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

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, NCT01985256). Tumor-selective p...

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Autores principales: Takahashi, Masamichi, Valdes, Gilmer, Hiraoka, Kei, Inagaki, Akihito, Kamijima, Shuichi, Micewicz, Ewa, Gruber, Harry E., Robbins, Joan M., Jolly, Douglas J., McBride, William H., Iwamoto, Keisuke S., Kasahara, Noriyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246057/
https://www.ncbi.nlm.nih.gov/pubmed/25301172
http://dx.doi.org/10.1038/cgt.2014.38
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author Takahashi, Masamichi
Valdes, Gilmer
Hiraoka, Kei
Inagaki, Akihito
Kamijima, Shuichi
Micewicz, Ewa
Gruber, Harry E.
Robbins, Joan M.
Jolly, Douglas J.
McBride, William H.
Iwamoto, Keisuke S.
Kasahara, Noriyuki
author_facet Takahashi, Masamichi
Valdes, Gilmer
Hiraoka, Kei
Inagaki, Akihito
Kamijima, Shuichi
Micewicz, Ewa
Gruber, Harry E.
Robbins, Joan M.
Jolly, Douglas J.
McBride, William H.
Iwamoto, Keisuke S.
Kasahara, Noriyuki
author_sort Takahashi, Masamichi
collection PubMed
description 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, 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 was confirmed in the highly aggressive, radioresistant human glioblastoma cell line U87-EGFRvIII 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.
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spelling pubmed-42460572015-04-10 Radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector Takahashi, Masamichi Valdes, Gilmer Hiraoka, Kei Inagaki, Akihito Kamijima, Shuichi Micewicz, Ewa Gruber, Harry E. Robbins, Joan M. Jolly, Douglas J. McBride, William H. Iwamoto, Keisuke S. Kasahara, Noriyuki Cancer Gene Ther Article 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, 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 was confirmed in the highly aggressive, radioresistant human glioblastoma cell line U87-EGFRvIII 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. 2014-10-10 2014-10 /pmc/articles/PMC4246057/ /pubmed/25301172 http://dx.doi.org/10.1038/cgt.2014.38 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Takahashi, Masamichi
Valdes, Gilmer
Hiraoka, Kei
Inagaki, Akihito
Kamijima, Shuichi
Micewicz, Ewa
Gruber, Harry E.
Robbins, Joan M.
Jolly, Douglas J.
McBride, William H.
Iwamoto, Keisuke S.
Kasahara, Noriyuki
Radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector
title Radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector
title_full Radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector
title_fullStr Radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector
title_full_unstemmed Radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector
title_short Radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector
title_sort radio-sensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246057/
https://www.ncbi.nlm.nih.gov/pubmed/25301172
http://dx.doi.org/10.1038/cgt.2014.38
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