Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine

Smee, D. F.; Martin, John; Verheyden, Julien P.M.; Matthews, Thomas R.

doi:10.1128/aac.23.5.676

Cited by 271 publications

(136 citation statements)

References 18 publications

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“…Our data confirm the potential of DHPG in the treatment of various other experimental HSV infections, including intravaginal infections in mice treated orally (23) and guinea pigs treated systemically (9), intraperitoneal and orofacial infections in mice treated systemically (5, 8), and intranasal infections of mice treated orally and systemically (6). DHPG is active whether given orally, by s.c. or intraperitoneal injection, or, as shown in our experiments, by topical application at the inoculation site.…”

supporting

confidence: 67%

“…The clearance of infectious virus from ganglia during the acute phase of infection was followed by early establishment of latency. 9-(1,3-Dihydroxy-2-propoxymethyl)guanine (0.03 ,ug/ml) significantly inhibited the synthesis of infectious virus in explant cultures of latently infected ganglia, and at concentrations higher than 8 ,Lg/ml no infectious virus was detectable in ganglia explant cultures.The acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), synthesized by the procedures described by Ogilvie and Gillian (20), Martin et al (19a), and Ashton et al (1) has been shown to be an effective inhibitor of herpes simplex virus (HSV) and cytomegalovirus replication in cell cultures (1, 2, 4, 5,19,23,26). DHPG proved to be superior to acyclovir (ACV) in the treatment of HSV-induced encephalitis and vaginitis in mice (1, 5, 6, 8,26) and was effective in reducing the severity of primary and recrudescent lesions induced by genital infection of guinea pigs (9) and by eye infections in rabbits (27).…”

mentioning

confidence: 99%

“…The acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), synthesized by the procedures described by Ogilvie and Gillian (20), Martin et al (19a), and Ashton et al (1) has been shown to be an effective inhibitor of herpes simplex virus (HSV) and cytomegalovirus replication in cell cultures (1, 2, 4, 5,19,23,26). DHPG proved to be superior to acyclovir (ACV) in the treatment of HSV-induced encephalitis and vaginitis in mice (1, 5, 6, 8,26) and was effective in reducing the severity of primary and recrudescent lesions induced by genital infection of guinea pigs (9) and by eye infections in rabbits (27).…”

mentioning

confidence: 99%

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Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the acute local phase of herpes simplex virus-induced skin infections in mice and the establishment of latency

Klein¹,

Friedman‐Kien²

1985

Antimicrob Agents Chemother

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The effect of topical and systemic treatment with 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the evolution of herpes simplex virus-induced skin infection in hairless mice was investigated. Systemic (subcutaneous) treatment with a 10-mg/kg dose and topical-applications with a 5% cream started up to 48 h after infection prevented the development of severe skin lesions and a fatal outcome. However, the establishment of latent infections was prevented only by topical treatment started at 6 h after infection. Systemic (50 mg/kg) and topical treatments started 48 h after infection reduced virus titers in the skin and ganglia and promoted rapid clearance of virus from these sites. The clearance of infectious virus from ganglia during the acute phase of infection was followed by early establishment of latency. 9-(1,3-Dihydroxy-2-propoxymethyl)guanine (0.03 ,ug/ml) significantly inhibited the synthesis of infectious virus in explant cultures of latently infected ganglia, and at concentrations higher than 8 ,Lg/ml no infectious virus was detectable in ganglia explant cultures.The acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), synthesized by the procedures described by Ogilvie and Gillian (20), Martin et al. (19a), and Ashton et al. (1) has been shown to be an effective inhibitor of herpes simplex virus (HSV) and cytomegalovirus replication in cell cultures (1, 2, 4, 5,19,23,26). DHPG proved to be superior to acyclovir (ACV) in the treatment of HSV-induced encephalitis and vaginitis in mice (1, 5, 6, 8,26) and was effective in reducing the severity of primary and recrudescent lesions induced by genital infection of guinea pigs (9) and by eye infections in rabbits (27). Although 4 to 35 times more DHPG is required to inhibit cytomegalovirus in cell cultures than is necessary to inhibit HSV (26). DHPG is a more potent inhibitor of cytomegalovirus than is ACV. DHPG is an efficient substrate for HSV-induced thymidine kinase (1, 2,26) and is more rapidly converted to the corresponding triphosphate derivative in virus-infected cells than is ACV (1, 10). The triphosphate of DHPG competitively inhibits incorporation of dGTP into DNA catalyzed by the DNA polymerase specified by HSV (7,25).In this study we have investigated the effect of DHPG on experimental HSV-induced skin infections in hairless mice and have examined the ability of the drug to prevent the colonization of sensory ganglia and the establishment of latency by the virus. In addition we have determined the concentration of DHPG required to prevent the reactivation of HSV in explant cultures of latently infected mouse trigeminal ganglia. stock virus, and the quantification of inocula have been described in a previous publication (16). MATERIALS AND METHODSInoculation of mice. Female hairless mice of the fully immunocompetent HRS/J strain were obtained from Jackson Laboratories, Bar Harbor, Maine, and used in the experiments at the age of 6 to 8 weeks. The mice were inoculated percutaneously on a triangular area of the snout by rubbing a virus susp...

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supporting

confidence: 67%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the acute local phase of herpes simplex virus-induced skin infections in mice and the establishment of latency

Klein¹,

Friedman‐Kien²

1985

Antimicrob Agents Chemother

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“…There are several reports in which HSV-infected cells phosphorylated GCV more favorably than ACV when evaluated by kinase activities. 6,8,10 A total of 200 ng of ponicidin per mL, for example, enhanced the cytotoxicity of GCV against HSV-TK gene-transfected COS-1 cells by at least 20-fold. This means that less than one-twentieth the therapeutic dose of GCV in combination with ponicidin may produce the same efficacy as its therapeutic dose in cancer gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of ganciclovir toxicity in the herpes simplex virus thymidine kinase/ganciclovir administration system by ponicidin

Hayashi

Sun

et al. 2000

Cancer Gene Ther

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The herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) administration system is commonly used in gene therapy trials. We have evaluated the effect of ponicidin, a diterpenoid isolated from a plant, Rabdosia ternifolia, on the cell-killing activity of the anti-herpes drugs acyclovir (ACV) and GCV. Ponicidin preferentially activated HSV-1-specific TK but not cellular kinases. In HSV-infected cells, ponicidin significantly accumulated the phosphorylated metabolites of GCV and suppressed the extracellular release of GCV. These data suggested that the cytotoxicities of ACV and GCV in HSV-TK-expressing cells might be potentiated by ponicidin. After transfected with the HSV-1 TK gene, COS-1 and several human cancer cells became highly sensitive to the cytotoxic properties of the nucleoside analogs. When ponicidin at the concentration without antiviral activities (0.2 g/mL) was combined with ACV or GCV, the cytotoxic levels in HSV-TK-expressing cells were enhanced by 3-to 87-fold and 5-to 52-fold, respectively, compared with the nucleoside alone. When the stability of the bioactivity of ponicidin in the blood of mice was evaluated, the substance showed relatively long-lasting effects on the potentiation of the anti-herpetic and cytotoxic activities of GCV after intravenous administration. These data suggest that the combined use of ponicidin with GCV will be effective for cancer gene therapy, because high cytotoxicity in viral TK-expressing cells should yield more rapid and enhanced tumor elimination.

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“…It was shown to be 26 times more potent than acyclovir against HCMV in vitro ( Morse et al, 1993). Previous studies reported excellent in vitro activity of GCV against human herpes virus type 6, human herpes simplex viruses types 1 and 2, varicella-zoster virus, and Epstein-Barr virus (Smee et al, 1983;Andrei et al, 1991;Shigeta et al, 1991;Snoeck et al, 1991;Konno et al, 1993). It was approved for the induction and maintenance therapy of HCMV retinitis in AIDS patients in 1989 and has been widely used.…”

mentioning

confidence: 99%

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Macha¹,

Mitra²

2002

Drug Metab Dispos

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ABSTRACT:The present study was carried out to delineate the ocular pharmacokinetics of ganciclovir (GCV) following intravitreal administration. Another objective was to achieve sustained therapeutic concentrations of GCV in the vitreous over a prolonged period of time using its acyl monoester prodrugs (acetate, propionate, butyrate, and valerate). New Zealand albino male rabbits (2-2.5 kg) were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous using a 21-guage needle, and a linear microdialysis probe was implanted in the anterior chamber across the cornea using a 25-guage needle. The probes were perfused with isotonic phosphate buffer saline (pH 7.4) at a flow rate of 2 l/min. The drugs were administered (0.2 moles) intravitreally and the samples were collected every 20 min over a period of 10 h. The vitreal terminal elimination half-life (t 1/2 ␤) of GCV was found to be 426 ؎ 109 min. The hydrolysis rate and vitreal clearance of the prodrugs increased with the ascending ester chain length. The vitreal elimination half-lives (t 1/2k10 ) of GCV, acetate, propionate, butyrate, and valerate esters of GCV were 170 ؎ 37, 117 ؎ 50, 122 ؎ 13, 55 ؎ 26, and 107 ؎ 14 min, respectively. A parabolic relationship was observed between the vitreal elimination rate constant and the ester chain length. Mean residence time (MRT) of the regenerated GCV following prodrug administration was found to be three to four times the value obtained after GCV injection. In conclusion, these studies have shown that the ester prodrugs generated therapeutic concentrations of GCV in vivo, and the MRT of GCV could be enhanced by 3-to 4-fold through prodrug modification.

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Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine

Abstract: The antiherpetic effects of a novel purine acyclic nucleoside, 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), were compared with those of acyclovir in cell culture § and in mice. The

Cited by 271 publications

References 18 publications

Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the acute local phase of herpes simplex virus-induced skin infections in mice and the establishment of latency

Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the acute local phase of herpes simplex virus-induced skin infections in mice and the establishment of latency

Potentiation of ganciclovir toxicity in the herpes simplex virus thymidine kinase/ganciclovir administration system by ponicidin

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

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