Background: Epstein-Barr virus associated gastric carcinoma (EBVaGC) is considered a distinct GC
disease entity, with the virus persisting in a latent phase. Treatment with Epirubicin, Capecitabine and
Cisplatin (ECC combination) showed survival benefit in patients with GC in clinical trials (MAGIC study
and CRITICS study) when compared to chemotherapy with Capecitabine and Cisplatin (GCb/Cis). Current
treatment protocols for GC do not consider virus involvement.
Methods: In this study, we tested a CytoLytic Virus Activation (CLVA) strategy consisting of the ECC
combination or GCb/Cis together with the HDAC inhibitor Valproic acid (VPA) to define whether EBV
reactivation and subsequent antiviral treatment with Ganciclovir (GCV) could be used as virus-targeted
therapy for EBVaGC. Drug combinations with VPA and GCV were evaluated in multiple cell lines and in
an EBVaGC mouse model based on human naturally EBV-infected SNU-719 cells.
Results: EBV reactivation was demonstrated by lytic mRNA transcripts and proteins in treated cells, and
the virus-reactivating capacity of different CLVA drug combinations was compared in C666.1, AGS-BX1
and SNU-719 cell lines. In an EBVaGC mouse model, GCb/Cis with VPA and GCV strongly reduced tumor
volume and showed the highest potential for EBV-reactivation. Upon a single round of CLVA treatment,
EBV DNA levels in circulation decreased, and loss of EBV-positive cells in treated tumors was observed.
In vivo EBV-reactivation was revealed by the presence of lytic gene transcripts and proteins in tumor tissues
6 days after treatment.
Conclusion: In EBVaGC model systems, CLVA treatment showed a more potent virus reactivation and
killing of tumor cells when compared to standard chemotherapy alone, suggesting that addition of VPA plus
GCV to the ECC or GCb/Cis combination should be considered in future clinical studies.
Epstein-Barr virus associated posttransplant malignant lymphoma in renal allograft recipients
