title: Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy.
abstract: Replication-incompetent adenoviruses (Ad) carrying the herpes simplex thymidine kinase (HSVtk) gene have been used in a number of human cancer gene therapy trials, however transduction has generally been limited to a small minority of tumor cells. To solve this problem, replication-competent adenoviral vectors carrying transgenes such as HSVtk have been developed. However, contradictory evidence exists regarding the efficacy of these new vectors. Accordingly, we constructed and tested a replication-competent E3-deleted adenoviral vector containing the HSVtk suicide gene driven by the endogenous E3 promoter (Ad.wt.tk). This virus showed high level production of the HSVtk transgene and was more efficacious than a non-replicating virus in vitro, after injection into flank tumors, and against established intraperitoneal tumors. However, addition of ganciclovir (GCV) therapy to cells or tumor-bearing animals treated with the replicating vector containing the HSVtk suicide gene did not result in increased cell killing. Our results indicate that addition of HSVtk to a replicating Ad virus will not likely be useful in augmenting antitumor effects.
authors: Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
authors: E S
authors: ES
authors: Lambright
authors: K
authors: K
authors: Amin
authors: R
authors: R
authors: Wiewrodt
authors: S D
authors: SD
authors: Force
authors: M
authors: M
authors: Lanuti
authors: K J
authors: KJ
authors: Propert
authors: L
authors: L
authors: Litzky
authors: L R
authors: LR
authors: Kaiser
authors: S M
authors: SM
authors: Albelda
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D015552:Injections, Intralesional; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir