Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses

Freitas, Vicki R.; Smee, Donald F.; Chernow, Marlene; Boehme, Richard; Matthews, Thomas R.

doi:10.1128/aac.28.2.240

Cited by 124 publications

(73 citation statements)

References 35 publications

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“…It has previously been shown that CMV infection increases cellular thymidine kinase activity, and CMV-infected fibroblasts exhibit an increase in dTIP pools (Estes and Huang, 1977;Wachsman et ei., 1995). In fact dramatic increases were seen in all dNTPs upon CMV infection when compared to uninfected cells, in agreement with previous data (Freitas et et., 1985). This increase in thymidine kinase activity may explain the enhanced phosphorylation of AZT in CMV-infected fibroblast cells.…”

Section: Drugssupporting

confidence: 82%

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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Section: Drugssupporting

confidence: 82%

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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“…gancyclovir (Field et al, 1983;Freitas et al, 1985). Similarly, varicella-zoster virus (VZV) is a cause of significant morbidity which can be treated with acyclovir (McKendrick et al, 1986), although there is a clear need for more effective chemotherapy.…”

mentioning

confidence: 99%

High level expression of DNA polymerases from herpesviruses

Ertl

Thomas²,

Powell³

1991

Journal of General Virology

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The DNA polymerase genes of human cytomegalovirus (HCMV) and varicella-zoster virus (VZV) were inserted separately into the polyhedrin gene of Autographa ealifornica nuclear polyhedrosis virus (AcNPV) by cotransfection of Spodoptera frugiperda (SFg) cells with baculovirus transfer vectors carrying the genes and AcNPV infectious DNA. Infection of SF9 cells with the recombinant viruses resulted in expression from the polyhedrin promoter of proteins of the expected Mrs. These proteins possessed DNA polymerase activities similar to that of the enzymes induced by the respective herpesvirus in infected cells, and were identified as HCMV and VZV DNA polymerase using inhibitors and specific antisera reactive with each enzyme.

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“…Target plasma trough levels retained during therapeutic drug monitoring ranged from 1 to 2 mg/l. Therefore, the choice of in vitro drug concentrations used for incubation was based on these target levels and previous in vitro studies [14][15][16][17][18]. Table 1.…”

Section: Discussionmentioning

confidence: 99%

Effect of Duration and Intensity of Ganciclovir Exposure on Lymphoblastoid Cell Toxicity

Janoly‐Dumenil

Rouvet

Bleyzac³

et al. 2009

Antivir Chem Chemother

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Introduction: Human cytomegalovirus infection is still a major complication after pediatric bone marrow transplantation and could be fatal in some cases. The toxicity of the drug in dividing transplanted haematopoietic cells combined with the suppression of cell growth caused by the virus remains a major problem in managing human cytomegalovirus infection. Methods: The aim of the current in vitro study was to evaluate the effect of the intensity (1-20 mg/l) and duration (1, 2, 7 or 14 days) of ganciclovir exposure on toxicity in B lymphoblastoid cells (using cell counting and viability measurements). Results: A correlation was found between the dose of ganciclovir exposure and a decrease in total cell number when duration exceeded 2 days (r 2 =0.92 and 0.93 after 7 and 14 days, respectively). High levels (20 mg/l) of ganciclovir were not more toxic than lowest levels (1 mg/l) for the shortest durations of ganciclovir exposure (1 and 2 days). Moreover, 50% cytotoxic concentrations markedly decreased with the duration of ganciclovir exposure (374-3 mg/l from 1 to 14 days respectively) after 14 days of culture. Conclusions: This in vitro study demonstrated for the first time that ganciclovir exhibited an in vitro durationdependent toxicity on haematopoietic-derived cells when in vivo doses of the drug were used.Human cytomegalovirus (HCMV) remains a major problem after bone marrow transplantation (BMT) and can be fatal in some cases [1][2][3][4][5][6]. Ganciclovir (GCV) is considered the standard treatment for HCMV after paediatric BMT [1,7]; however, because of a lack of paediatric recommendations, GCV therapy is still based on adult schedules and adapted to patient weight. The major problem with GCV is haematological toxicity [8,9] and myelosuppressive effects [9]. In fact, due to the resemblance of GCV to guanosine, this nucleoside analogue is likely to have adverse effects on mammalian DNA synthesis in addition to its effect on viral replication [10]. GCV is particularly toxic to rapidly dividing populations of blood cells and their precursors [10]. This side effect represents an in vivo risk factor for post-transplantation death [8], opportunistic infection [2] and tardive HCMV infection because of high immunosuppression [7]. The duration of treatment is a risk factor for this potentially fatal situation [2,7]. Despite the clinical use of GCV for 20 years, few studies have determined the toxicity of GCV on haematopoietic cells [9][10][11][12] and no studies have tested both dose and duration effects on cell toxicity using B lymphoblastoid cell lines (BLCLs), which exhibit a high similarity to the target cells for GCV toxicity in vivo. This led us to study the effect of GCV exposure on the growth of BLCLs. The present study is a preliminary report from a project aimed at evaluating the antiviral effect of shorter treatments at higher doses, which is supposed to be less toxic for bone marrow.

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Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses

Cited by 124 publications

References 35 publications

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

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

High level expression of DNA polymerases from herpesviruses

Effect of Duration and Intensity of Ganciclovir Exposure on Lymphoblastoid Cell Toxicity

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