Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy.
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 (HSVtk), 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 HSVtk 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 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/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 alpha v (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 HSVtk 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.
Smythe
W R
WR
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Hwang
H C
HC
Elshami
A A
AA
Amin
K M
KM
Albelda
S M
SM
Kaiser
L R
LR
D000256:Adenoviridae / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000628:therapy*; D015815:Cell Adhesion Molecules; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism / Q000628:therapy*; D008654:Mesothelioma / Q000378:metabolism / Q000628:therapy*; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis; D016024:Receptors, Cytoadhesin / Q000096:biosynthesis; D017469:Receptors, Fibronectin / Q000096:biosynthesis; D019030:Receptors, Vitronectin; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D015815:Cell Adhesion Molecules; D016023:Integrins; D010980:Platelet Membrane Glycoproteins; D016024:Receptors, Cytoadhesin; D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin; D015774:Ganciclovir