Use of replication-competent retroviral vectors in an immunocompetent intracranial glioma model.

Weijun Wang, Chien Kuo Tai, Allan D. Kershaw, Sounkary K. Solly, David Klatzmann, Noriyuki Kasahara, Thomas C. Chen

Research output: Contribution to journalArticle

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Abstract

OBJECT: The authors had previously reported on a replication-competent retrovirus (RCR) that has been demonstrated to be stable, capable of effective transduction, and able to prolong survival in an intracranial tumor model in nude mice. The purpose of this study was further investigation of this gene therapy option. METHODS: The transduction efficiency of RCR in RG2, an immunocompetent intracranial tumor model, was tested in Fischer 344 rats. The immune response to the RCR vector was expressed by the quantification of CD4, CD8, and CD11/b in tumors. The pharmaceutical efficacy of the suicide gene CD in converting prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) was measured using fluorine-19 nuclear magnetic resonance (19F-NMR) spectroscopy. Animal survival data were plotted on Kaplan-Meier survival curves. Finally, the biodistribution of RCR was determined using quantitative real-time polymerase chain reaction (RT-PCR) for the detection of retroviral env gene. There was no evidence of viral transduction in normal brain cells. Neither severe inflammation nor immunoreaction occurred after intracranial injection of RCR-green fluorescent protein compared with phosphate-buffered saline (PBS). The 19F-NMR spectroscopy studies demonstrated that RCR-CD was able to convert 5-FC to 5-FU effectively in vitro. The infection of RG2 brain tumors with RCR-CD and their subsequent treatment with 5-FC significantly prolonged survival compared with that in animals with RG2 transduced tumors treated with PBS. In contrast to the nude mouse model, evidence of virus dissemination to the systemic organs after intracranial injection was not detected using RT-PCR. CONCLUSIONS: The RCR-mediated suicide gene therapy described in this paper effectively transduced malignant gliomas in an immunocompetent in vivo rodent model, prolonging survival, without evidence of severe intracranial inflammation, and without local transduction of normal brain cells or systemic organs.

Original languageEnglish (US)
JournalNeurosurgical focus [electronic resource].
Volume20
Issue number4
StatePublished - 2006
Externally publishedYes

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Retroviridae
Glioma
Flucytosine
Magnetic Resonance Spectroscopy
Nude Mice
Fluorouracil
Genetic Therapy
Suicide
Real-Time Polymerase Chain Reaction
Neoplasms
Phosphates
Inflammation
env Genes
Injections
Fluorine
Inbred F344 Rats
Prodrugs
Brain
Kaplan-Meier Estimate
Green Fluorescent Proteins

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Use of replication-competent retroviral vectors in an immunocompetent intracranial glioma model. / Wang, Weijun; Tai, Chien Kuo; Kershaw, Allan D.; Solly, Sounkary K.; Klatzmann, David; Kasahara, Noriyuki; Chen, Thomas C.

In: Neurosurgical focus [electronic resource]., Vol. 20, No. 4, 2006.

Research output: Contribution to journalArticle

Wang, Weijun ; Tai, Chien Kuo ; Kershaw, Allan D. ; Solly, Sounkary K. ; Klatzmann, David ; Kasahara, Noriyuki ; Chen, Thomas C. / Use of replication-competent retroviral vectors in an immunocompetent intracranial glioma model. In: Neurosurgical focus [electronic resource]. 2006 ; Vol. 20, No. 4.
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abstract = "OBJECT: The authors had previously reported on a replication-competent retrovirus (RCR) that has been demonstrated to be stable, capable of effective transduction, and able to prolong survival in an intracranial tumor model in nude mice. The purpose of this study was further investigation of this gene therapy option. METHODS: The transduction efficiency of RCR in RG2, an immunocompetent intracranial tumor model, was tested in Fischer 344 rats. The immune response to the RCR vector was expressed by the quantification of CD4, CD8, and CD11/b in tumors. The pharmaceutical efficacy of the suicide gene CD in converting prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) was measured using fluorine-19 nuclear magnetic resonance (19F-NMR) spectroscopy. Animal survival data were plotted on Kaplan-Meier survival curves. Finally, the biodistribution of RCR was determined using quantitative real-time polymerase chain reaction (RT-PCR) for the detection of retroviral env gene. There was no evidence of viral transduction in normal brain cells. Neither severe inflammation nor immunoreaction occurred after intracranial injection of RCR-green fluorescent protein compared with phosphate-buffered saline (PBS). The 19F-NMR spectroscopy studies demonstrated that RCR-CD was able to convert 5-FC to 5-FU effectively in vitro. The infection of RG2 brain tumors with RCR-CD and their subsequent treatment with 5-FC significantly prolonged survival compared with that in animals with RG2 transduced tumors treated with PBS. In contrast to the nude mouse model, evidence of virus dissemination to the systemic organs after intracranial injection was not detected using RT-PCR. CONCLUSIONS: The RCR-mediated suicide gene therapy described in this paper effectively transduced malignant gliomas in an immunocompetent in vivo rodent model, prolonging survival, without evidence of severe intracranial inflammation, and without local transduction of normal brain cells or systemic organs.",
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