by low-dose hydroxyurea of the purine-based dideoxynucleoside 2',3'-dideoxyinosine and the pyrimidine-based dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine. For 2',3'-dideoxyinosine, the enhancement arises from a specific depletion of dATP by hydroxyurea, resulting in a favorable shift of the 2',3'-dideoxyadenosine 5'-triphosphate/dATP ratio. For the pyrimidine dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine, the more modest anti-HIV enhancement results from hydroxyurea-induced increases of pyrimidine kinase activities in the salvage pathway and, hence, increased 5'-phosphorylation of these drugs, while depletion of the corresponding deoxynucleoside 5'-triphosphates (dTTP and dCTP) plays no significant role.
Gao
W Y
WY
Experimental Retrovirology Section, National Cancer Institute, Bethesda, MD 20892, USA.
Johns
D G
DG
Chokekuchai
S
S
Mitsuya
H
H
D000248:Adenosine Kinase / Q000378:metabolism; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D016049:Didanosine / Q000494:pharmacology*; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D010766:Phosphorylation; D011533:Proviruses / Q000187:drug effects / Q000235:genetics; D014541:Uridine Kinase / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D016047:Zalcitabine / Q000378:metabolism / Q000494:pharmacology*; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology*
D015215:Zidovudine; D016047:Zalcitabine; D000248:Adenosine Kinase; D014541:Uridine Kinase; D016049:Didanosine; D006918:Hydroxyurea