Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells.
Tumor cells infected with a retrovirus vector (VIK) containing the herpes simplex virus thymidine kinase (HSV-TK) gene can be selectively killed by treatment with nucleoside analogues, such as ganciclovir. To mediate delivery of the HSV-TK gene to "recipient" tumor cells, "donor" C6 rat glioma cells infected with the VIK vector (C6VIK) were superinfected with wild type Moloney murine leukemia virus (WT Mo-MLV). These modified donor cells (C6VIKWT) produced both wild type retrovirus and the VIK vector. In culture, C6VIKWT cells were 300-fold more sensitive to the toxicity of ganciclovir than were C6VIK cells, suggesting that the presence of wild type retrovirus contributed to the toxicity. Co-culture of C6VIKWT cells with the C6 subline, C6BAG, sensitized the latter to ganciclovir treatment. Nude mice inoculated subcutaneously with a mixture of C6VIKWT and C6BAG cells showed regression of subsequent tumors when treated with ganciclovir. The observations show that tumor cells modified in culture by infection with a retrovirus bearing the HSV-TK gene and wild type retrovirus are not only sensitive to ganciclovir, but can transfer this sensitivity to neighboring "naive" tumor cells in culture and in vivo.
Takamiya
Y
Y
Neurosurgery Service, Massachusetts General Hospital-East, Charlestown.
Short
M P
MP
Ezzeddine
Z D
ZD
Moolten
F L
FL
Breakefield
X O
XO
Martuza
R L
RL
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008979:Moloney murine leukemia virus / Q000201:enzymology / Q000235:genetics; D051381:Rats; D012190:Retroviridae / Q000201:enzymology* / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase; D015774:Ganciclovir