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Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation

 Hyun Gyu Lee  ;  Hyemi Kim  ;  Eun Jung Kim  ;  Pil-Gu Park  ;  Seung Myung Dong  ;  Tae Hyun Choi  ;  Hyunki Kim  ;  Curtis R. Chong  ;  Jun O. Liu  ;  Jianmeng Chen  ;  Richard F. Ambinder  ;  S. Diane Hayward  ;  Jeon Han Park  ;  Jae Myun Lee 
 ONCOTARGET , Vol.6(31) : 31018-31029, 2015 
Journal Title
Issue Date
Animals ; Antimetabolites, Antineoplastic/pharmacology* ; Antineoplastic Combined Chemotherapy Protocols/pharmacology* ; Antiviral Agents/pharmacology* ; Carcinoma/diagnosis ; Carcinoma/drug therapy* ; Carcinoma/genetics ; Carcinoma/virology ; Cell Line, Tumor ; Deoxycytidine/analogs & derivatives* ; Deoxycytidine/pharmacology ; Dose-Response Relationship, Drug ; Drug Repositioning ; Enzyme Induction ; Epstein-Barr Virus Infections/diagnosis ; Epstein-Barr Virus Infections/drug therapy* ; Epstein-Barr Virus Infections/virology ; Female ; Ganciclovir/pharmacology* ; Herpesvirus 4, Human/drug effects* ; Herpesvirus 4, Human/enzymology ; Herpesvirus 4, Human/pathogenicity ; Humans ; Mice, Inbred NOD ; Mice, SCID ; Molecular Targeted Therapy* ; Protein Kinases/biosynthesis ; RNA Interference ; Signal Transduction/drug effects ; Stomach Neoplasms/diagnosis ; Stomach Neoplasms/drug therapy* ; Stomach Neoplasms/genetics ; Stomach Neoplasms/virology ; Thymidine Kinase/biosynthesis ; Time Factors ; Transfection ; Tumor Burden/drug effects ; Viral Proteins/biosynthesis ; Virus Activation/drug effects ; Xenograft Model Antitumor Assays
EBVaGC mouse model ; Epstein-Barr virus-associated gastric carcinoma ; ataxia telangiectasia-mutated ; gemcitabine ; p53
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.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Park, Pil Gu(박필구) ORCID logo https://orcid.org/0000-0002-3024-3439
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
Lee, Hyun Gyu(이현규)
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