Document 0790
 DOCN  M94B0790
 TI    Mechanism of disproportionate antiviral activity of
       2',3'-dideoxynucleoside analogs and their classification (Meeting
       abstract).
 DT    9412
 AU    Gao WY; Agbaria R; Driscoll JS; Mitsuya H; NCI, Bethesda, MD 20892
 SO    Proc Annu Meet Am Assoc Cancer Res; 35:A1841 1994. Unique Identifier :
       AIDSLINE ICDB/94603527
 AB    The mechanism of disproportionate anti-HIV-1 activity of
       2',3'-dideoxynucleoside (ddN) in resting and activated target cells was
       studied. The in vitro activity of various ddNs against human
       immunodeficiency type 1 (HIV-1) profoundly differed from each other. The
       divergent antiviral activity was associated with different anabolic
       phosphorylation of each ddN analog and the counterpart dN.
       Dideoxynucleosides suppressed the counterpart dNTP formation in target
       cells, which was dependent on the activation state of the cells and
       individual ddN. The comparative order of the reduction was ddC much
       greater than d4T, 3TC, ddI, and ddG greater than AZT greater than
       F-ara-ddA. Based on the phosphorylation profiles, ddN analogs can be
       classified into two groups depending on the activation state of a target
       cell: (1) Cell activation-dependent ddNs such as AZT and
       2',3'-didehydro-2',3'-dideoxythymidine (d4T) that are preferentially
       phosphorylated, yielding higher ratios of ddNTP/dNTP, and exert more
       potent anti-HIV activity in activated cells than in resting cells; and
       (2) Cell activation-independent ddNs including 2',3'-dideoxyinosine
       (ddI), 2',3'-dideoxyadenosine (ddA), 2'-fluoro
       2',3'-dideoxyadenine-arabinofuranoside (F-ara-ddA),
       2',3'-dideoxyguanosine (ddG), 2',3'-dideoxycytidine (ddc), and
       3'-thia-2',3'-dideoxycytidine (3TC) that achieve higher ratios of
       ddNTP/dNTP and exert more potent activity against the virus in resting
       cells. These results may provide a basis for the explanation of the
       divergent degrees of antiretroviral activity of ddN analogs observed
       when tested in tissue culture and when administered to patients with
       HIV-1 infection.
 DE    Antiviral Agents/CLASSIFICATION/*TOXICITY  Cells/DRUG EFFECTS/PHYSIOLOGY
       Cells, Cultured  Comparative Study
       Dideoxynucleosides/CLASSIFICATION/*TOXICITY  HIV-1/*DRUG EFFECTS/GROWTH
       & DEVELOPMENT  Human  Structure-Activity Relationship  MEETING ABSTRACT

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).