Cytolytic virus activation therapy and treatment monitoring for Epstein-Barr virus associated nasopharyngeal carcinoma in a mouse tumor model.

Abstract

Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein-Barr virus (EBV). Expression of viral proteins in the tumor cells is highly restricted. EBV reactivation by CytoLytic Virus Activation (CLVA) therapy triggers de novo expression of early viral kinases (PK and TK) and uses antiviral treatment to kill activated cells. The mechanism of tumor elimination by CLVA was analyzed in NPC mouse model using C666.1 cells. Valproic acid (VPA) was combined with gemcitabine (GCb) to stimulate EBV reactivation, followed by antiviral treatment with ganciclovir (GCV). A single cycle of CLVA treatment resulted in specific tumor cell killing as indicated by reduced tumor volume, loss of EBV-positive cells in situ, and paralleled by decreased EBV DNA levels in circulation, which was more pronounced than treatment with GCb alone. In vivo reactivation was confirmed by presence of lytic gene transcripts and proteins in tumors 6 days after GCb/VPA treatment. Virus reactivation was visualized by [124 I]-FIAU accumulation in tumors using PET-scan. This studied showed that CLVA therapy is a potent EBV-specific targeting approach for killing tumor cells. The [124 I]-FIAU appears valuable as PET tracer for studies on CLVA drug dosage and kinetics in vivo, and may find clinical application in treatment monitoring.

• Authors: Zlata Novalić, Sandra A W M Verkuijlen, Mariska Verlaan, Jos L H Eersels, Inge de Greeuw, Carla F M Molthoff, Jaap M Middeldorp, Astrid E Greijer
• Journal: Journal of medical virology (J Med Virol) Vol. 89 Issue 12 Pg. 2207-2216 (12 2017) ISSN: 1096-9071 [Electronic] United States
• PMID: 28853217 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.

Chemical References

• Antiviral Agents
• DNA, Viral
• Deoxycytidine
• Valproic Acid
• Ganciclovir
• Gemcitabine

Topics

• Animals
• Antiviral Agents (blood, pharmacology, therapeutic use)
• Carcinoma (drug therapy, virology)
• DNA, Viral (genetics)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Epstein-Barr Virus Infections (complications, drug therapy, virology)
• Ganciclovir (administration & dosage, blood, therapeutic use)
• Herpesvirus 4, Human (drug effects, physiology)
• Humans
• Mice
• Mice, Nude
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms (drug therapy, virology)
• Treatment Outcome
• Tumor Cells, Cultured
• Valproic Acid (pharmacology, therapeutic use)
• Viral Load (methods)
• Virus Activation
• Gemcitabine