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Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model

Cancer Gene Therapy volume 20, pages 336–341 (2013)Cite this article

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Abstract

In the present study, we compared the therapeutic effect of tumor-selective retroviral replicating vectors (RRV) expressing the yeast cytosine deaminase (CD) delivered by convection-enhanced delivery (CED) or simple injection, followed by systemic administration of the pro-drug, 5-fluorocytosine (5-FC). Treatment with RRV-CD and systemic 5-FC significantly increased survival in rodent U87MG glioma model in comparison with controls (P<0.01). Interestingly, CED of RRV-CD followed by 5-FC further enhanced survival in this animal model in comparison with intra-tumoral injection of RRV-CD, followed by systemic 5-FC (P<0.05). High expression levels of Ki-67 were found in untreated tumors compared with treated. Untreated tumors were also much larger than treated. CED resulted in excellent distribution of RRV while only partial distribution of RRV was obtained after injection. Furthermore, RRV-CD and CD were also found in tumors from treated rats at study end points. These results demonstrated that RRV vectors may efficiently transduce and stably propagate in malignant human glioma, thereby achieving a significant in situ amplification effect after initial administration. We conclude that delivery of RRV into the glioma by CED provides much wider vector distribution than simple injection, and this correlated with better therapeutic outcomes.

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Acknowledgements

This study was supported with funds from Tocagen, San Diego, CA, USA and by a translational NIH grant to NK (U01-NS059821).

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Authors and Affiliations

  1. Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA

    D Yin, Y Zhai, A P Kells, J Forsayeth & K S Bankiewicz

  2. Tocagen, San Diego, CA, USA

    H E Gruber, C E Ibanez, J M Robbins & D J Jolly

  3. Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    N Kasahara

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  1. D Yin
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Correspondence to K S Bankiewicz.

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Competing interests

Harry Gruber, Carlos Ibanez, Joan Robbins and Douglas Jolly are employees of Tocagen, which funded this study. Noriyuki Kasahara is a consultant and co-founder of Tocagen and has received research support from the company.

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Yin, D., Zhai, Y., Gruber, H. et al. Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model. Cancer Gene Ther 20, 336–341 (2013). https://doi.org/10.1038/cgt.2013.25

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