Lee Hyun Gyu, Kim Hyemi, Kim Eun Jung, Park Pil-Gu, Dong Seung Myung, Choi Tae Hyun, Kim Hyunki, Chong Curtis R, Liu Jun O, Chen Jianmeng, Ambinder Richard F, Hayward S Diane, Park Jeon Han, Lee Jae Myun
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.
Oncotarget. 2015 Oct 13;6(31):31018-29. doi: 10.18632/oncotarget.5041.
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.
病毒基因组在爱泼斯坦-巴尔病毒（EBV）相关胃癌（EBVaGC）中持续存在，这表明新型EBV靶向疗法具有适用性。抗病毒核苷药物更昔洛韦（GCV）仅在EBV编码的胸苷激酶（TK）/蛋白激酶（PK）表达时，在病毒裂解周期的情况下才有效。在本研究中，对约翰霍普金斯药物库进行筛选，确定吉西他滨为与GCV联合治疗的候选药物。利用EBVaGC来源的肿瘤细胞中EBV-TK或PK的药理学诱导来研究GCV在体外和体内的联合治疗。发现吉西他滨通过激活EBVaGC中的共济失调毛细血管扩张突变（ATM）/p53基因毒性应激途径成为一种裂解诱导剂。使用EBVaGC小鼠模型和基于[125I]氟阿糖腺苷（FIAU）的裂解激活成像系统，我们在体内系统中评估了吉西他滨诱导的裂解激活，并证实了吉西他滨-GCV联合治疗的疗效。这种针对病毒酶的抗肿瘤策略可能为EBVaGC提供一种新的治疗方法。
