Document 0213
 DOCN  M94A0213
 TI    Inhibition of ribonucleotide reductase by 2'-substituted deoxycytidine
       analogs: possible application in AIDS treatment.
 DT    9412
 AU    Bianchi V; Borella S; Calderazzo F; Ferraro P; Chieco Bianchi L;
       Reichard P; Department of Biology, University of Padova, Italy.
 SO    Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8403-7. Unique Identifier :
       AIDSLINE MED/94359939
 AB    After phosphorylation to the corresponding diphosphates,
       2'-azido-2'-deoxycytidine and 2'-difluorocytidine act as powerful
       inhibitors of ribonucleotide reductase. Phosphorylation requires
       deoxycytidine kinase, an enzyme with particularly high activity in
       lymphoid cells. Therefore, the deoxycytidine analogs can be expected to
       inhibit the reductase with some specificity for the lymphoid system.
       Pretreatment of human CEM lymphoblasts with the analogs considerably
       increased the phosphorylation of 3'-deoxy-3'-azidothymidine (AzT). The
       increased phosphorylation of AzT is caused by a prolongation of the S
       phase of the cell cycle. Our results suggest the possibility of a
       combination of 2'-substituted deoxycytidine analogs with AzT in the
       treatment of AIDS. Gao et al. [Gao, W.-Y., Cara, A., Gallo, R. C. &
       Lori, F. (1993) Proc. Natl. Acad. Sci. USA 90, 8925-8928] have suggested
       the use of the ribonucleotide reductase inhibitor hydroxyurea for this
       purpose, since the resulting decrease in the size of deoxyribonucleotide
       pools decreases the processivity of the HIV reverse transcriptase. From
       our results it would appear that the 2'-substituted deoxycytidine
       analogs might be preferable to hydroxyurea.
 DE    Acquired Immunodeficiency Syndrome/*DRUG THERAPY  Antiviral Agents
       Cells, Cultured  Comparative Study  Cytidine/ANALOGS &
       DERIVATIVES/PHARMACOLOGY  Deoxycytidine/*ANALOGS &
       DERIVATIVES/PHARMACOLOGY/THERAPEUTIC USE  Human
       Hydroxyurea/PHARMACOLOGY  In Vitro  Prodrugs  Ribonucleotide
       Reductases/*ANTAGONISTS & INHIB  Support, Non-U.S. Gov't
       Zidovudine/*ADMINISTRATION & DOSAGE/METABOLISM  JOURNAL ARTICLE

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