Treatment of latent rabbit and human papillomavirus infections with 9-(2-phosphonylmethoxy)ethylguanine (PMEG)

Kreider, John W.; Balogh, Karla K.; Olson, Robert O.; Martin, John

doi:10.1016/0166-3542(90)90065-f

Cited by 54 publications

(34 citation statements)

References 17 publications

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“…Systemic administration was least effective. When PMEG was given subcutaneously to CRPV-infected rabbits at doses of 0.01, 0.1, or 1 mg/kg twice a day, the highest dose showed some therapeutic effect, but treatment was terminated after 10 days due to severe toxicity (18). The intermediate metabolite of GS-9191, cPrPMEDAP, showed a ϳ50% reduction in papilloma growth and was tolerated when dosed topically at 1%, while a similar topical administration of 0.1% PMEG for 8 weeks was not tolerated (6).…”

Section: Discussionmentioning

confidence: 99%

“…In animal models, PMEG has antiproliferative effects; however, the utility of PMEG as an antiproliferative agent is limited by its poor cellular permeability and toxicity (18,23). An N 6 -substituted prodrug of PMEG, 9-(2-phosphonylmethoxyethyl)-N 6 -cyclopropyl-2,6-diaminopurine (cPrPMEDAP) has similar antiproliferative effects in vitro (9,13) and reduced toxicity in vivo but, like PMEG, is negatively charged at physiologic pH and has poor permeability into the skin.…”

Section: M Respectively) Gs-9191 Was Markedly More Potent Than Pmegmentioning

confidence: 99%

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GS-9191 Is a Novel Topical Prodrug of the Nucleotide Analog 9-(2-Phosphonylmethoxyethyl)Guanine with Antiproliferative Activity and Possible Utility in the Treatment of Human Papillomavirus Lesions

Wolfgang

Shibata

Wang

et al. 2009

Antimicrob Agents Chemother

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GS-9191 is a novel double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine (PMEG) designed as a topical agent to permeate skin and be metabolized to the active nucleoside triphosphate analog in the epithelial layer. The prodrug was shown to be metabolized intracellularly to 9-(2-phosphonylmethoxyethyl)-N 6 -cyclopropyl-2,6,diaminopurine (cPrPMEDAP) and subsequently deaminated to PMEG. The active form, PMEG diphosphate, was shown to be a potent inhibitor of DNA polymerase ␣ and ß while showing weaker activity against mitochondrial DNA polymerase ␥ (50% enzyme inhibition observed at 2.5, 1.6, and 59.4 M, respectively). GS-9191 was markedly more potent than PMEG or cPrPMEDAP in a series of human papillomavirus ( Human papillomaviruses (HPV) cause proliferative lesions in the skin and squamous mucosa, predominantly in the form of hyperplasias, papillomas, and condylomas. Currently recommended treatments for HPV-mediated diseases include patient-applied treatments (podofilox gel or imiquimod cream), provider-applied treatments (cryotherapy, podophyllin resin, and trichloroacetic acid), or surgical removal of the lesion (infrared coagulation, laser surgery, and a loop electrical excision procedure) (5). The primary pharmacological therapy for external anogenital warts is topically applied imiquimod cream (Aldara), a nucleoside-like compound that acts as an immune response modifier. This therapy has limited efficacy in males relative to females (33% versus 72%, respectively), a high incidence of recurrence, local tolerability issues, and a relatively long duration of treatment (up to 16 weeks) (26). Podofilox gel (Condylox package insert; Watson Pharmaceuticals, Inc., Corona, CA), which is also applied externally, is an antiproliferative agent (antimitotic agent) with similar efficacy as imiquimod (12,27,28). Cidofovir, a nucleotide analog with antiproliferative and antiviral activity (1), has been tested as a potential treatment for anogenital warts and has shown positive effects (25; also J. Douglas, T. Corey, S Tyring, J. Kreisel, B. Bowden, D. Crosby, T. Berger, M. Conant, B. McGuire, H. S. Jaffe, presented at the 4th Conference on Retroviruses and Opportunistic Infections, Washington DC, 22 to 26 January, 1997). While the existing antiproliferative agents have proven therapeutic utility, there is a need for new agents that are better tolerated and have an improved response rate and/or a shorter duration of treatment.The acyclic nucleotide, 9-(2-phosphonylmethoxyethyl)guanine (PMEG) forms an active phosphorylated metabolite, PMEG diphosphate (PMEG-DP), in cells, which inhibits the growth of various transformed cell lines due to potent inhibition of the nuclear DNA polymerases ␣, ␦ and ε, resulting in inhibition of DNA synthesis and/or DNA repair (15,16,21). In animal models, PMEG has antiproliferative effects; however, the utility of PMEG as an antiproliferative agent is limited by its poor cellular permeability and toxicity (18,23). An N 6 -substituted prodrug of PMEG, 9-(2-phosphonylmethoxyeth...

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Section: Discussionmentioning

confidence: 99%

Section: M Respectively) Gs-9191 Was Markedly More Potent Than Pmegmentioning

confidence: 99%

GS-9191 Is a Novel Topical Prodrug of the Nucleotide Analog 9-(2-Phosphonylmethoxyethyl)Guanine with Antiproliferative Activity and Possible Utility in the Treatment of Human Papillomavirus Lesions

Wolfgang

Shibata

Wang

et al. 2009

Antimicrob Agents Chemother

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“…PMEG also showed antitumor activity in two types of mouse transplantable tumors, P388 lymphocytic leukemia and B16 melanoma (4). In addition, the analog suppressed the growth of papillomavirus-induced condylomas on human foreskin xenografts in mice (5).…”

Section: Pmegmentioning

confidence: 97%

Incorporation and Excision of 9-(2-Phosphonylmethoxyethyl)guanine (PMEG) by DNA Polymerase δ and ε in Vitro

Kramata¹,

Downey²,

Paborsky³

1998

Journal of Biological Chemistry

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PMEG (9-(2-phosphonylmethoxyethyl)guanine) is an acyclic nucleotide analog being evaluated for its antiproliferative activity. We examined the inhibitory effects of PMEG diphosphate (PMEGpp) toward DNA polymerases (pol) ␦ and ⑀ and found it to be a competitive inhibitor of both these enzymes. The apparent K i values for PMEGpp were 3-4 times lower than the K m values for dGTP. The analog was shown to function as a substrate and to be incorporated into DNA by both enzymes. Examination of the ability of pol ␦ and pol ⑀ to repair the incorporated PMEG revealed that pol ⑀ could elongate PMEG-terminated primers in both matched and mismatched positions with an efficiency equal to 27 and 85% that observed for dGMP-terminated control templateprimers. Because PMEG acts as an absolute DNA chain terminator, the elongation of PMEG-terminated primers is possible only by cooperation of the 3-5-exonuclease and DNA polymerase activities of the enzyme. In contrast to pol ⑀, pol ␦ exhibited negligible activity on these template-primers, indicating that pol ⑀, but not pol ␦, can repair the incorporated analog. PMEG1 (9-(2-phosphonylmethoxyethyl)guanine) ( Fig. 1) is a member of a new class of acyclic nucleotide analogs characterized as phosphonylmethyl ethers. Several analogs in this class have demonstrated broad spectrum antiviral activity (1). PMEG is being evaluated as an antitumor agent for cancer treatment. Its anti-proliferative activity has been demonstrated in vitro against human leukemic cells (2) as well as a number of solid tumor cell lines (3). PMEG also showed antitumor activity in two types of mouse transplantable tumors, P388 lymphocytic leukemia and B16 melanoma (4). In addition, the analog suppressed the growth of papillomavirus-induced condylomas on human foreskin xenografts in mice (5).Once inside the cells, cellular enzymes phosphorylate the analog to PMEG mono-and diphosphate (6). The diphosphate form (PMEGpp) is an analog of dGTP. Although the mechanism of action of PMEG has not yet been determined, PMEG diphosphate has been shown to be a potent inhibitor of rat DNA polymerase ␣ and ⑀ (7) and to be incorporated into DNA in vitro by human DNA polymerase ␣ and ␦ (8, 9). Therefore, it can potentially inhibit cellular DNA synthesis.DNA polymerases ␣, ␦, and ⑀ are the enzymes cooperating in chromosomal DNA replication (10). Pol ␣, associated with DNA primase activity, synthesizes RNA-DNA primers for initiation of DNA replication at ori sites and for priming of Okazaki fragments on the lagging strand of DNA. Pol ␦, in cooperation with proliferating cell nuclear antigen (PCNA) and other protein factors, synthesizes the leading strand of DNA. Pol ⑀, which is dispensable for SV40 DNA replication (11) but not for cellular DNA replication (12), may be required as a second DNA polymerase on the lagging DNA strand (13). In contrast to pol ␣, both pol ␦ and pol ⑀ have intrinsic 3Ј-5Ј-exonuclease activity associated with a proofreading function (14). Both enzymes are necessary for the repair of cellular DNA damage after UV ...

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“…(R)-9-(2-Phosphonomethoxypropyl) adenine (PMPA), one of the PMEA-related analogues, has recently shown encouraging results for the prevention and treatment of simian immunodeficiency virus infection in primate models (Tsai etal., 1995;Bischofberger et al, 1996). Among others, 9-(2-phosphonomethoxyethyl)guanine (PMEG) was found to be highly effective against papillomavirus infection (Kreider et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Incorporation of Selected Nucleoside Phosphonates and Anti-Human Immunodeficiency Virus Nucleotide Analogues into DNA by Human DNA Polymerases α, β and γ

Cihlář

Chen

1997

Antivir Chem Chemother

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SummaryIncorporation of selected diphosphates of nucleoside phosphonates and friphosphotes of currently approved anti-human immunodeficiency virus nucleoside analogues into DNA by human DNA polymerases a,~and y was studied. All three polymerases were able to incorporate diphosphates of 9-(2-phosphonomethoxyethyl)adenine (PMEApp), 9-(2-phosphonomethoxyethyl)guanine (PMEGpp), (R)-9-(2-phosphonomethoxypropyl)adenine (PMPApp), (R)-9-(2-phosphononomethoxypropyl)-2,6-diaminopurine (PMPDAPpp) and (2R,5R)-9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine (D4APpp) into primer/template DNA of defined sequence. After incorporation, these nucleoside phosphonates acted as terminators of primer extension. Kinetic constants of their incorporation were determined and compared with those for incorporation of ddATP, ddCTP, (-)-2'-deoxy-3'-thiacytidine triphosphate (3TC-TP),~',3'-dide hydro-3'-deoxythymidine triphosphate (d4T-TP) and 3'-azido-3'-deoxythymidine triphosphate (AZT-TP).Relative efficiencies of incorporation (percentage of the incorporation efficiency for the corresponding natural deoxynucleoside triphosphate) by DNA polymerase a ranged from 0.05% for 3TC-TP to 51% for PMEGpp. DNA polymerase~catalysed the incorporation with relative efficiencies ranging from 0.014% for AZT-TP to 125% for ddCTP, and efficiencies of incorporation by DNA polymerase y varied between 0.13% for 3TC-TP and 25% for ddCTP. Generally, the lowest incorporation efficiencies with all three polymerases were found for PMPApp (0.06-1 .4%) and PMPDAPpp (0.075-2.2%).

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Treatment of latent rabbit and human papillomavirus infections with 9-(2-phosphonylmethoxy)ethylguanine (PMEG)

Cited by 54 publications

References 17 publications

GS-9191 Is a Novel Topical Prodrug of the Nucleotide Analog 9-(2-Phosphonylmethoxyethyl)Guanine with Antiproliferative Activity and Possible Utility in the Treatment of Human Papillomavirus Lesions

GS-9191 Is a Novel Topical Prodrug of the Nucleotide Analog 9-(2-Phosphonylmethoxyethyl)Guanine with Antiproliferative Activity and Possible Utility in the Treatment of Human Papillomavirus Lesions

Incorporation and Excision of 9-(2-Phosphonylmethoxyethyl)guanine (PMEG) by DNA Polymerase δ and ε in Vitro

Incorporation of Selected Nucleoside Phosphonates and Anti-Human Immunodeficiency Virus Nucleotide Analogues into DNA by Human DNA Polymerases α, β and γ

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