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Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy

1995; Elsevier BV; Volume: 109; Issue: 4 Linguagem: Inglês

10.1016/s0022-5223(95)70342-x

1097-685X

W. Roy Smythe, Harry C. Hwang, Ashraf A. Elshami, Kunjlata M. Amin, Steven M. Albelda, Larry R. Kaiser,

Cancer Research and Treatments

Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSV tk ), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSV tk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 μmol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 μmol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 μmol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor αv (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSV tk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro. (J THORAC CARDIOVASC SURG 1995;109:626-31)