Document Detail


Novel adenoviral gene delivery system targeted against head and neck cancer.
MedLine Citation:
PMID:  18176343     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: The clinical applicability of adenovirus-mediated gene therapy is limited by the lack of tumor-targeted strategies. Ubiquitous expression of the coxsackie-adenovirus receptor, the native binding site for adenovirus, broadens viral tropism and increases systemic toxicity. Adenoviruses can be genetically engineered to target tumor-specific cell surface biomarkers. Here, we present a novel recombinant adenovirus vector (Ad5-Flag-LDS) that demonstrated a marked targeting bias against Hsp47, a biomarker for head and neck squamous cell carcinoma (HNSCC). METHODS: Cell surface expression of Hsp47 was determined in six human HNSCC cell lines and in negative and positive control cells. Colocalization of LDS and Hsp47 was assessed by immunocytochemistry in Ad5-Flag-LDS-transfected cells, and subsequent transgene expression was determined. The contribution of the Hsp47 biomarker in mediating targeted gene transfer was evaluated with a blocking assay. Ad5-Flag-LDS-targeting efficacy in a mixed cell population was determined by immunofluorescence. RESULTS: HNSCC cells had significantly higher Hsp47 biomarker density than control cell lines. After Ad5-Flag-LDS transfection, significant colocalization was found between the LDS peptide and Hsp47 biomarker, indicating that viral entry occurred via Hsp47-LDS binding. This unique tumor-targeted entry feature significantly enhanced gene transfer relative to an untargeted adenoviral vector. Blockade of Hsp47 biomarkers abrogated transgene expression, indicating that Hsp47 has a dominant role in Ad5-Flag-LDS targeting. Ad5-Flag-LDS-targeting selectivity was maintained in a cell mixture, producing greater transgene expression in Hsp47-expressing cells. CONCLUSIONS: The enhanced targeting achieved with Ad5-Flag-LDS highlights a potential strategy for clinically applicable targeted gene therapy against HNSCC or any tumor type expressing Hsp47.
Authors:
Daqing Li; Wei Guang; Waleed M Abuzeid; Soumitra Roy; Guang-Ping Gao; John J Sauk; Bert W O'Malley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Laryngoscope     Volume:  118     ISSN:  0023-852X     ISO Abbreviation:  Laryngoscope     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-03-31     Completed Date:  2008-06-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8607378     Medline TA:  Laryngoscope     Country:  United States    
Other Details:
Languages:  eng     Pagination:  650-8     Citation Subset:  IM    
Affiliation:
Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. lidaqing@mail.med.upenn.edu
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics*
Animals
CHO Cells
Carcinoma, Squamous Cell / therapy*
Cell Line, Tumor
Cricetinae
Cricetulus
Flow Cytometry
Gene Expression Regulation, Viral / genetics
Gene Transfer Techniques*
Genetic Vectors / genetics*
Green Fluorescent Proteins / genetics
HSP47 Heat-Shock Proteins / genetics
Head and Neck Neoplasms / therapy*
Humans
Immunohistochemistry
Luminescent Agents
Targeted Gene Repair
Transfection
Transgenes / genetics
Tumor Markers, Biological / genetics
Virus Attachment
Grant Support
ID/Acronym/Agency:
R01 DE14562/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/HSP47 Heat-Shock Proteins; 0/Luminescent Agents; 0/Tumor Markers, Biological; 147336-22-9/Green Fluorescent Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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