Virus-associated RNA I-deleted adenovirus, a potential oncolytic agent targeting EBV-associated tumors.
Given the growing number of tumor types recognizably associated with EBV infection, it is critically important that therapeutic strategies are developed to treat such tumors. Replication-selective oncolytic adenoviruses represent a promising new platform for anticancer therapy. Virus-associated I (VAI) RNAs of adenoviruses are required for efficient translation of viral mRNAs. When the VAI gene is deleted, adenovirus replication is impeded in most cells (including HEK 293 cells). EBV-encoded small RNA1 is uniformly expressed in most EBV-associated human tumors and can functionally substitute for the VAI RNAs of adenovirus. It enables replication to proceed through complementation of VAI-deletion mutants. We hypothesized that VAI-deleted adenovirus would selectively replicate in EBV-positive tumor cells due to the presence of EBV-encoded small RNA1 with no (or poor) replication in normal or EBV-negative tumor cells. In this report, we show that high levels of replication occurred in the VAI-deleted mutant in the EBV-positive tumor cells compared with low (or negligible) levels in EBV-negative and normal human primary cells. Correspondingly, high toxicity levels were observed in EBV-positive tumor cells but not in EBV-negative tumor or normal human primary cells. In vivo, VAI-deleted adenovirus showed superior antitumoral efficacy to wild-type adenovirus in EBV-positive tumor xenografts, with lower hepatotoxicity than wild-type adenovirus. Our data suggest that VAI-deleted adenovirus is a promising replication-selective oncolytic virus with targeting specificity for EBV-associated tumors.
Wang
Yaohe
Y
Cancer Research UK Molecular Oncology Unit, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK.
Xue
Shao-An
SA
Hallden
Gunnel
G
Francis
Jennelle
J
Yuan
Ming
M
Griffin
Beverly E
BE
Lemoine
Nick R
NR
D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D004854:Herpesvirus 4, Human; D006801:Humans; D008099:Liver / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy* / Q000821:virology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
C099537:Epstein-Barr virus encoded RNA 1; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D012367:RNA, Viral; C052835:adenovirus associated RNA