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M94B0812.TXT
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1994-11-11
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Document 0812
DOCN M94B0812
TI Anti-human immunodeficiency virus activities of the beta-L enantiomer of
2',3'-dideoxycytidine and its 5-fluoro derivative in vitro.
DT 9412
AU Gosselin G; Schinazi RF; Sommadossi JP; Mathe C; Bergogne MC; Aubertin
AM; Kirn A; Imbach JL; Laboratoire de Chimie Bioorganique, URA Centre
National de la; Recherche Scientifique 488, Universite de Montpellier
II,; Sciences et Techniques du Languedoc, France.
SO Antimicrob Agents Chemother. 1994 Jun;38(6):1292-7. Unique Identifier :
AIDSLINE MED/94379781
AB The L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to
inhibit selectively human immunodeficiency virus type 1 (HIV-1) in
vitro. In the current study, the potent anti-HIV activity of L-DDC was
confirmed and extended to several HIV-1 and HIV-2 strains in various
cell culture systems, including primary human lymphocytes and
macrophages. Furthermore, its 5-fluoro congener,
beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more
potent anti-HIV activity and a higher therapeutic index in acutely
infected human peripheral blood mononuclear cells. These compounds had
no marked activity against HIV-1 isolates resistant to the oxathiolane
pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine
[(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but
3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to
L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor
cells indicated that L-DDC and L-FDDC had median inhibitory
concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and
L-FDDC were significantly less toxic than AZT, DDC, and FDDC when
erythroid progenitor cells were used. L-FDDC had the highest selectivity
indices (6,000 and 9,000 for erythroid and myeloid progenitor cells,
respectively) of all the compounds evaluated. Further preclinical
development of L-FDDC is warranted in order to determine its potential
usefulness in the treatment of HIV infections.
DE Antiviral Agents/*PHARMACOLOGY Bone Marrow/DRUG EFFECTS Cell Line
Drug Resistance Human HIV/*DRUG EFFECTS Stereoisomers Support,
Non-U.S. Gov't Support, U.S. Gov't, Non-P.H.S. Support, U.S. Gov't,
P.H.S. Zalcitabine/*ANALOGS & DERIVATIVES/*PHARMACOLOGY/TOXICITY
JOURNAL ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).