RRC ID 18102
Author Kawashima R, Abei M, Fukuda K, Nakamura K, Murata T, Wakayama M, Seo E, Hasegawa N, Mizuguchi H, Obata Y, Hyodo I, Hamada H, Yokoyama KK.
Title EpCAM- and EGFR-targeted selective gene therapy for biliary cancers using Z33-fiber-modified adenovirus.
Journal Int. J. Cancer
Abstract A critical issue in adenovirus (Ad)-based cancer gene therapy is to improve the specificity of gene delivery to cancer cells for better efficacy and safety. We explored methods of retargeting Ad vectors for selective gene therapy of human biliary cancers using the Ad incorporating an IgG Fc-binding motif (Z33) from the Staphylococcus protein A (Ad-FZ33) combined with tumor-specific antibodies. Flow cytometry analysis revealed high-expression levels of epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR) on human biliary cancer cells. Ad-FZ33 expressing LacZ combined with antibodies against EpCAM or EGFR, followed by β-gal assay, demonstrated highly efficient gene transduction in these biliary cancer cells, compared to the treatment with control antibody or without antibody. Ad-FZ33 expressing uracil phosphoribosyl transferase (UPRT), an enzyme which greatly enhances the toxicity of 5-fluorouracil (FU), combined with antibodies against EpCAM or EGFR, remarkably enhanced the sensitivity of biliary cancer cells to 5-FU. By contrast, the treatment did not affect the 5-FU sensitivity of the cells not expressing EpCAM or EGFR including normal hepatocytes. Finally, treatments with the UPRT-expressing Ad-FZ33 with antibodies against EpCAM or EGFR, followed by 5-FU administration, significantly suppressed the growth of biliary cancer xenografts in nude mice. These results indicate that the gene therapy mediated by the Z33 fiber modified Ad with anti-EpCAM or anti-EGFR antibodies offers a potentially effective therapeutic modality against biliary cancers.
Volume 129(5)
Pages 1244-53
Published 2011-9-1
DOI 10.1002/ijc.25758
PMID 21710497
MeSH Adenocarcinoma / genetics Adenocarcinoma / immunology Adenocarcinoma / therapy* Adenoviridae / genetics* Animals Antibodies, Monoclonal / therapeutic use Antigens, Neoplasm / genetics* Antigens, Neoplasm / immunology Antimetabolites, Antineoplastic / therapeutic use Biliary Tract Neoplasms / genetics Biliary Tract Neoplasms / immunology Biliary Tract Neoplasms / therapy* Blotting, Western Cell Adhesion Molecules / antagonists & inhibitors Cell Adhesion Molecules / genetics* Cell Adhesion Molecules / immunology Combined Modality Therapy Epithelial Cell Adhesion Molecule ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics* ErbB Receptors / immunology Female Flow Cytometry Fluorouracil / therapeutic use Genetic Therapy* Genetic Vectors / therapeutic use Humans Immunoglobulin Fc Fragments / genetics Immunoglobulin G / genetics Mice Mice, Inbred BALB C Mice, Nude RNA, Messenger / genetics Reverse Transcriptase Polymerase Chain Reaction Staphylococcal Protein A / genetics Tumor Cells, Cultured
IF 7.36
Times Cited 8
Human and Animal Cells Hep G2 (RCB0459) HuH-7 (RCB1366)