Carcinoembryonic Antigen–Targeted Selective Gene Therapy for Gastric Cancer through FZ33 Fiber-Modified Adenovirus Vectors
Open Access
- 15 June 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 12 (12), 3803-3813
- https://doi.org/10.1158/1078-0432.ccr-06-0024
Abstract
Purpose: A major problem when using the adenoviral vectors for gene therapy applications is thought to be related to low transduction efficiency in cancer cells or to side effects in normal cells. There is an urgent requirement to improve the specificity of gene delivery in the context of cancer gene therapy. Experimental Design: We constructed a genetically modified adenovirus incorporating an IgG Fc-binding motif from the Staphylococcus protein A, Z33, within the HI loop (Adv-FZ33). A remarkable degree of targeted gene delivery to gastric cancer cells was obtained with Adv-FZ33 with the fully human anti–carcinoembryonic antigen (CEA) monoclonal antibody, C2-45. Results:In vitro LacZ or EGFP gene expression after Adv-FZ33 infection via C2-45 was 20 times higher than control monoclonal antibody in MKN-45 at 1,000 viral particles/cell. We generated Ax3CAUP-FZ33 (UP-FZ33), which is an Adv-FZ33 derivative vector expressing a therapeutic gene (i.e., Escherichia coli uracil phosphoribosyltransferase), which converts 5-fluorouracil (5-FU) directly to 5-fluoro-UMP. UP-FZ33 with C2-45 enhanced the cytotoxicity of 5-FU by 10.5-fold in terms of IC50 against MKN-45 compared with control IgG4. In a nude mouse peritoneal dissemination model, tumor growth in mice treated with UP-FZ33/C2-45/5-FU was significantly suppressed, and tumor volumes were less than one-fourth of those of the control IgG4 group (P < 0.05). The median survival time of the UP-FZ33/C2-45/5-FU group was significantly longer than those treated with PBS or 5-FU only (P < 0.01). Conclusions: These data suggest that CEA-targeted FZ33 mutant adenovirus-mediated gene delivery offers a strong and selective therapeutic modality against CEA-producing cancers.Keywords
This publication has 40 references indexed in Scilit:
- Effective Gene Transfer to Human Melanomas via Integrin-Targeted Adenoviral VectorsHuman Gene Therapy, 2002
- Global cancer statistics in the year 2000The Lancet Oncology, 2001
- The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissuesSeminars in Cancer Biology, 1999
- Selective expression of carcinoembryonic antigen promoter in cancer cell linesDiseases of the Colon & Rectum, 1998
- Adenovirus-Mediated Inducible Gene Expression through Tetracycline-Controllable Transactivator with Nuclear Localization SignalBiochemical and Biophysical Research Communications, 1997
- Tumor-specific accumulation of 125I-labeled mouse-human chimeric anti-CEA antibody in a xenografted human cancer model demonstrated by whole-body autoradiography and immunostainingNuclear Medicine and Biology, 1996
- A Reference of the GOLD Classification of Monoclonal Antibodies against Carcinoembryonic Antigen to the Domain Structure of the Carcinoembryonic Antigen MoleculeHybridoma, 1995
- Biochemical Characterization of 25 Distinct Carcinoembryonic Antigen (CEA) Epitopes Recognized by 57 Monoclonal Antibodies and Categorized into Seven Groups in Terms of Domain Structure of the CEA MoleculeHybridoma, 1992
- Highly Effective Extraction of Carcinoembryonic Antigen with Phosphatidylinositol-Specific Phospholipase CTumor Biology, 1991
- Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion moleculeCell, 1989