Lack of synergy in the inhibition of HIV-1 reverse transcriptase by combinations of the 5′-triphosphates of various anti-HIV nucleoside analogs

White, E. Lucile; Parker, William B.; Ross, L. J. N.; Shannon, William M.

doi:10.1016/0166-3542(93)90039-l

Cited by 26 publications

(27 citation statements)

References 28 publications

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“…Instead, they observed a modest increase in the level of ddI-triphosphate following AZT-ddI coexposure of these cells. White and coworkers (27) conducted experiments in some respects analogous to those reported here and found no increase in AZT-DNA incorporation by HIV viral reverse transcriptase when AZT and a second nucleoside analogue (i.e., dideoxyadenosine triphosphate, dideoxycytidine triphosphate, or carbovir) were administered together. Their investigations differed from the present work in several respects, including the fact that they used an extracellular system and evaluated incorporation of AZT by HIV reverse transcriptase instead of DNA polymerase (as was done in the current cell culture studies).…”

Section: Discussionmentioning

confidence: 95%

Zidovudine–didanosine coexposure potentiates DNA incorporation of zidovudine and mutagenesis in human cells

Meng

Walker

Olivero

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Drug combinations that include nucleoside reverse transcriptase inhibitors (NRTIs) are remarkably effective in preventing maternalviral transmission of HIV during pregnancy. However, there may be potential long-term risks for children exposed in utero. Examination of the genotoxic and mutagenic effects of two NRTIs, zidovudine [AZT (3-azido-3-deoxythymidine)] and didanosine [ddI (2,3-dideoxyinosine)], in cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure, as compared with single-drug exposures. Dose-related increases in DNA incorporation of AZT (as measured by a competitive RIA) and mutagenicity at the HPRT and TK loci (as assessed by cell-cloning assays) were observed in cells exposed in culture to AZT, or equimolar combinations of AZT ؉ ddI, at exposure concentrations ranging from 3 to 30 times the maximum plasma levels found in humans. Because mutagenesis is strongly associated with tumor induction in experimental models, children exposed transplacentally to combinations of NRTIs may be at risk for cancer development later in life.

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Section: Discussionmentioning

confidence: 95%

Zidovudine–didanosine coexposure potentiates DNA incorporation of zidovudine and mutagenesis in human cells

Meng

Walker

Olivero

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…The combination of AZT-TP and ddA-TP, however, does not produce synergy when tested against the RT (White et al, 1993), indicating that the mechanism of synergy does not consist of interactions at the level of the RT. The increased activation of ddl in the presence of AZT shown here may explain, in part, the synergy of the combination of AZT + ddl.…”

Section: Discussionmentioning

confidence: 98%

“…The synergistic mechanism of the combination of AZT and ddl is, however, unknown. According to a recent study, RT is not synergistically inhibited by AZT-TP and ddA-TP in combination (White et al, 1993), so the mechanism of synergy does not appear to lie at the level of RT per se.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Metabolism of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine in Combination in the Absence and Presence of Ribavirin

Palmer

Cox

1994

Antivir Chem Chemother

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SummaryWe examined the intracellular ph9sphorylation of 3'-azido-3'-deoxythymidine (AZT)Jhd 2',3'-dideoxyinosine (ddl) and the effects on rNTP and dNTP pools when AZT and ddl were incubated separately and in combination in lymphocytes. We also compared the effect of adding ribavirin (RBV) to the two-drug combination of AZT + ddl.AZT and ddl, used singly or in combination, had no effect on the dNTP pools of CEM Iymphoblastoid cells. Neither did the combination of AZT + ddl have any effect on the rNTP pools. RBV, a known inhibitor of IMP dehydrogenase, caused a decrease in GTP and an increase in dTTP whether incubated alone or with the drug combination of AZT + ddl. The addition of AZT + ddl therefore did not alter the effects of RBV upon cellular nucleotide pools.AZT was phosphorylated to a much greater extent than ddl. The activation of ddl to ddA-TP was increased 2-fold in the presence of AZT, whereas AZT phosphorylation was unchanged when combined with ddl. This increase in ddl activation may explain in part the synergistic antiviral activity of the combination of AZT + ddl. The increased activation was not due to increased phosphorylation of ddl resulting from IMP dehydrogenase inhibition.The addition of 10 IlM RBV to the two-drug combination of AZT + ddl did not change the intracellular phosphorylation of AZT or ddl. The activation of ddl to ddA-TP, when combined with AZT, appeared to be maximal and could not be further increased by addition of RBV to this combination.

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“…For the K i studies, HIV-1 RT activity was measured in 50-l reaction mixtures containing 50 mM Tris (pH 8.0), 50 mM KCl, 10 mM MgCl 2 , 4 mM ␤-mercaptoethanol, 3% glycerol, 1 mg of bovine serum albumin per ml, 6.6 g of primed 16S rRNA from Escherichia coli per ml, 10 M dATP, 10 M dCTP, 10 M dGTP, and various concentrations of [ 3 H]dTTP (36). Purified recombinant HIV-1 BH10 RT was used for these experiments (40). The K m for dTTP was 1.67 M, and that for the rRNA template was 0.66 g/ml.…”

Section: Cells and Virusesmentioning

confidence: 99%

SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

Buckheit

Watson

Fliakas-Boltz

et al. 2001

Antimicrob Agents Chemother

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Lack of synergy in the inhibition of HIV-1 reverse transcriptase by combinations of the 5′-triphosphates of various anti-HIV nucleoside analogs

Cited by 26 publications

References 28 publications

Zidovudine–didanosine coexposure potentiates DNA incorporation of zidovudine and mutagenesis in human cells

Zidovudine–didanosine coexposure potentiates DNA incorporation of zidovudine and mutagenesis in human cells

Intracellular Metabolism of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine in Combination in the Absence and Presence of Ribavirin

SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

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