Gene therapy for esophageal carcinoma: the use of an explant model to test adenoviral vectors ex vivo.
Adenoviral gene therapy might be a promising therapeutic strategy for esophageal carcinoma. However, adenoviral transduction efficacy in vivo is still limited. This efficacy can be improved by the insertion of an Arg-Gly-Asp (RGD) peptide in the HI-loop of the viral fiber knob. Indeed in established esophageal cell lines, we observed an up to six-fold improved transduction using the RGD-targeted adenovirus. Established cell lines, however, are easily transformed and do not represent the more complex in vivo histology and anatomy. Therefore, we set up an esophageal explant model using esophageal biopsies from patients. Viability is a limiting factor for this system. Cultured squamous epithelium, intestinal metaplasia and squamous cell carcinoma had a sufficient viability to study adenoviral transduction. Viability of the cultured adenocarcinoma biopsies was poor. Adenoviral transduction in the explant model was poor and was localized in particular cells. The transduction of the nontargeted and RGD-targeted adenovirus was similar in localization and efficacy. In conclusion, we established an esophageal explant system to test the transduction of adenoviral vectors ex vivo. The transduction was limited and localized in specific cells. RGD-targeted adenovirus did not show an improved transduction in this system.
Marsman
Willem A
WA
Department of Experimental Hepatology, Academic Medical Center, Amsterdam, The Netherlands. w.a.marsman@amc.uva.nl
Buskens
Christianne J
CJ
Wesseling
John G
JG
Offerhaus
G Johan A
GJ
Bergman
Jacques J G H M
JJ
Tytgat
Guido N J
GN
van Lanschot
J Jan B
JJ
Bosma
Piter J
PJ
D000256:Adenoviridae / Q000235:genetics*; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007120:Immunochemistry; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000032:analysis; D014161:Transduction, Genetic / Q000379:methods
C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D009842:Oligopeptides; D011991:Receptors, Virus; C047981:arginyl-glycyl-aspartic acid