Effect of Adenoviral-mediated Thymidine Kinase Transduction and Ganciclovir Therapy on Tumor-associated Endothelial Cells

Abstract

Transduction of the herpes simplex virus thymidine kinase (HSV-tk) into vascular endothelial cells using a replication-defective adenoviral vector (Ad.CMV-tk) to confer sensitivity to ganciclovir (GCV) was investigated. The cytotoxic sensitivity of bovine aortic endothelial cells (BAEC) to GCV following Ad.CMV-tk transduction at multiplicity of infection of 100 was ten-fold that of 9L glioma cells in vitro. Deoxyribonucleic acid fragmentation was detected in these BAEC. A co-culture experiment using BAEC transduced with Ad.CMV-tk (BAEC-tk) and 9L cells expressing β-galactosidase (9L-Lac Z) showed about 70% tumoricidal effect under the conditions of one BAEC-tk cell in 10 9L-Lac Z cells. Tumor-bearing Fisher 344 rats, an experimental brain tumor model, received Ad.CMV-tk intratumorally at 7 days after tumor implantation, and were subsequently treated with intraperitoneal GCV (100 mg/kg). Histological examination found the vascular endothelial cells adjacent to 9L glioma tissue revealed apoptosis. These results suggest that vascular endothelial cells are an attractive target for adenoviral-mediated HSV-tk gene therapy.