Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector

M. Takahashi, G. Valdes, K. Hiraoka, A. Inagaki, S. Kamijima, E. Micewicz, H. E. Gruber, J. M. Robbins, D. J. Jolly, W. H. McBride, K. S. Iwamoto, N. Kasahara

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

A tumor-selective non-lytic retroviral replicating vector (RRV), Toca 511, and an extended-release formulation of 5-fluorocytosine (5-FC), Toca FC, are currently being evaluated in clinical trials in patients with recurrent high-grade glioma (NCT01156584, NCT01470794 and NCT01985256). Tumor-selective propagation of this RRV enables highly efficient transduction of glioma cells with cytosine deaminase (CD), which serves as a prodrug activator for conversion of the anti-fungal prodrug 5-FC to the anti-cancer drug 5-fluorouracil (5-FU) directly within the infected cells. We investigated whether, in addition to its direct cytotoxic effects, 5-FU generated intracellularly by RRV-mediated CD/5-FC prodrug activator gene therapy could also act as a radiosensitizing agent. Efficient transduction by RRV and expression of CD were confirmed in the highly aggressive, radioresistant human glioblastoma cell line U87EGFRvIII and its parental cell line U87MG (U87). RRV-transduced cells showed significant radiosensitization even after transient exposure to 5-FC. This was confirmed both in vitro by a clonogenic colony survival assay and in vivo by bioluminescence imaging analysis. These results provide a convincing rationale for development of tumor-targeted radiosensitization strategies utilizing the tumor-selective replicative capability of RRV, and incorporation of radiation therapy into future clinical trials evaluating Toca 511 and Toca FC in brain tumor patients.

Original languageEnglish (US)
Pages (from-to)405-410
Number of pages6
JournalCancer gene therapy
Volume21
Issue number10
DOIs
StatePublished - Oct 25 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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    Takahashi, M., Valdes, G., Hiraoka, K., Inagaki, A., Kamijima, S., Micewicz, E., Gruber, H. E., Robbins, J. M., Jolly, D. J., McBride, W. H., Iwamoto, K. S., & Kasahara, N. (2014). Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. Cancer gene therapy, 21(10), 405-410. https://doi.org/10.1038/cgt.2014.38