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

Cancer Gene Therapy volume 9, pages 917–924 (2002)Cite this article

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 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.

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Acknowledgements

This study was supported by grants from Finnish Academy, Kuopio University Hospital (EVO Grants 5022 and 5118), Sigrid Juselius Foundation, Northern Savo Cancer Foundation, Finnish Society of Oncology, and Ark Therapeutics. The authors thank Aila Erkinheimo, Mervi Nieminen, Tommi Heikura, and Sirpa Laitinen for skillful technical assistance, and Marja Poikolainen for preparing the manuscript.

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Authors and Affiliations

  1. AI Virtanen Institute, University of Kuopio, Kuopio, Finland

    Kristiina Tyynelä, Anu-Maaria Sandmair, Marita Turunen, Risto Kauppinen & Seppo Ylä-Herttuala

  2. Department of Oncology, Kuopio University Hospital, Kuopio, Finland

    Kristiina Tyynelä, Marita Turunen & Risto Johansson

  3. Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland

    Anu-Maaria Sandmair & Matti Vapalahti

  4. Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland

    Ritva Vanninen & Pauli Vainio

  5. NMR Research Group, University of Kuopio, Kuopio, Finland

    Risto Kauppinen

  6. Department of Medicine, Kuopio University Hospital, Kuopio, Finland

    Risto Johansson & Seppo Ylä-Herttuala

  7. Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

    Matti Vapalahti & Seppo Ylä-Herttuala

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  1. Kristiina Tyynelä
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Tyynelä, K., Sandmair, AM., Turunen, M. et al. Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model. Cancer Gene Ther 9, 917–924 (2002). https://doi.org/10.1038/sj.cgt.7700515

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