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Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

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Author: Kuhlmann, K.F.D. · Geer, M.A. van · Bakker, C.T. · Dekker, J.E.M. · Havenga, M.J.E. · Oude Elferink, R.P.J. · Gouma, D.J. · Bosma, P.J. · Wesseling, J.G.
Type:article
Date:2009
Institution: TNO Kwaliteit van Leven
Source:Cancer Gene Therapy, 7, 16, 585-597
Identifier: 285078
doi: doi:10.1038/cgt.2009.4
Keywords: Biology · Biomedical Research · Adenovirus · Fiber-chimeric · Pancreatic cancer · Serotype · adenovirus vector · bacterial enzyme · coxsackie virus and adenovirus receptor · cytosine deaminase · flucytosine · green fluorescent protein · red fluorescent protein · virus DNA · virus fiber protein · Adenovirus fiber gene · Adenovirus fiber knob 5 · Adenovirus type 16 · Adenovirus type 50 · antineoplastic activity · article · bacterial gene · cancer cell culture · cell viability · controlled study · cytosine deaminase gene · drug cytotoxicity · drug efficacy · drug mechanism · drug specificity · fiber chimeric human adenovirus 5 · gene directed enzyme prodrug therapy · gene expression · gene targeting · human · Human adenovirus · Human adenovirus 5 · human cell · human tissue · liver cell culture · molecular cloning · nonhuman · pancreas adenocarcinoma · priority journal · protein domain · protein expression · suicide gene · viral gene delivery system · virus fiber · virus gene · Adenoviridae · Cell Line · Cell Line, Tumor · Flow Cytometry · Gene Therapy · Genetic Vectors · Green Fluorescent Proteins · Humans · Pancreatic Neoplasms · Polymerase Chain Reaction · Recombinant Fusion Proteins · Recombination, Genetic · Transduction, Genetic · Viral Envelope Proteins · Adenoviridae

Abstract

Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved gene transfer, a library of Ad vectors based on Ad5 and carrying fiber molecules consisting of 16 other serotypes were transduced to human pancreatic carcinoma cell lines. Adenoviruses containing fibers from serotype 16 and 50 showed increased gene transfer and were further analyzed. In a gene-directed prodrug activation system using cytosine deaminase, these adenoviruses proved to be effective in eradicating primary pancreatic tumor cells. Fiber-chimeric Ad5 containing fiber 16 and wild-type Ad5 were also transduced ex vivo to slices of normal human pancreatic tissue and pancreatic carcinoma tissue obtained during surgery. It was shown that fiber-chimeric Ad5 with fiber 16 revealed an improved gene delivery to primary pancreatic tumor tissue compared to Ad5. In conclusion, fiber-chimeric adenoviruses carrying fiber 16 and 50 reveal a significantly enhanced gene transfer and an increased specificity to human pancreatic adenocarcinoma compared to Ad5, whereas transduction to normal pancreatic tissue was decreased. These findings expand the therapeutic window of Ad gene therapy for pancreatic cancer. © 2009 Nature Publishing Group All rights reserved.