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M94B0790.TXT
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1994-11-11
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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).