Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model

Adenovirus (Adv)-mediated herpes simplex virus thymidine kinase (adv/tk) gene therapy combined with ganciclovir (GCV) medication is a promising approach for the treatment of malignant glioma. However, optimal administration and the effect of possible adjuvant treatments have not been fully examined. In the present study, we examined the efficacy of adv/tk/GCV gene therapy in a syngeneic BT4C rat malignant glioma model, either as a single administration or given as three injections during three consecutive days. The effect of combined adv-mediated macrophage colony-stimulating factor (MCSF) and adv/tk gene transfer was also studied. BT4C malignant glioma cells were injected into the right corpus callosum of BDIX rats (n=112). Before gene therapy, the presence of tumors was verified by MRI. The rats were divided into eight groups as follows: group I (n=20) received a single adv/tk gene transfer (total dose 4×108 pfu) and GCV treatment for 14 days; group II (n=5) received the same gene transfer without GCV; group III (n=28) received three adv/tk injections (total dose 4×108 pfu) on three consecutive days and GCV for 14 days; group IV (n=5) received three similar adv/tk injections without GCV medication; group V (n=13) received three adv/MCSF injections (total dose 2×108 pfu) on three consecutive days and GCV medication; group VI (n=12) received three adv/tk and adv/MCSF (total dose 6×108 pfu) injections on three consecutive days followed by GCV medication; and group VII (n=12) the same treatment without GCV. Group VIII (n=17) consisted of wild-type BT4C malignant glioma tumors without any treatment. Treatment effect and tissue responses were characterized by general histology, immunohistochemistry, MRI, and survival of the study groups. The best treatment effect and survival was found in rats treated with adv/tk gene transfer once a day for three consecutive days (P<.05). No improvement of the treatment effect was seen after the combined adv/tk and adv/MCSF gene transfer compared with the repeated adv/tk gene transfer. The results show that 20% of the rats can be cured (survival >6 months) after optimized adv/tk gene therapy. It is concluded that repeated intratumoral administration of adv/tk is a promising approach for the treatment of malignant glioma tumors in vivo.

[1]  D. Klatzmann,et al.  A Phase I/II Study of Herpes Simplex Virus Type 1 Thymidine Kinase "Suicide" Gene Therapy for Recurrent Glioblastoma , 1998 .

[2]  S. Ylä-Herttuala,et al.  Low Efficacy of Gene Therapy for Rat BT4C Malignant Glioma Using Intra-Tumoural Transduction with Thymidine Kinase Retrovirus Packaging Cell Injections and Ganciclovir Treatment , 1999, Acta Neurochirurgica.

[3]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[4]  Z. Ram,et al.  In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. , 1992, Science.

[5]  M. Ammirati,et al.  Reoperation in the treatment of recurrent intracranial malignant gliomas. , 1987, Neurosurgery.

[6]  Z. Ram,et al.  Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells , 1997, Nature Medicine.

[7]  R. Grossman,et al.  Adenovirus‐mediated gene therapy of experimental gliomas , 1994, Journal of neuroscience research.

[8]  R. Bjerkvig,et al.  Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C glioma model: Effect of the percentage of thymidine kinase-positive glioma cells on treatment effect, survival time, and tissue reactions , 2000, Cancer Gene Therapy.

[9]  R. Grossman,et al.  Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  Rolf F. Barth,et al.  Rat brain tumor models in experimental neuro-oncology:The 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 Gliomas , 2004, Journal of Neuro-Oncology.

[11]  S. Ylä-Herttuala,et al.  Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. , 1998, Human gene therapy.

[12]  James M. Wilson,et al.  Efficient catheter-mediated gene transfer into the heart using replication-defective adenovirus. , 1994, Gene therapy.

[13]  N. Rainov A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. , 2000, Human gene therapy.

[14]  A. Lusis,et al.  Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins , 1990, Nature.

[15]  R. Grossman,et al.  Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Ylä-Herttuala,et al.  Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. , 2000, Human gene therapy.