| 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 |
5.145
|
| Times Cited |
14
|
|
WOS Category
|
ONCOLOGY
|
| Resource |
| Human and Animal Cells |
Hep G2(RCB0459)
HuH-7(RCB1366) |
