title: Adenovirally delivered enzyme prodrug therapy with herpes simplex virus-thymidine kinase in composite tissue free flaps shows therapeutic efficacy in rat models of glioma.
abstract: BACKGROUND
  Free flap gene therapy exploits a novel therapeutic window when viral vectors can be delivered into a flap ex vivo. The authors investigated the therapeutic potential of an adenovirally-delivered thymidine kinase/ganciclovir prodrug system expressed following vector delivery into a free flap.
  
  
  METHODS
  The authors demonstrated direct in vitro cytotoxicity by treating a panel of malignant cell lines with the thymidine kinase/ganciclovir system and demonstrated significant cell kill proportional to the multiplicity of infection of adenoviral vector expressing thymidine kinase. Bystander cytotoxicity was demonstrated using conditioned media from producer cells (expressing adenovirally-delivered thymidine kinase and treated with ganciclovir) to demonstrate cytotoxicity in naive tumor cells. The authors investigated the effect of adenoviral vector expressing thymidine kinase/ganciclovir therapy in vivo, using models of microscopic and macroscopic residual disease in a rodent superficial inferior epigastric artery flap model.
  
  
  RESULTS
  The authors observed retardation of tumor volume growth in both microscopic (p = 0.0004) and macroscopic (p = 0.0005) residual disease models and prolongation of animal survival. Gene expression studies demonstrated that viral genomic material was found predominantly in flap tissues but declined over time.
  
  
  CONCLUSIONS
  The authors describe the utility of virally delivered enzyme/prodrug therapy, using a free flap as a vehicle for delivery. They discuss the merits and limitations of this approach and the unique role of therapeutic free flaps among reconstructive techniques available to the plastic surgeon.
authors: London, Surrey, and Leeds, United Kingdom; and Rochester, Minn. From the Targeted Therapy Team, Institute of Cancer Research; the Department of Plastic Surgery, Royal Marsden Hospital; the Postgraduate Medical School, University of Guildford; the Leeds Institute of Molecular Medicine; and the Molecular Medicine Program, Mayo Clinic.
authors: Rohit
authors: R
authors: Seth
authors: Aadil A
authors: AA
authors: Khan
authors: Timothy D
authors: TD
authors: Pencavel
authors: Michelle J
authors: MJ
authors: Wilkinson
authors: Joan N
authors: JN
authors: Kyula
authors: Guy
authors: G
authors: Simpson
authors: Hardev
authors: H
authors: Pandha
authors: Alan
authors: A
authors: Melcher
authors: Richard
authors: R
authors: Vile
authors: Paul A
authors: PA
authors: Harris
authors: Kevin J
authors: KJ
authors: Harrington
mesh_terms: D065767:Activation, Metabolic; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D024201:Bystander Effect; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology; D003673:Defective Viruses / Q000235:genetics; D019074:Epigastric Arteries; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D018316:Gliosarcoma / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007763:Lac Operon; D018365:Neoplasm, Residual; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013524:Surgical Flaps / Q000821:virology; D013937:Thymidine Kinase / Q000008:administration & dosage* / Q000378:metabolism; D016042:Transplantation, Heterotopic; D014764:Viral Proteins / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D011355:Prodrugs; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir
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