EpCAM- and EGFR-targeted selective gene therapy for biliary cancers using Z33-fiber-modified adenovirus
| Autor: | Ichinosuke Hyodo, Takehide Murata, Kazunari K. Yokoyama, Naoyuki Hasegawa, Yuichi Obata, Kiminori Nakamura, Mariko Wakayama, Rei Kawashima, Masato Abei, Hiroyuki Mizuguchi, Kuniaki Fukuda, Hirofumi Hamada, Emiko Seo |
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| Rok vydání: | 2011 |
| Předmět: |
Antimetabolites
Antineoplastic Cancer Research Genetic enhancement Blotting Western Genetic Vectors Mice Nude Adenocarcinoma Gene delivery Adenoviridae Viral vector Mice chemistry.chemical_compound Antigen Antigens Neoplasm Tumor Cells Cultured Animals Humans RNA Messenger Epidermal growth factor receptor Staphylococcal Protein A Mice Inbred BALB C biology Reverse Transcriptase Polymerase Chain Reaction Antibodies Monoclonal Epithelial cell adhesion molecule Genetic Therapy Epithelial Cell Adhesion Molecule Flow Cytometry Combined Modality Therapy Molecular biology Immunoglobulin Fc Fragments ErbB Receptors Biliary Tract Neoplasms Oncology chemistry Immunoglobulin G Cancer cell biology.protein Female Fluorouracil Antibody Cell Adhesion Molecules |
| Zdroj: | International Journal of Cancer. 129:1244-1253 |
| ISSN: | 0020-7136 |
| DOI: | 10.1002/ijc.25758 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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