Preservation of the bystander cytocidal effect of irradiated herpes simplex virus thymidine kinase (HSV-tk) modified tumor cells.
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.
Vrionis
F D
FD
Department of Neurosurgery, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Wu
J K
JK
Qi
P
P
Cano
W G
WG
Cherington
V
V
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D002296:Carcinosarcoma / Q000235:genetics / Q000628:therapy*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002472:Cell Transformation, Viral; D015774:Ganciclovir / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D015967:Gene Expression Regulation, Viral / Q000528:radiation effects; D015316:Genetic Therapy / Q000379:methods*; D007278:Injections, Spinal; D010957:Plasmids; D051381:Rats; D018139:Simplexvirus; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects / Q000637:transplantation
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir