Differential antiviral activities and intracellular metabolism of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine in human cells

Mukherji, Elora; Au, Jessie L.-S.; Mathes, Lawrence E.

doi:10.1128/aac.38.7.1573

Cited by 27 publications

(18 citation statements)

References 34 publications

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“…It is important to note that the ddATP content found in our PBMC model (picomole) is much higher than that reported in the literature (femtomole) (18,23,27). Such discrepancies are most likely attributable to the differences between the cellular models and the detection methods of ddATP contents (mainly HPLC/UV detection and radiolabeled experiments studies) used in these previous studies.…”

Section: Discussioncontrasting

confidence: 50%

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Determination of ddATP Levels in Human Immunodeficiency Virus-Infected Patients Treated with Dideoxyinosine

Saint

Terreux

Duval

et al. 2004

Antimicrob Agents Chemother

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Clinical failures of the highly active antiretroviral therapy could result from inefficient intracellular concentrations of antiviral drugs. The determination of drug contents in target cells of each patient would be useful in clinical investigations and trials. The purpose of this work was to quantify the intracellular concentration of ddATP, the active metabolite of dideoxyinosine (ddI), in peripheral blood mononuclear cells (PBMCs) of human immunodeficiency virus (HIV)-infected patients treated with ddI. We have raised antibodies against ddA-citrate, a stable isostere of ddATP selected on the basis of its structural and electronic analogies with ddATP. The anti-ddA-citrate antibodies recognized ddATP and ddA with nanomolar affinities and cross-reacted neither with any of the nucleotide reverse transcriptase inhibitors used in HIV therapy nor with their phosphorylated metabolites. The three phosphorylated metabolites of ddI (ddAMP, ddADP, and ddATP) were purified by anion exchange chromatography and the amount of each metabolite was determined by radioimmunoassay with or without prior phosphatase treatment. The intracellular levels of the three ddI metabolites were measured both in an in vitro model and in PBMCs of HIV-infected patients under ddI treatment. The possibility to measure intracellular levels of ddATP from small blood samples of HIV-infected patients treated with ddI could be exploited to develop individual therapeutic monitoring.Highly active antiretroviral therapy has been used successfully for treatment of human immunodeficiency virus (HIV) disease. The most common highly active antiretroviral therapy regimens consist of a combination of at least one protease inhibitor and two nucleoside reverse transcriptase inhibitors. Contrary to protease inhibitors, the expression of nucleoside reverse transcriptase inhibitor activity requires intracellular metabolism of the nucleoside precursor into its corresponding 5Ј-triphosphate nucleotide by the host cell kinases. The active metabolite (nucleoside reverse transcriptase inhibitor-triphosphate) competitively inhibits the HIV reverse transcriptase and acts as a chain terminator of the proviral DNA.The presence and activity of the intracellular kinases are highly dependent on the type and activation state of the target cell (37). Studies conducted in HIV-infected patients failed to establish a clear relationship between the plasma nucleoside reverse transcriptase inhibitor concentration and the antiviral efficiency of these drugs (3, 4, 18, 39). However, a clinical study showed a significant and linear relationship between the intracellular nucleoside reverse transcriptase inhibitor-triphosphate (zidovudine-triphosphate and lamivudine-triphosphate) concentrations, the percent change in CD4 ϩ cells and the rate of decline of HIV RNA in plasma (17). Thus, intracellular contents of active drugs in target cells seem to give a much better indication of therapeutic efficiency than plasma concentrations of drug precursors.The intracellular metabolism of ddI leads...

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Section: Discussioncontrasting

confidence: 50%

“…The intracellular ddATP levels were found to be the lowest among various ddNTPs (23,27). Thus, most of the technologies previously described were not sensitive enough to detect intracellular ddATP in HIV-infected patients.…”

Section: Discussionmentioning

confidence: 96%

Determination of ddATP Levels in Human Immunodeficiency Virus-Infected Patients Treated with Dideoxyinosine

Saint

Terreux

Duval

et al. 2004

Antimicrob Agents Chemother

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“…25,28,[30][31][32][33][34]36,54 In one experimental study, FIV replication was significantly suppressed in animals treated with didanosine, but treatment contributed to the development of antiretroviral toxic neuropathy (EBM grade II). 55 < FeLV Didanosine is also active against FeLV in vitro, 42,44 but its in vivo efficacy is unknown.…”

Section: Stavudinementioning

confidence: 99%

“…[40][41][42][43][44][45] It has also been shown to be effective in treating cats with early experimental infection. When treated less than 1 week after challenge, cats were protected from bone marrow infection and persistent viraemia (EBM grade II).…”

mentioning

confidence: 99%

Efficacy of antiviral chemotherapy for retrovirus-infected cats

Hartmann

2015

Journal of Feline Medicine and Surgery

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“…These drugs have two mechanisms in their inhibition of HIV replication. Firstly they compete with endogenous deoxynucleoside-5'-triphosphates for the viral reverse transcriptase and secondly, once incorporated into proviral DNA, they cause chain termination of the DNA strand (Waqar et al, 1984;Mitsuya and Broder, 1986;Mukherji et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Zalcitabine (ddC) Phosphorylation and Drug Interactions

Veal

Barry

Back

1995

Antivir Chem Chemother

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SummaryZalcitabine (2',3'-dideoxycytidine; ddC) is an inhibitor of HIV reverse transcriptase. The intracellular metabolism of ddC in peripheral blood mononuclear cells (PBMCs), U937 cells and Molt 4 cells were investigated, and phosphate metabolites were determined by on-line radiometric HPLC. Comparable levels of all three ddC phosphate metabolites were formed in PHA-stimulated PBMCs, U937 cells and Molt 4 cells.Zidovudine (ZDV), didanosine (ddl) and stavudine (d4T) had no significant effect on ddC (O.06JlM) phosphorylation in PBMCs whereas the endogenous nucleoside, cytidine decreased phosphorylation in a concentration-dependent manner (e.g. 41% inhibition of total phosphate formation at 6JlM cytidine, 85% inhibition at 60JlM).The cytotoxic anticancer drug doxorubicin caused a decrease in ddC phosphorylation in U937/Moit 4 cells (e.g. 56% inhibition of total phosphate formation in U937 cells; 55% in Molt 4 cells at a doxorubicin concentration of 60JlM), whilst the antiviral agent ribavirin exhibited no inhibitory effects.

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Differential antiviral activities and intracellular metabolism of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine in human cells

Abstract: Dideoxynucleosides such as 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI)

Cited by 27 publications

References 34 publications

Determination of ddATP Levels in Human Immunodeficiency Virus-Infected Patients Treated with Dideoxyinosine

Determination of ddATP Levels in Human Immunodeficiency Virus-Infected Patients Treated with Dideoxyinosine

Efficacy of antiviral chemotherapy for retrovirus-infected cats

Zalcitabine (ddC) Phosphorylation and Drug Interactions

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