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

Palmer, Sarah; Cox, Susan

doi:10.1177/095632029400500608

Cited by 12 publications

(12 citation statements)

References 36 publications

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“…Mechanisms focusing on alterations in dNTP pools or alterations in the amount of AZT triphosphate formed seem unlikely, given that Palmer and Cox (26) found that the level of AZT phosphorylation was unchanged regardless of whether human lymphoblastoid cells were incubated with AZT alone or in combination with ddI. Instead, they observed a modest increase in the level of ddI-triphosphate following AZT-ddI coexposure of these cells.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Cell cellular dNTP pools, in agreement with recent observations (Gao et el., 1993;Palmer and Cox, 1994b;Palmer and Cox, 1995). AZT was phosphorylated to a much lower extent in uninfected fibroblasts than in lymphocytes, but the amount of AZT TP formed represented a greater percent of the total AZT metabolites.…”

Section: Drugsmentioning

confidence: 99%

Intracellular Metabolism of 3′-Azido-3′-Deoxythymidine in the Presence of Ganciclovir or Foscarnet

Palmer

Rasmussen

Harmenberg³

et al. 1996

Antivir Chem Chemother

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SummaryComparisons were made between the intracellular phosphorylation of 3'-azido-3'-deoxythymidine (AZT) alone and in combination with ganciclovir (GCV) or foscarnet (PFA) in lymphocytes, uninfected fibroblasts and CMV-infected fibroblasts. The effects of AZT and the combinations of AZT with GCV or PFA on cellular dNTP pools were also examined.The phosphorylation of AZT was not altered by the presence of GCV or PFA in lymphocytes, and neither AZT nor the combinations of AZT with GCV or PFA changed the levels of cellular dNTP pools in these cells. AZT was phosphorylated to a greater extent in lymphocytes when compared to fibroblasts, but the proportion of AZT di-and triphosphates was greater in fibroblasts.The infection of fibroblasts with CMV enhanced AZT phosphorylation and increased the levels of cellular dNTP pools. GCV caused a specific reduction in AZT phosphorylation in CMV-infected fibroblasts, with a seven-fold drop in AZT triphosphate compared to AZT alone. GCV did not affect AZT phosphorylation in uninfected fibroblasts, nor did GCV reduce the dTTP pool compared to AZT alone. The effects of GCV upon AZT phosphorylation in CMV-infected cells may shed light on the antagonistic effects of GCV upon the anti-HIV activity of AZT, and are of importance for the development of effective combination therapies for the treatment of AIDS patients infected with CMV.

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“…However, ribavirin and doxorubicin significantly reduced ZDV phosphorylation in all cells. Ribavirin has been shown previously to antagonize the phosphorylation of pyrimidine dideoxynucleosides (2), and the mechanism is thought to involve a ribavirin-induced increase in nucleoside TP levels leading to feedback inhibition of thymidine kinase (29) and hence conversion of ZDV to ZDV-MP (20). As doxorubicin exerts its pharmacological effect by insertion between DNA base pairs, it is not clear how it alters ZDV phosphorylation.…”

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confidence: 95%

Drug Interactions With Zidovudine Phosphorylation in Vitro

Hoggard

Veal

Wild

et al. 1994

AIDS

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We have investigated the effect of a range of drugs (some commonly coadministered with zidovudine [ZDV] to human immunodeficiency virus-positive patients) on intracellular phosphorylation of ZDV by stimulated peripheral blood mononuclear cells, Molt 4 cells, and U937 cells in vitro. Of the drugs tested (azoles, antiviral agents, antibiotics, and anticancer agents), only doxorubicin and ribavirin caused inhibition of anabolite formation as measured by high-performance liquid chromatography. This in vitro approach may provide important leads to potential interactions at the phosphorylation level in patients with human immunodeficiency virus disease. It is reassuring that so many commonly administered drugs do not alter ZDV phosphorylation.Zidovudine (ZDV), in common with other nucleoside analogs, requires intracellular phosphorylation via ZDV monophosphate (ZDV-MP) and ZDV diphosphate (ZDV-DP) to the active form ZDV triphosphate (ZDV-TP) which competitively inhibits viral reverse transcriptase and results in proviral DNA chain termination (1,13,19,21,23,26).Pharmacokinetic drug-drug interactions involving ZDV may occur at various stages, including absorption, hepatic metabolism (to glucuronide conjugate), and renal excretion of both ZDV and ZDV-glucuronide. Numerous studies have been conducted in these areas and have been recently reviewed (5, 18). However, since intracellular phosphorylation is a key event in the antiretroviral action of ZDV, it is important to design appropriate studies to investigate factors that may modify phosphorylation and hence drug efficacy. In a previous study (28) we demonstrated that didanosine and zalcitabine had no effect on ZDV phosphorylation in vitro in peripheral blood mononuclear cells (PBMCs). In the present work we describe the effect of a number of drugs (antiviral agents, antibiotics, antifungal agents, and others) regularly coadministered with ZDV to human immunodeficiency virus-positive patients on in vitro phosphorylation in activated PBMCs, Molt 4 cells, and U937 cells. A decrease in phosphorylation may have implications for in vivo efficacy of the nucleoside.RPMI medium was purchased from Gibco, Life Technologies Ltd. Penicillin-streptomycin and L-glutamine were obtained from Northumbria Biologicals. Fetal calf serum was acquired from Sera Lab, Sussex, United Kingdom. Mono-poly resolving medium and ribavirin were obtained from ICN Biomedicals Inc., Irvine, Calif. Doxorubicin was obtained from Farmitalia Carlo Erba Ltd., St. Albans, Herts, United Kingdom. Acyclovir, ganciclovir, foscarnet, fluconazole, and ketoconazole and itraconazole were gifts from Wellcome Research Laboratories, Syntex Pharmaceuticals Ltd., Astra Pharmaceuticals, Pfizer Central Research, and Janssen Research Foundation, respectively. All other drugs and chemicals were purchased from Sigma Chemical Co. Ltd.PBMCs were isolated from venous blood obtained from healthy volunteers as previously described (28) and were seeded in 5-cm-diameter petri dishes (3 ϫ 10 6 cells per plate). The mitogen phytohemaggl...

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

Cited by 12 publications

References 36 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 in the Presence of Ganciclovir or Foscarnet

Drug Interactions With Zidovudine Phosphorylation in Vitro

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