INHIBITION OF RIBONUCLEOTIDE REDUCTASE BY 2'-SUBSTITUTED DEOXYCYTIDINE ANALOGS - POSSIBLE APPLICATION IN AIDS TREATMENT

Citation
V. Bianchi et al., INHIBITION OF RIBONUCLEOTIDE REDUCTASE BY 2'-SUBSTITUTED DEOXYCYTIDINE ANALOGS - POSSIBLE APPLICATION IN AIDS TREATMENT, Proceedings of the National Academy of Sciences of the United Statesof America, 91(18), 1994, pp. 8403-8407
Citations number
21
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
91
Issue
18
Year of publication
1994
Pages
8403 - 8407
Database
ISI
SICI code
0027-8424(1994)91:18<8403:IORRB2>2.0.ZU;2-O
Abstract
After phosphorylation to the corresponding diphosphates, 2'-azido-2'-d eoxycytidine and 2'-difluorocytidine act as powerful inhibitors of rib onucleotide 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 w ith some specificity for the lymphoid system. Pretreatment of human CE M lymphoblasts with the analogs considerably increased the phosphoryla tion of 3'-deoxy-3'-azidothymidine (AzT). The increased phosphorylatio n 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'-substitute d 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 proce ssivity of the HIV reverse transcriptase. From our results it would ap pear that the 2'-substituted deoxycytidine analogs might be preferable to hydroxyurea.