DIFFERENTIAL SENSITIVITY OF THORACIC MALIGNANT-TUMORS TO ADENOVIRUS-MEDIATED DRUG SENSITIZATION GENE-THERAPY

Malignant mesothelioma may prove to be an attractive candidate for som atic gene therapy with replication-deficient recombinant adenovirus tr ansfer of a toxic, or drug sensitization gene, Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effec tive tumor cell killing system, To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivit y to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir requ ired to kill 50% of the cells (IC50) as a measure of sensitivity, we d etected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mu mol/L gancyclovir), and non-small-ce ll carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 1 00 mu mol/L). In contrast, an ovarian carcinoma line was extremely res istant (IC50 > 2000 mu mol/L), To study the possible mechanisms for th ese differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CM VlacZ) and expression of the vitronectin receptor cu, (an integrin cel l adhesion molecule shown to be required far adenovirus internalizatio n after initial binding), We found that the degree of lacZ transductio n correlated with HSVtk sensitivity, whereas vitronectin receptor expr ession did not, suggesting that differences in initial viral binding a bility, rather than internalization, may explain the sensitivity diffe rences seen in vitro.