ENHANCED GENE TRANSFER EFFICIENCIES OF RGD FIBER-MUTANT ADENOVIRUS VECTOR FOR THE GENE THERAPY FOR ORAL SQUAMOUS CELL CARCINOMA
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Recently, preclinical studies of gene therapy in many types of tumors, including oral squamous cell carcinoma, have been performed. In vivo gene therapy for oral squamous cell carcinoma based on adenoviral vector-mediated gene delivery been limited by the low efficacy of gene transfer to tumor cells. It is thought to be caused by low expression of coxsackie-adenovirus receptor (CAR) in oral cancer cells. Thus, CAR-independent gene transfer was expected to bring enranced transduction efficiency in oral squamous cell carcinoma. So, we constructed a fiber mutant adenovirus that includes an integrin-binding motif: CDCRGDCFC, in the HI loop of the fiber knob domain, by the COS-TPC method. We encoded LacZ into adenovirus (AxCAZ-F/WT) or a genetically modified adenovirus (AxCAZ-F/RGD) that contained an RGD motif within the HI loop of the knob, in vitro, and oral cancer cell lines were infected by these viruses. After 48hr, the LacZ activity was measured, and the transduction efficiencies of both viruses were compared. As a result, the transduction efficiency of the fiber mutant adenovirus (AxCAZ-F/RGD) remarkably enhanced, by approximately 10-fold higher efficiency, than that of wild-type fiber adenovirus (AxCAZ-F/WT). Furthermore we examined the expression of CAR and integrin. Low expression of coxsackie-adenovirus receptor (CAR) in oral cancer cell lines commonly observed using a quantitative real-time RT-PCR method based on Taq Man chemistry. The flow cytometric examination of the oral cancer cell lines also revealed no or trace-amount expression of alpha v beta 3 integrin, which mediates adenovirus internalization, and overexpression of the alpha 3 betal integrin, which recognizes the Arg-Gly-Asp (RGD) peptide motif. These data demonstrate that genetically altered RGD fiber-mutant adenovirus vectors are capable of more efficient gene transfer in gene therapy for oral squamous cell carcinoma.
- 日本頭頸部癌学会の論文
日本頭頸部癌学会 | 論文
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