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EpCAM‐ and EGFR‐targeted selective gene therapy for biliary cancers using Z33‐fiber‐modified adenovirus
Author(s) -
Kawashima Rei,
Abei Masato,
Fukuda Kuniaki,
Nakamura Kiminori,
Murata Takehide,
Wakayama Mariko,
Seo Emiko,
Hasegawa Naoyuki,
Mizuguchi Hiroyuki,
Obata Yuichi,
Hyodo Ichinosuke,
Hamada Hirofumi,
Yokoyama Kazunari K.
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25758
Subject(s) - epithelial cell adhesion molecule , epidermal growth factor receptor , antibody , cancer research , genetic enhancement , cancer cell , microbiology and biotechnology , cancer , biology , flow cytometry , immunology , gene , biochemistry , genetics
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.