20 juin 2013 4 20 /06 /juin /2013 07:26
Cancer Gene Therapy (2013) 20, 336–341; doi:10.1038/cgt.2013.25; published online 24 May 2013 Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model D Yin1, Y Zhai1, H E Gruber2, C E Ibanez2, J M Robbins2, A P Kells1, N Kasahara3, J Forsayeth1, D J Jolly2 and K S Bankiewicz1 1Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA 2Tocagen, San Diego, CA, USA 3Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA Correspondence: Professor KS Bankiewicz, Department of Neurosurgery, University of California San Francisco, 1855 Folsom Street, MCB 226, San Francisco, CA 94103-0555, USA. E-mail: Krystof.Bankiewicz@ucsf.edu Received 4 January 2013; Accepted 20 March 2013 Advance online publication 24 May 2013 Top of page 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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