Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation
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Hyun Gyu Lee1,*, Hyemi Kim1,2,*, Eun Jung Kim3, Pil-Gu Park1, Seung Myung Dong4, Tae Hyun Choi3, Hyunki Kim5, Curtis R. Chong6,7, Jun O. Liu8,9, Jianmeng Chen9, Richard F. Ambinder9, S. Diane Hayward9, Jeon Han Park1, Jae Myun Lee1,2
1Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea
2Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
3Radiopharmaceutical Research Team, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
4Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
5Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
6Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA
7Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, MA, USA
8Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
9Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
*These authors have contributed equally to this work
Jae Myun Lee, e-mail: email@example.com
Keywords: Epstein-Barr virus-associated gastric carcinoma, gemcitabine, ataxia telangiectasia-mutated, p53, EBVaGC mouse model
Received: March 16, 2015 Accepted: August 24, 2015 Published: September 04, 2015
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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