TY - JOUR
T1 - Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C glioma model
T2 - Effect of the percentage of thymidine kinase-positive glioma cells on treatment effect, survival time, and tissue reactions
AU - Sandmair, Anu Maaria
AU - Turunen, Marita
AU - Tyynelä, Kristiina
AU - Loimas, Sami
AU - Vainio, Pauli
AU - Vanninen, Ritva
AU - Vapalahti, Matti
AU - Bjerkvig, Rolf
AU - Jänne, Juhani
AU - Ylä-Herttuala, Seppo
N1 - Funding Information:
We thank Dr. A. Dusty Miller for pLXSN vector; Drs. Jukka Luoma, Pauliina Lehtolainen, Leo Paljärvi, and Asla Pitkänen for critical comments; and Marja Poikolainen for preparing the manuscript. This study was supported by grants from the Finnish Academy, Kuopio University Hospital (EVO grant 5118), Finnish Society of Neurosurgery, and European Union Biomed II program (BMH 4-CT98-3469).
PY - 2000
Y1 - 2000
N2 - Herpes simplex virus thymidine kinase (HSV-tk) gene transfer and ganciclovir (GCV) administration have been suggested for the treatment of malignant gliomas. To understand tissue responses and possible ways to improve the treatment effect, we studied tumor growth, tissue reactions, and survival time after HSV-tk/GCV treatment in a syngeneic BT4C rat glioma model by mixing various ratios of stably transfected HSV-tk-expressing BT4C-tk glioma cells with wild-type BT4C glioma cells (percentage of BT4C-tk cells: 0%, 1%, 10%, 30%, 50%, and 100%), followed by injection into BDIX rat brains (n = 79). With the exception of some animals with end-stage tumors, very little astroglia or microglia reactivity was detected in the wild-type tumors as analyzed by immunocytochemistry using glial fibrillary acid protein (GFAP)-, vimentin-, human histocompatibility leukocyte antigen-DR-, OX-42-, and CD68-specific monoclonal antibodies. After 14 days of GCV treatment, tumors induced with ≥10% BT4C-tk cells showed a significant reduction in tumor size (P < .05) and prolonged survival-time (P<.01). Astrogliosis, as indicated by a strong GFAP and vimentin immunoreactivity, was seen in the tumor scar area. GFAP and vimentin reactivity was already present after the GCV treatment in tumors induced with 1% BT4C-tk cells. Much less human histocompatibility leukocyte antigen-DR-positive microglia was seen in the treated animals, indicating low microglia reactivity and immunoactivation against the tumor. However, GCV-treated tumors were positive for apoptosis, indicating that apoptosis is an important mechanism for cell death in the BT4C-tk glioma model. Our results suggest that ≥10% transfection efficiency is required for a successful reduction in BT4C glioma tumor size with HSV- tk/GCV treatment in vivo. Tissue reactions after 14 days of GCV treatment are characterized by astrogliosis and apoptosis, whereas microglia response and immunoactivation of the brain cells appear to play a minor role. Stimulation of the microglia response by gene transfer or other means might improve the efficacy of the HSV-tk/GCV treatment in vivo.
AB - Herpes simplex virus thymidine kinase (HSV-tk) gene transfer and ganciclovir (GCV) administration have been suggested for the treatment of malignant gliomas. To understand tissue responses and possible ways to improve the treatment effect, we studied tumor growth, tissue reactions, and survival time after HSV-tk/GCV treatment in a syngeneic BT4C rat glioma model by mixing various ratios of stably transfected HSV-tk-expressing BT4C-tk glioma cells with wild-type BT4C glioma cells (percentage of BT4C-tk cells: 0%, 1%, 10%, 30%, 50%, and 100%), followed by injection into BDIX rat brains (n = 79). With the exception of some animals with end-stage tumors, very little astroglia or microglia reactivity was detected in the wild-type tumors as analyzed by immunocytochemistry using glial fibrillary acid protein (GFAP)-, vimentin-, human histocompatibility leukocyte antigen-DR-, OX-42-, and CD68-specific monoclonal antibodies. After 14 days of GCV treatment, tumors induced with ≥10% BT4C-tk cells showed a significant reduction in tumor size (P < .05) and prolonged survival-time (P<.01). Astrogliosis, as indicated by a strong GFAP and vimentin immunoreactivity, was seen in the tumor scar area. GFAP and vimentin reactivity was already present after the GCV treatment in tumors induced with 1% BT4C-tk cells. Much less human histocompatibility leukocyte antigen-DR-positive microglia was seen in the treated animals, indicating low microglia reactivity and immunoactivation against the tumor. However, GCV-treated tumors were positive for apoptosis, indicating that apoptosis is an important mechanism for cell death in the BT4C-tk glioma model. Our results suggest that ≥10% transfection efficiency is required for a successful reduction in BT4C glioma tumor size with HSV- tk/GCV treatment in vivo. Tissue reactions after 14 days of GCV treatment are characterized by astrogliosis and apoptosis, whereas microglia response and immunoactivation of the brain cells appear to play a minor role. Stimulation of the microglia response by gene transfer or other means might improve the efficacy of the HSV-tk/GCV treatment in vivo.
KW - Apoptosis
KW - Astroglia
KW - Bystander effect
KW - Gene transfer
KW - Glial fibrillary acid protein
KW - Glioma
KW - Microgila
KW - Nuclear magnetic resonance imaging
KW - Thyroidine kinase
UR - http://www.scopus.com/inward/record.url?scp=0034128036&partnerID=8YFLogxK
U2 - 10.1038/sj.cgt.7700132
DO - 10.1038/sj.cgt.7700132
M3 - Article
C2 - 10766347
AN - SCOPUS:0034128036
SN - 0929-1903
VL - 7
SP - 413
EP - 421
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 3
ER -