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The Combination of Adenoviral HSV TK Gene Therapy and Radiation is Effective in Athymic Mouse Glioblastoma Xenografts without Increasing Toxic Side Effects

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Abstract

Object: In mouse models of prostate and breast cancer therapeutic effects are enhanced when adenoviral HSV TK gene therapy is combined with ionizing radiation. In the present study, we adopted this approach for the treatment of human glioblastoma xenografts in an athymic mouse model and assessed treatment results as well as toxic side effects.

Methods: About 72 nude mice received intracerebral inoculations of 2 × 105 U87ΔEGFR cells. On day 7 after tumor implantation the study population was randomized into six treatment arms: (1) intratumoral buffer inoculation on day 7, (2) intratumoral adenoviral vector injection (2 × 109 vp) on day 7, (3) single dose radiation (2.1 Gy) on day 9, (4) adenoviral injection + radiation, (5) adenoviral injection + ganciclovir (GCV) (20 ug/g twice daily from day 8 to 17), (6) adenoviral injection + GCV + radiation. On day 21 half of the animals were sacrificed for histological evaluation of the brain tumors, the other half was assessed for survival.

Results: This study showed significantly prolonged median survival time of 5 days for the GCV treated groups. The addition of radiation decreased the frequency of neurological symptoms and delayed the onset of deficits without altering the expression of thymidine kinase in the tumor cells.

Conclusions: We conclude that adenoviral HSV TK gene therapy in combination with adjuvant radiotherapy does not generate increased toxic side effects in glioblastoma treatment. The prolonged survival time of animals receiving gene therapy and the reduced occurrence of neurological symptoms in irradiated mice constitute promising features of the combined treatment.

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Authors and Affiliations

  1. Molecular Neuro-Oncology Laboratory, Massachusetts General Hospital East, Charlestown, USA

    Ulf Nestler, Hiroaki Wakimoto & E. Antonio Chiocca

  2. Department of Neurosurgery, Massachusetts General Hospital East, Charlestown, USA

    Hiroaki Wakimoto & E. Antonio Chiocca

  3. Department of Neurology, Massachusetts General Hospital East, Charlestown, USA

    Fred H. Hochberg

  4. Department of Radiation Oncology, Massachusetts General Hospital East, Charlestown, USA

    Ulf Nestler & Arnab Chakravarti

  5. Laboratory of Neuropathology, Massachusetts General Hospital East, Charlestown, USA

    Anat Stemmer-Rachamimov

  6. Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA

    Alona Muzikansky

  7. Harvard Gene Therapy Initiative, Harvard Medical School, Boston, MA, USA

    Fernando Siller-Lopez, Laura K. Aguilar & Estuardo Aguilar-Cordova

  8. Advantagene Inc, San Diego, CA, USA

    Estuardo Aguilar-Cordova

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  1. Ulf Nestler
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Nestler, U., Wakimoto, H., Siller-Lopez, F. et al. The Combination of Adenoviral HSV TK Gene Therapy and Radiation is Effective in Athymic Mouse Glioblastoma Xenografts without Increasing Toxic Side Effects. J Neurooncol 67, 177–188 (2004). https://doi.org/10.1023/B:NEON.0000021897.53969.ca

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