title: Combination therapy with conditionally replicating adenovirus and replication defective adenovirus.
abstract: Low gene transfer rate is the most substantial hurdle in the practical application of gene therapy. One strategy to improve transfer efficiency is the use of a conditionally replicating adenovirus (CRAD) that can selectively replicate in tumor cells. We hypothesized that conventional E1-deleted adenoviruses (ad) can become replication-competent when cotransduced with a CRAD to selectively supply E1 in trans in tumors. The resulting selective production of large numbers of the E1-deleted ad within the tumor mass will increase the transduction efficiency. We used a CRAD (Delta24RGD) that produces a mutant E1 without the ability to bind retinoblastoma but retaining viral replication competence in cancer cells with a defective pRb/p16. Ad-lacZ, adenovirus-luciferase (ad-luc), and adenovirus insulin-like growth factor-1R/dominant-negative (ad-IGF-1R/dn; 482, 950) are E1-deleted replication-defective adenoviruses. The combination of CRAD and ad-lacZ increased the transduction efficiency of lacZ to 100% from 15% observed with ad-lacZ alone. Transfer of media of CRAD and ad-lacZ cotransduced cells induced the transfer of lacZ (media transferable bystander effect). Combination of CRAD and ad-IGF-1R/dn increased the production of truncated IGF-1R or soluble IGF-1R > 10 times compared with transduction with ad-IGF-1R/dn alone. Combined intratumoral injection of CRAD and ad-luc increased the luciferase expression about 70 times compared with ad-luc alone without substantial systemic spread. Combined intratumoral injection of CRAD and ad-IGF-1R/482 induced stronger growth suppression of established lung cancer xenografts than single injections. The combination of CRAD and E1-deleted ad induced tumor-specific replication of CRAD and E1-deleted ad and increased the transduction rate and therapeutic efficacy of these viruses in model tumors.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37322-6838, USA.
authors.forename: Choon-Taek
authors.initials: CT
authors.lastname: Lee
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Joyce E
authors.initials: JE
authors.lastname: Ohm
authors.forename: Sorena
authors.initials: S
authors.lastname: Nadaf
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017498:Adenovirus E1 Proteins / Q000172:deficiency / Q000235:genetics; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D017526:Receptor, IGF Type 1 / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes; D014779:Virus Replication / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017498:Adenovirus E1 Proteins; D008156:Luciferases; D017526:Receptor, IGF Type 1