Preservation of the bystander cytocidal effect of irradiated herpes simplex virus thymidine kinase (HSV-tk) modified tumor cells

• Published in: Journal of neuro-oncology 1996-12, Vol.30 (3), p.225-236
• Main Authors: VRIONIS, F. D, WU, J. K, QI, P, CANO, W. G, CHERINGTON, V
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - pharmacology; Biological and medical sciences; Blotting, Western; Carcinosarcoma - genetics; Carcinosarcoma - therapy; Cell Survival - drug effects; Cell Survival - radiation effects; Cell Transformation, Viral; Ganciclovir - pharmacology; Gene Expression Regulation, Neoplastic - radiation effects; Gene Expression Regulation, Viral - radiation effects; Genetic Therapy - methods; Injections, Spinal; Medical sciences; Other treatments; Plasmids; Rats; Simplexvirus; Thymidine Kinase - genetics; Treatment. General aspects; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - radiation effects; Tumor Cells, Cultured - transplantation; Tumors
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/BF00177273

In vitro and animal experiments have demonstrated the potential efficacy of using the bystander effect alone in the treatment of brain tumors. A known problem in some in vitro and in vivo experiments is that a fraction of cells engineered to express the herpes simplex virus thymidine kinase (HSV-tk) gene survive ganciclovir (GCV) treatment and undergo cell division. To prevent the recurrent growth of HSV-tk+ cells in the presence of GCV we examined the potential use of lethal or sublethal irradiation of Walker 256 carcinosarcoma cells selected for expression of the HSV-tk gene (Walker-tk+). Western blot analysis of Walter-tk+ cells showed similar levels of HSV-tk protein expression at 0, 1, 3, 6 and 9 days after lethal gamma-irradiation. In vitro, there was no difference in the bystander effect exerted by non-irradiated, sublethally irradiated or lethally irradiated Walker-tk+ cells on wild-type Walker cells in the presence of GCV. In vivo experiments demonstrated long-term survival (100 days) in rats implanted intrathecally with sublethally or lethally irradiated Walker-tk+ cells with GCV treatments. Intrathecal implantation of irradiated Walker-tk+ cells either pre-mixed with Walker cells or used in in situ treatment of established Walker tumors resulted in prolonged animal survival compared to controls (p < 0.05). These experiments suggest that the bystander tumoricidal effect is preserved despite gamma-irradiation of the HSV-tk modified tumor cells and that irradiation could be an effective method to prevent long-term resistance to GCV in HSV-tk+ tumor cells.