Seth, R., Khan, A. A., Pencavel, T. D., Wilkinson, M. J., Kyula, J. N., Simpson, G., Pandha, H., Melcher, A., Vile, R., Harris, P. A., Harrington, K. J. (2015) Adenovirally Delivered Enzyme Prodrug Therapy with Herpes Simplex Virus-Thymidine Kinase in Composite Tissue Free Flaps Shows Therapeutic Efficacy in Rat Models of Glioma. PLASTIC AND RECONSTRUCTIVE SURGERY, 135 (2). pp. 475-487. ISSN 0032-1052

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Abstract

Introduction: 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.

Item Type:	Article
Authors (ICR Faculty only):	Harrington, Kevin
All Authors:	Seth, R., Khan, A. A., Pencavel, T. D., Wilkinson, M. J., Kyula, J. N., Simpson, G., Pandha, H., Melcher, A., Vile, R., Harris, P. A., Harrington, K. J.
Additional Information:	ISI Document Delivery No.: CA2UQ Times Cited: 0 Cited Reference Count: 31 Seth, Rohit Khan, Aadil A. Pencavel, Timothy D. Wilkinson, Michelle J. Kyula, Joan N. Simpson, Guy Pandha, Hardev Melcher, Alan Vile, Richard Harris, Paul A. Harrington, Kevin J. Wellcome Trust Research Training Fellowship [WT098937MA]; British Association of Plastic, Reconstructive and Aesthetic Surgeons; Royal College of Surgeons of England; Royal College of Surgeons of Edinburgh; Royal College of Surgeons of Ireland; Cancer Research UK; Oracle Cancer Trust; Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre Aadil A. Khan, M.R.C.S., is funded by a Wellcome Trust Research Training Fellowship (WT098937MA), and the British Association of Plastic, Reconstructive and Aesthetic Surgeons. Aadil A. Khan, M.R.C.S., and Timothy D. Pencavel, M.R.C.S., received funding from the Royal College of Surgeons of England, and Rohit Seth, M.R.C.S., received funding from the Royal College of Surgeons of Edinburgh and Ireland. Kevin J. Harrington, Ph.D., is supported by Cancer Research UK, the Oracle Cancer Trust, and the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre. Lippincott williams & wilkins Philadelphia
Uncontrolled Keywords:	primary breast-cancer gene-therapy reconstruction interleukin-12 radiation antitumor immunotherapy risk
Research teams:	ICR divisions > Cancer Biology > Targeted Therapy ICR divisions > Radiotherapy and Imaging > Targeted Therapy
Depositing User:	Alexander Smithson
Date Deposited:	16 Mar 2015 13:26
Last Modified:	16 Mar 2015 13:26
URI:	http://publications.icr.ac.uk/id/eprint/13947

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