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Clinical Cancer Research Vol. 5, 2571-2579, September 1999
© 1999 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Selective Gene Delivery to Head and Neck Cancer Cells via an Integrin Targeted Adenoviral Vector1

Keizo Kasono, Jerry L. Blackwell, Joanne T. Douglas, Igor Dmitriev, Theresa V. Strong, Paul Reynolds, David A. Kropf, William R. Carroll, Glenn E. Peters, R. Pat Bucy, David T. Curiel2 and Victor Krasnykh

Gene Therapy Program [K. K., J. L. B., J. T. D., I. D., T. V. S., P. R., V. K., D. T. C.] and Departments of Otolaryngology [D. A. K., W. R. C., G. E. P.] and Clinical Pathology [R. P. B.], University of Alabama at Birmingham, Birmingham, Alabama 35294

In vivo cancer gene therapy approaches for squamous cell carcinoma of the head and neck (SCCHN) based on adenoviral vector-mediated gene delivery have been limited by the suboptimal efficacy of gene transfer to tumor cells. We hypothesized that this issue was due to deficiency of the primary adenoviral receptor, the coxsackie-adenovirus receptor (CAR), on the tumor targets. Studies of CAR levels on SCCHN cell lines confirmed that their relative refractoriness to the adenoviral vector was based on this deficiency. To circumvent this deficiency, we applied an adenoviral vector targeted to a tumor cell marker characteristic of SCCHN. In this regard, integrins of the {alpha}2ß1 and {alpha}3ß1 class are frequently overexpressed in SCCHN. Furthermore, these integrins recognize the RGD peptide motif. On this basis, we applied an adenoviral vector genetically modified to contain such a peptide within the HI loop of the fiber protein as a means to alter viral tropism. Studies confirmed that the CAR-independent gene delivery achieved via this strategy allowed enhanced gene transfer efficiencies to SCCHN tumor cells. Importantly, this strategy could achieve preferential augmentation of gene transfer in tumor cells compared with normal cells. The ability to achieve enhanced and specific gene transfer to tumor cells via adenoviral vectors has important implications for gene therapy strategies for SCCHN and for other neoplasms in general.




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Copyright © 1999 by the American Association for Cancer Research.