Journal
ONCOTARGET
Volume 6, Issue 31, Pages 31018-31029Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5041
Keywords
Epstein-Barr virus-associated gastric carcinoma; gemcitabine; ataxia telangiectasia-mutated; p53; EBVaGC mouse model
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Funding
- National Research Foundation of Korea (NRF) - Korea government [NRF-2007-0056423, NRF-2015R1A2A2A01005412]
- Korea Healthcare Technology R&D Project, Ministry of Health, Welfare, Republic of Korea [HI13C0826]
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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 [I-125] 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.
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