Abstract
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Objectives 5-Fluorocytosine (5-FC) is an attractive prodrug form of 5-Fluorouracil (5-FU) anticancer agent for reducing side effects of 5-FU chemotherapy. DPD has been studied as a rate-limiting factor of 5-FU metabolic pathway. In this study, we monitored the therapeutic efficacy of MSC/CD with 5-FC against in glioblastoma (GBM) cells in vitro and in vivo by molecular imaging and investigated its relationship to DPD gene expression levels in GBM cells.
Methods Human bone marrow derived MSC expressing CD were produced using a retrovial system. Primary GBM cells from a patient (GBM28, GBM37; before and after Temozolomide-radiation therapy) and human glioma cell lines (U373, U87MG) were transducted with luciferase and co-cultured with MSC/CD. The anti-cancer effects of MSC/CD with 5-FC and tumor were monitored by bioluminescence imaging (BLI). The level of 5-FU metabolism related gene expression in GBM cells were analyzed by microarray and real-time PCR. In vivo therapeutic effects of MSC/CD using BALB/c nude mice bearing xenografted tumors was monitored by BLI and MRI.
Results Results: BLI results showed that the anticancer effect of MSC/CD with 5-FC against GBM cells was dependent on both the ratio of MSC to tumor and also the 5-FC dosage. The therapeutic effect showed 30% more sensitive in the lower DPD expressed cells, GBM37 and U87MG, than in GBM28 and U373 cells, respectively. Furthermore, the growth of U87MG tumor xenografts transplanted with MSC/CD was restrained dramatically in compared to control (only U87MG tumor xenografts).
Conclusions In this study, we monitored the anticancer effect of 5-FC with MSC/CD in vitro and in vivo tumor models using molecular imaging according to expression of DPD in GBM cells. Therefore, we could use DPD expression level as a useful therapeutic marker for 5-FC prodrug therapy with MSC/CD.