Eradication of murine brain tumors by direct inoculation of concentrated high titer-recombinant retrovirus harboring the herpes simplex virus thymidine kinase gene.
Implantation of retrovirus-producing cells within a tumor has been demonstrated to eliminate malignant brain tumors effectively in animal models. In our previous study, the implantation of high-titer retrovirus-producing fibroblasts into tumors resulted in highly efficient transduction in vivo. The transduced glioma cells migrated far from the implantation site, potentiating the induction of the remarkable bystander effect. It is also possible, however, that the implantation of murine fibroblast-derived virus-producing cells may induce an immune response in patients. In this study, we prepared retroviruses carrying the herpes simplex virus thymidine kinase (HTK) gene with titers of 1.4--2.5 x 10(11) colony-forming units (c.f.u.)/ml, and stereotactically inoculated only 3 microl of the HTK-bearing retroviruses into the brain tumors of mice. Following repetitive ganciclovir (GCV) intraperitoneal injection, effective killing of glioma cells in the mouse brain was observed. The transduction efficiency was nearly as high as that observed for the implantation of high-titer retrovirus-producing fibroblasts. Eighty percent of brain tumor-bearing mice were completely cured by our treatment protocol using concentrated HTK-harboring retroviruses. Our results suggest that repeated inoculations of high-titer retroviruses carrying the HTK gene followed by GCV treatment may be a promising strategy for the clinical treatment of malignant gliomas.
Tamura
K
K
Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Tamura
M
M
Ikenaka
K
K
Yoshimatsu
T
T
Miyao
Y
Y
Nanmoku
K
K
Shimizu
K
K
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D012190:Retroviridae / Q000235:genetics; D015996:Survival Rate; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir