Abstract
The constant presence of the viral genome in Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) suggests the applicability of novel EBV-targeted therapies. The antiviral nucleoside drug, ganciclovir (GCV), is effective only in the context of the viral lytic cycle in the presence of EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression. In this study, screening of the Johns Hopkins Drug Library identified gemcitabine as a candidate for combination treatment with GCV. Pharmacological induction of EBV-TK or PK in EBVaGC-originated tumor cells were used to study combination treatment with GCV in vitro and in vivo. Gemcitabine was found to be a lytic inducer via activation of the ataxia telangiectasia-mutated (ATM)/p53 genotoxic stress pathway in EBVaGC. Using an EBVaGC mouse model and a [125I] fialuridine (FIAU)-based lytic activation imaging system, we evaluated gemcitabine-induced lytic activation in an in vivo system and confirmed the efficacy of gemcitabine-GCV combination treatment. This viral enzyme-targeted anti-tumor strategy may provide a new therapeutic approach for EBVaGCs.
Keywords:
EBVaGC mouse model; Epstein-Barr virus-associated gastric carcinoma; ataxia telangiectasia-mutated; gemcitabine; p53.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antiviral Agents / pharmacology*
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Carcinoma / diagnosis
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Carcinoma / drug therapy*
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Carcinoma / genetics
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Carcinoma / virology
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Cell Line, Tumor
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Deoxycytidine / analogs & derivatives*
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Deoxycytidine / pharmacology
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Dose-Response Relationship, Drug
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Drug Repositioning
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Enzyme Induction
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Epstein-Barr Virus Infections / diagnosis
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Epstein-Barr Virus Infections / drug therapy*
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Epstein-Barr Virus Infections / virology
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Female
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Ganciclovir / pharmacology*
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Gemcitabine
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Herpesvirus 4, Human / drug effects*
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Herpesvirus 4, Human / enzymology
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Herpesvirus 4, Human / pathogenicity
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Humans
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Mice, Inbred NOD
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Mice, SCID
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Molecular Targeted Therapy*
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Protein Kinases / biosynthesis
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RNA Interference
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Signal Transduction / drug effects
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Stomach Neoplasms / diagnosis
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / genetics
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Stomach Neoplasms / virology
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Thymidine Kinase / biosynthesis
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Time Factors
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Transfection
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Tumor Burden / drug effects
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Viral Proteins / biosynthesis
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Virus Activation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antimetabolites, Antineoplastic
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Antiviral Agents
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Viral Proteins
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Deoxycytidine
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Protein Kinases
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Thymidine Kinase
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Ganciclovir
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Gemcitabine