title: 2-aminopurine enhances the oncolytic activity of an E1b-deleted adenovirus in hepatocellular carcinoma cells.
abstract: Adenoviruses with deletions of viral genes have been extensively studied as potential cancer therapeutics. Although a high degree of cancer selectivity has been demonstrated with these conditionally replicating adenoviruses, low levels of virus replication can be detected in normal cells. Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells. Recent studies have shown that co-administration of chemotherapeutic drugs may increase the activity of these viruses without affecting their specificity. We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines. Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Sharon
authors.forename: Michael
authors.initials: M
authors.lastname: Schümann
authors.forename: Sheena
authors.initials: S
authors.lastname: MacLeod
authors.forename: Robyn
authors.initials: R
authors.lastname: McPherson
authors.forename: Shyambabu
authors.initials: S
authors.lastname: Chaurasiya
authors.forename: Andrew
authors.initials: A
authors.lastname: Shaw
authors.forename: Mary M
authors.initials: MM
authors.lastname: Hitt
mesh_terms: D015075:2-Aminopurine / Q000494:pharmacology*; D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D019943:Amino Acid Substitution; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy* / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004249:DNA Damage; D017353:Gene Deletion; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology* / Q000821:virology; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D017501:Adenovirus E1B Proteins; D012367:RNA, Viral; D015075:2-Aminopurine