Preclinical System for Evaluating Topical Podofilox Treatment of Papillomas: Dose-Response and Duration of Growth Prior to Treatment

Kreider, John W.; Christensen, Neil D.; Christian, Carole; Pickel, M.

doi:10.1111/1523-1747.ep12614781

Cited by 12 publications

(6 citation statements)

References 16 publications

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“…To evaluate the potential of BET inhibitors to treat papillomavirus warts, we tested the effect of topical delivery of I-BET762 in the CRPV cutaneous wart model in rabbits, which has been successfully used to evaluate topical anti-viral drug treatments and vaccines (Christensen, 2005; Christensen et al, 2001; Christensen et al, 2000; Kreider et al, 1992; Wolfgang et al, 2009). …”

Section: Resultsmentioning

confidence: 99%

BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo

et al. 2018

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The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti-papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra-Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non-histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions. The BET protein BRD4 has been shown to be involved in the papillomavirus life cycle, as a co-factor for viral E2 and also mediating viral partitioning in some virus types. We set out to study the activity of small molecule BET bromodomain inhibitors in models of papillomavirus infection. Several BET inhibitors reduced HPV11 E1ˆE4 mRNA expression in vitro and topical therapeutic administration of an exemplar compound I-BET762, abrogated CRPV cutaneous wart growth in rabbits, demonstrating translation of anti-viral effects to efficacy in vivo. Additionally I-BET762 markedly reduced viability of HPV16 infected W12 cells compared to non-infected C33A cells. The molecular mechanism for the cytotoxicity to W12 cells is unknown but may be through blocking viral-dependent cell-survival factors. We conclude that these effects, across multiple papillomavirus types and in vivo, highlight the potential to target BET bromodomains to treat HPV infection.

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Section: Resultsmentioning

confidence: 99%

BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo

et al. 2018

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“…The CRPV model is well characterized and has been used previously to evaluate the antipapillomavirus activity of various treatments (4,6,7,19). The model involves the induction of discrete papillomas on the back of a rabbit within 28 days by infecting scarified skin with CRPV virus.…”

Section: Discussionmentioning

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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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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“…The species and tissue restriction of papillomaviruses prevent direct preclinical testing of HPV infections in vivo in laboratory settings in immunocompetent hosts. The CRPV/rabbit model has been the most effective animal model for testing due to a number of outcomes that are relevant to the clinical situation, especially including cutaneous lesions that are amenable to topical, intralesional and systemic treatments (Kreider, Balogh et al, 1990; Kreider, Christensen et al, 1992; Ostrow, Forslund et al, 1992; Lofgren, Ronn et al, 1994; Shikowitz, Steinberg et al, 1986; Christensen, 2005). …”

Section: Discussionmentioning

confidence: 99%

“…We and others have used the CRPV rabbit model for testing various anti-virals for activity against papillomavirus infections and the model shows correlates with clinical treatments with the same compounds (Kreider, Christensen et al, 1992; Christensen, Pickel et al, 2000). In addition, the CRPV rabbit model has been used to test unformulated cidofovir topically, intralesionally and systemically (Christensen, Pickel et al, 2000; Duan, Paris et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…We and others have used the cutaneous CRPV rabbit model extensively to examine anti-viral activities (Duan, Paris et al, 2000; Kreider, Christensen et al, 1992; Christensen, 2005), prophylactic and therapeutic vaccines (Breitburd, Kirnbauer et al, 1995; Jensen, Selvakumar et al, 1997; Leachman, Shylankevich et al, 2002) and virological studies (Hu, Cladel et al, 2007). In general, the observations obtained in the rabbit model show general correlations with clinical studies (Christensen, 2005), including the phenomenon of post-treatment recurrences (Christensen, Han et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Formulation of cidofovir improves the anti-papillomaviral activity of topical treatments in the CRPV/rabbit model

Christensen

Cladel

et al. 2014

Antiviral Research

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Current topical treatments for papillomas use ablative, cytotoxic and immunomodulating strategies and reagents. However, the effectiveness of topical treatments using different formulations has not been examined in preclinical models or clinical trials. The purpose of this study was to determine whether formulation of the small molecule acyclic nucleoside, cidofovir (CDV), could lead to improved therapeutic endpoints following topical treatment of papillomas using the cottontail rabbit papillomavirus (CRPV)/rabbit model. Different formulations with a set dose of 1% cidofovir were tested to establish comparative data. The results demonstrated that anti-papilloma treatments with topical CDV were greatly enhanced when formulated versus unformulated. Best results were obtained with CDV formulated in cremophor, then in carbomer 940, and then in DMSO. Further studies indicated that effective formulations led to complete cures of papillomas at dilutions less than 0.3% CDV. These studies together with previous observations demonstrated that unformulated CDV under the same treatment regime required doses of 2% to achieve cures demonstrating that much less compound can be used when properly formulated.

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Preclinical System for Evaluating Topical Podofilox Treatment of Papillomas: Dose-Response and Duration of Growth Prior to Treatment

Cited by 12 publications

References 16 publications

BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo

BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo

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

Formulation of cidofovir improves the anti-papillomaviral activity of topical treatments in the CRPV/rabbit model

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