INHIBITORS OF IMP DEHYDROGENASE STIMULATE THE PHOSPHORYLATION OF THE ANTIVIRAL NUCLEOSIDE 2',3'-DIDEOXYGUANOSINE

被引:30
作者
AHLUWALIA, G
COONEY, DA
BONDOC, LL
CURRENS, MJ
FORD, H
JOHNS, DG
MITSUYA, H
FRIDLAND, A
机构
[1] NCI, DIV CANC TREATMENT, CLIN ONCOL PROGRAM, BETHESDA, MD 20892 USA
[2] ST JUDE CHILDRENS RES HOSP, DIV BIOCHEM & CLIN PHARMACOL, MEMPHIS, TN 38101 USA
关键词
D O I
10.1016/0006-291X(90)90827-A
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The inosinate dehydrogenase (IMPD) inhibitors ribavirin, tiazofurin and mycophenolic acid were found to stimulate by as much as 20-fold the anabolism of the anti-HIV agent 2′,3′dideoxyguanosine to its 5′-diphosphate (ddGDP) in a human T-cell culture system (Molt-4 cells). Stimulation of the further conversion to ddGTP (the active form of the drug) was lesser in magnitude but still highly significant (up to 4-fold at appropriate concentrations of ribavirin or tiazofurin). In parallel with these increases, the inhibitors also produced increases of up to 35-fold in IMP levels. These results support the proposal that the initial phosphorylation of ddGuo is catalyzed by a phosphotransferase (5′-nucleotidase) which utilizes IMP as its phosphate donor (Johnson and Fridland, [1989] Molec. Pharmacol. 36, 291-295). Concomitant with this increase in 5′-phosphorylation of ddGuo, an increase in its anti-HIV activity of up to 6.5-fold was observed when this agent was combined with ribavirin (5μM) in the CEM cell assay system. © 1990.
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页码:1297 / 1303
页数:7
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