title: Combination therapy of conditionally replicating adenovirus and histone             deacetylase inhibitors.
abstract: Combination therapy of adenoviral gene therapy and a histone deacetylase (HDAC) inhibitor is important due to the enhancing effect of HDAC inhibitors on adenoviral transduction and transcription. However, contradictory results have been reported on the effect of combination of CRAd (conditionally replicating adenovirus) and HDAC inhibitors. This study was designed to investigate the interaction of CRAd and HDAC inhibitors and determine the ideal way to combine the two agents. Combination of HDAC inhibitors (SK7041, SBHA and vorinostat) at pre- and post-transductional periods with CRAd enhanced the transduction of CRAd and expression of luciferase expression from Δ24-luc in vitro. However, suppression of luciferase expression from Δ24-luc injected tumor mass was observed by in vivo tumor bioluminescence imaging and drug interaction analysis also showed an antagonistic interaction that was probably related with the inhibitory effect of the HDAC inhibitor on adenoviral replication. Suppression of p21 induction by p21 siRNA reversed the suppressive effect of vorinostat on the replication of CRAd, but still failed to reverse the antagonistic interaction. Addition of vorinostat at the pre-transductional period revealed an improvement in the transduction efficiency of CRAd and also induced a synergistic interaction between CRAd and vorinostat, which was possibly related with prevention of the suppressive effect of vorinostat on adenoviral replication. In conclusion, the addition of HDAC inhibitor before CRAd injection showed synergistic antitumor effects, which warrants further investigation on the sequence of HDAC inhibitor and CRAd treatment in an animal tumor model.
authors.affiliation: Department of Internal Medicine, Respiratory Center, Seoul National                     University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Dal Rae
authors.initials: DR
authors.lastname: Kim
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Park
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lim
authors.forename: Jong Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Sei-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Ho-Il
authors.initials: HI
authors.lastname: Yoon
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Yeon-Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Choon-Taek
authors.initials: CT
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D034622:RNA Interference; D011991:Receptors, Virus / Q000235:genetics; D014161:Transduction, Genetic; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D018797:Cell Cycle Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011991:Receptors, Virus; D000077337:Vorinostat