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Carcinoembryonic Antigen–Targeted Selective Gene Therapy for Gastric Cancer through FZ33 Fiber-Modified Adenovirus Vectors
- Source :
- Clinical Cancer Research. 12:3803-3813
- Publication Year :
- 2006
- Publisher :
- American Association for Cancer Research (AACR), 2006.
-
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.
- Subjects :
- Cancer Research
Genetic enhancement
Genetic Vectors
Molecular Sequence Data
Mutant
CHO Cells
Biology
Gene delivery
Adenoviridae
Nude mouse
Carcinoembryonic antigen
Antigen
Stomach Neoplasms
Cell Line, Tumor
Cricetinae
medicine
Animals
Humans
Amino Acid Sequence
Promoter Regions, Genetic
DNA Primers
Base Sequence
Cancer
Genetic Therapy
biology.organism_classification
medicine.disease
Carcinoembryonic Antigen
Globins
Oncology
Cancer cell
Immunology
biology.protein
Cancer research
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....27ceafc7d05a3d507d6f232eb7fd13c7