Document 0296
 DOCN  M9460296
 TI    Divergent anti-human immunodeficiency virus activity and anabolic
       phosphorylation of 2',3'-dideoxynucleoside analogs in resting and
       activated human cells.
 DT    9408
 AU    Gao WY; Agbaria R; Driscoll JS; Mitsuya H; Experimental Retrovirology
       Section, National Cancer Institute,; Bethesda, Maryland 20892.
 SO    J Biol Chem. 1994 Apr 29;269(17):12633-8. Unique Identifier : AIDSLINE
       MED/94230334
 AB    The mechanism of divergent anti-human immunodeficiency virus type 1
       (HIV-1) activity of various 2',3'-dideoxynucleoside analogs (ddNs) in
       peripheral blood mononuclear cells (PBM) was studied. We demonstrate
       that the in vitro anti-HIV-1 activity of various ddNs varies profoundly
       and that the divergent antiviral activity is related to the extent of
       anabolic phosphorylation of each ddN and its counterpart
       2'-deoxynucleoside (dN). We also show that certain ddNs cause a
       reduction of their counterpart dNTP formation in PBM in the following
       order: 2',3'-dideoxycytidine (ddC) >>
       2',3'-didehydro-2',3'-dideoxythymidine (d4T),
       3'-thia-2',3'-dideoxycytidine (3TC), 2',3'-dideoxyinosine (ddI),
       2',3'-dideoxyguanosine (ddG) > 3'-azido-2',3'-dideoxythymidine (AZT) >
       2'-beta-fluoro-2',3'-dideoxyadenosine (F-ara-ddA). Based on the
       phosphorylation profiles, anti-HIV-1 ddNs can be classified into two
       groups: (i) cell-activation-dependent ddNs such as AZT and d4T that are
       preferentially phosphorylated, yield higher ratios of ddNTP/dNTP, and
       exert more potent anti-HIV-1 activity in activated cells than in resting
       cells; and (ii) cell-activation-independent ddNs including ddI (and
       2',3'-dideoxyadenosine), F-ara-ddA, ddG, ddC, and 3TC that produce
       higher ratios of ddNTP/dNTP and exert more potent anti-HIV-1 activity in
       resting cells. These data should provide a basis for the elucidation of
       the mechanism of the divergent antiretroviral activity of ddNs.
 DE    Cells, Cultured  Deoxycytidine Kinase/METABOLISM
       Didanosine/PHARMACOLOGY  Dideoxynucleosides/*PHARMACOLOGY  Human
       HIV-1/*DRUG EFFECTS  Monocytes/DRUG EFFECTS/ENZYMOLOGY/MICROBIOLOGY
       Phosphorylation  Phytohemagglutinins/PHARMACOLOGY  Thymidine
       Kinase/METABOLISM  Zidovudine/PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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