title: Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model.
abstract: 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 4x10(8) 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 4x10(8) 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 2x10(8) pfu) on three consecutive days and GCV medication; group VI (n=12) received three adv/tk and adv/MCSF (total dose 6x10(8) 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.
authors.affiliation: AI Virtanen Institute, University of Kuopio, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Tyynelä
authors.forename: Anu-Maaria
authors.initials: AM
authors.lastname: Sandmair
authors.forename: Marita
authors.initials: M
authors.lastname: Turunen
authors.forename: Ritva
authors.initials: R
authors.lastname: Vanninen
authors.forename: Pauli
authors.initials: P
authors.lastname: Vainio
authors.forename: Risto
authors.initials: R
authors.lastname: Kauppinen
authors.forename: Risto
authors.initials: R
authors.lastname: Johansson
authors.forename: Matti
authors.initials: M
authors.lastname: Vapalahti
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics* / Q000627:therapeutic use*; D014162:Transfection
chemical_list: D000998:Antiviral Agents; D011994:Recombinant Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir