Effect of adenoviral-mediated thymidine kinase transduction and ganciclovir therapy on tumor-associated endothelial cells.
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 beta-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.
Tanaka
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Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002417:Cattle; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects*; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy; D018316:Gliosarcoma; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051381:Rats; D014161:Transduction, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014764:Viral Proteins
D000998:Antiviral Agents; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1; D015774:Ganciclovir