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Factors Limiting Adenovirus-mediated Gene Transfer into Human Lung and Pancreatic Cancer Cell Lines¹

Departments of Surgical Oncology [A. S. P.], Thoracic and Cardiovascular Surgery [P. E. K., J. A. R., B. F.], and Biomathematics [E. N. A.], Human Genetics Center [M. X.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Division of Infectious Disease, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [R. W. F.]

Adenoviral vectors are a widely used means of gene transfer. However, transgene expression after adenoviral administration varies among different carcinoma cell lines. We hypothesized that this variation is attributable, in part, to the presence of cell surface molecules involved in adenoviral infection. To test this, we first assessed adenovirus-mediated transgene expression in four human lung carcinoma cell lines and four human pancreatic carcinoma cell lines in terms of luciferase activities and found it to vary from 4.8 x 10⁴ to 6.1 x 10⁷ relative light units/µg of protein. Then, to determine whether the molecules involved in the entry of adenovirus into host cells were responsible for this variation, we evaluated the expression of v5, v, 3, 5, and 1 integrins and that of coxsackievirus and adenovirus receptor (CAR) in these cell lines. Statistical analysis revealed that the levels of 3 were associated with the levels of transgene expression. Blocking analysis showed that adenovirus-mediated gene transfer could be blocked by antibodies against these six molecules but not by the antibodies against 2 or 3 integrins, thus suggesting that the integrins v5, v, 3, 5, and 1 and CAR molecules could limit adenovirus-mediated gene transfer when their levels fell below a certain threshold. Furthermore, cells expressing low levels of 3 and resistant to conventional adenoviral vectors were susceptible to a vector containing the heparin-binding domain in its fiber, thus suggesting that redirecting vectors to receptors other than CAR may bypass the integrin pathway. These findings may have implications for improving the efficiency of adenovirus-mediated gene transfer and developing novel adenoviral vectors.

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