title: Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation.
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.
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyemi
authors.initials: H
authors.lastname: Kim
authors.affiliation: Radiopharmaceutical Research Team, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Pil-Gu
authors.initials: PG
authors.lastname: Park
authors.affiliation: Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea.
authors.forename: Seung Myung
authors.initials: SM
authors.lastname: Dong
authors.affiliation: Radiopharmaceutical Research Team, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Choi
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, MA, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Chong
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jianmeng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: S Diane
authors.initials: SD
authors.lastname: Hayward
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D004790:Enzyme Induction; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D011494:Protein Kinases / Q000096:biosynthesis; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D013937:Thymidine Kinase / Q000096:biosynthesis; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014764:Viral Proteins / Q000096:biosynthesis; D014775:Virus Activation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D014764:Viral Proteins; D003841:Deoxycytidine; D011494:Protein Kinases; D013937:Thymidine Kinase; D015774:Ganciclovir; D000093542:Gemcitabine
keywords: EBVaGC mouse model; Epstein-Barr virus-associated gastric carcinoma; ataxia telangiectasia-mutated; gemcitabine; p53