Review of antiviral therapy for herpes labialis, genital herpes and herpes zoster

Moomaw, Michelle D; Cornea, Paul; Rathbun, R Chris; Wendel, Karen A.

doi:10.1586/14787210.1.2.283

Cited by 26 publications

(16 citation statements)

References 76 publications

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“…For over 2 decades, acycloguanosine-based drugs have been routinely used for antiviral therapy in immunocompromised patients undergoing immunosuppressive regimens for anticancer treatment and bone marrow (stem cell) transplantation (e.g., ganciclovir for cytomegalovirus infection or acyclovir for herpes simplex infection) (37–38). The antiviral administration of ganciclovir or acyclovir in patients undergoing gene or cell therapy will be detrimental to cells transduced with HSV1-tk–based reporters and to the negative selection of HSV1-tk–expressing cells that will adversely impact HSV1-tk reporter imaging.…”

Section: Discussionmentioning

confidence: 99%

A New Pyrimidine-Specific Reporter Gene: A Mutated Human Deoxycytidine Kinase Suitable for PET During Treatment with Acycloguanosine-Based Cytotoxic Drugs

Likar¹,

Zurita²,

Dobrenkov³

et al. 2010

J Nucl Med

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In this article, we describe a series of new human-derived reporter genes based on human deoxycytidine kinase (dCK) suitable for clinical PET. Methods: Native dCK and its mutant reporter genes were tested in vitro and in vivo for their phosphorylation of pyrimidine-and acycloguanosine-based radiotracers including 29-deoxy-29-fluoroarabinofuranosylcytosine, 29-fluoro-29-deoxyarabinofuranosyl-5-ethyluracil (FEAU), penciclovir, and 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG) and clinically applied antiviral and anticancer drugs. Results: Cells transduced with dCK mutant reporter genes showed high in vitro and in vivo uptake of pyrimidine-based radiopharmaceuticals ( 18 F-FEAU) comparable to that of herpes simplex virus type-1 thymidine kinase (HSV1-tk)-transduced cells. These mutants did not phosphorylate acycloguanosine-based radiotracers ( 18 F-FHBG) or antiviral drugs (ganciclovir). Furthermore, the mutants displayed suicidal activation of clinically used pyrimidine-based prodrugs (cytarabine, gemcitabine). Conclusion: The mutants of human dCK can be used as pyrimidine-specific PET reporter genes for imaging with 18 F-FEAU during treatment with acycloguanosine-based antiviral drugs. Additionally, the prosuicidal activity of these reporters with pyrimidine-based analogs will allow for the safe elimination of transduced cells. (11)(12)(13). Furthermore, administration of ganciclovir, which is routinely used for antiviral therapy in immunocompromised patients who have received bone marrow (stem cell) transplants, will eliminate the adoptively transferred stem cells or lymphocytes transduced with the HSV1-tk reporter gene. To address this latter concern, we recently assessed a mutant of HSV1-tk bearing an arginine-to-glutamine substitution at position 176 that showed reduced phosphorylation activity toward acyclo-

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Section: Discussionmentioning

confidence: 99%

A New Pyrimidine-Specific Reporter Gene: A Mutated Human Deoxycytidine Kinase Suitable for PET During Treatment with Acycloguanosine-Based Cytotoxic Drugs

Likar¹,

Zurita²,

Dobrenkov³

et al. 2010

J Nucl Med

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“…Radiolabeled pyrimidine-based ( 124 I-FEAU, 18 F-FIAU, 18 F-FEAU, 18 F-FFEAU, and 18 F-FMAU) (15,17,(19)(20)(21) and acycloguanosine-based ( 18 F-GCV, 18 F-FHBG, and 18 F-FHPG) (22,(33)(34)(35) nucleoside analogs have been used to image HSV1-tk and HSV1-sr39tk reporter gene expression with PET. HSV1-tk can also phosphorylate a variety of cytotoxic pyrimidine and acycloguanosine derivatives, including clinically used antiviral drugs such as GCV, ACV, and BVdU (25)(26)(27). In a clinical setting in which a patient's condition requires the administration of antiviral drugs, cells expressing HSV1-tk as a reporter gene will be compromised by antiviral treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Among them are the acycloguanosine derivatives GCV (Cytovene; Roche) (25) and acyclovir (ACV; Zovirax; GlaxoSmithKline) (26) and pyrimidine-based bromovinyldeoxyuridine (BVdU; Brivudin; ZOSTEX) (27). However, the administration of these drugs in patients undergoing gene therapy with HSV1-tk will be detrimental to the transduced cells and will lead to negative imaging results with HSV1-tkspecific PET tracers.…”

mentioning

confidence: 99%

A New Acycloguanosine-Specific Supermutant of Herpes Simplex Virus Type 1 Thymidine Kinase Suitable for PET Imaging and Suicide Gene Therapy for Potential Use in Patients Treated with Pyrimidine-Based Cytotoxic Drugs

Likar

Dobrenkov²,

Olszewska³

et al. 2008

J Nucl Med

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The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene is widely used as a suicide gene in combination with ganciclovir (GCV) and as a nuclear imaging reporter gene with an appropriate reporter probe. Wild-type HSV1-tk recognizes a variety of pyrimidine and acycloguanosine nucleoside analogs, including clinically used antiviral drugs. PET of HSV1-tk reporter gene expression will be compromised in patients receiving nucleoside-based antiviral treatment. With the use of an acycloguanosine-specific mutant of the enzyme, PET of HSV1-tk reporter gene expression can be successfully performed with acycloguanosine-based radiotracers without interference from pyrimidine-based antiviral drugs. Methods: The levels of expression of wild-type HSV1-tk and HSV1-A167Ytk, HSV1-sr39tk, and HSV1-A167Ysr39tk mutants fused with green fluorescent protein (GFP) and transduced into U87 cells were normalized to the mean fluorescence of GFP measured by fluorescence-activated cell sorting. The levels of enzymatic activities of wild-type HSV1-tk and its mutants were compared by 2-h in vitro radiotracer uptake assays with 3 H-29-fluoro-29-deoxy-1-b-D-arabinofuranosyl-5-ethyluracil ( 3 H-FEAU), 3 H-pencyclovir ( 3 H-PCV), and 3 H-GCV and by drug sensitivity assays. PET with 18 F-FEAU and 18 F-9-[4-fluoro-3-(hydroxymethyl)butyl]guanine ( 18 F-FHBG) was performed in mice with established subcutaneous tumors, expressing wild-type HSV1-tk and its mutants, followed by tissue sampling. Results: FEAU accumulation was not detected in HSV1-A167Ysr39tk-expressing cells and xenografts. Lack of conversion of pyrimidine derivatives by the HSV1-A167Ysr39tk supermutant was also confirmed by a drug sensitivity assay, in which the 50% inhibitory concentrations for thymine 1-b-D-arabinofuranoside and bromovinyldeoxyuridine were found to be similar to those in nontransduced cells. In contrast, we found that HSV1-A167Ysr39tk could readily phosphorylate 3 H-GCV at levels similar to those of wild-type HSV1-tk and HSV1-A167Ytk but showed enhanced activity with 3 H-PCV in vitro and with 18 F-FHBG in vivo. Conclusion: We developed a new reporter gene, HSV1-A167Ysr39tk, which exhibits specificity and high phosphorylation activity for acycloguanosine derivatives. The resulting supermutant can be used for PET with 18 F-FHBG and suicidal gene therapy protocols with GCV in patients treated with pyrimidine-based cytotoxic drugs.

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“…The results of treating recurrent herpes labialis with antiviral agents during the first decades after the introduction of acyclovir were disappointing, since the benefits were modest and did not match the results obtained in animal models (for reviews see (20)(21)(22)). Penetration through the outer layers of the skin (stratum corneum) was identified as a key issue, as well as titne of initiation of treatment.…”

Section: Hit Hard Hit Earlymentioning

confidence: 99%

Prevention of Ulcerative Lesions by Episodic Treatment of Recurrent Herpes Labialis: A Literature Review

Harmenberg¹,

Öberg²,

Spruance³

2010

Acta Derm Venerol

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There are substantial difficulties involved in carrying out clinical studies of recurrent herpes labialis, since the disease has a rapid onset, short-lasting viral shedding period and is rapidly self-healing. The aim of this paper was to critically assess published reports of episodic treatment of herpes labialis and to review biological and methodological problems involved in such studies. Limited, but statistically significant, results have been shown with topical antivirals, such as acyclovir and penciclovir, improving healing times by approximately 10%. Orally administrated antivirals, such as valaciclovir and famciclovir, have subsequently found clinical use. However, these two oral medications have different profiles in phase 3 studies. Famciclovir showed additional improvement of efficacy in terms of lesion healing time, but no effect on prevention of ulcerative lesions, while valaciclovir appeared to have similar efficacy to that of acyclovir cream on lesion healing, but some additional efficacy with respect to prevention of ulcerative lesions. A formulation of acyclovir/hydrocortisone showed further improvement in prevention of ulcerative lesions, while retaining efficacy with respect to lesion healing.

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Review of antiviral therapy for herpes labialis, genital herpes and herpes zoster

Cited by 26 publications

References 76 publications

A New Pyrimidine-Specific Reporter Gene: A Mutated Human Deoxycytidine Kinase Suitable for PET During Treatment with Acycloguanosine-Based Cytotoxic Drugs

A New Pyrimidine-Specific Reporter Gene: A Mutated Human Deoxycytidine Kinase Suitable for PET During Treatment with Acycloguanosine-Based Cytotoxic Drugs

A New Acycloguanosine-Specific Supermutant of Herpes Simplex Virus Type 1 Thymidine Kinase Suitable for PET Imaging and Suicide Gene Therapy for Potential Use in Patients Treated with Pyrimidine-Based Cytotoxic Drugs

Prevention of Ulcerative Lesions by Episodic Treatment of Recurrent Herpes Labialis: A Literature Review

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