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

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 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 to controls (p<0.01). Interestingly, CED of RRV-CD followed by 5-FC further enhanced survival in this animal model in comparison to 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 to 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 cytosine deaminase 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.