Combined effects of mesenchymal stem cells carrying cytosine deaminase gene with 5-fluorocytosine and temozolomide in orthotopic glioma model

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, and current standard therapy provides modest improvements in progression-free and overall survival of patients. Innate tumor resistance and presence of the blood-brain barrier (BBB) require the development of multi-modal therapeutic regimens. Previously, cytosine deaminase (CD)-expressing mesenchymal stem cells (MSC/CD) were found to exhibit anticancer activity with a wide therapeutic index by converting 5-fluorocytosine (5-FC), a nontoxic prodrug into 5-fluorouracil (5-FU), a potent anticancer drug. In this study, we evaluated the efficacy of MSC/CD in a multi-modal combination regimen with temozolomide (TMZ). Cell viability test, cell cycle, and normalized isobologram analyses were performed. In vivo anticancer effects were tested in a mouse orthotopic glioma model. TMZ and MSC/CD with 5-FC synergistically interacted and suppressed U87 glioma cell line growth in vitro. Combined treatment with TMZ and 5-FU increased cell cycle arrest and DNA breakage. In an orthotopic xenograft mouse model, treatment with TMZ alone suppressed tumor growth; however, this effect was more intense with MSC/CD transplantation followed by the sequential treatment with 5-FC and TMZ. Therefore, we propose that sequential treatment with 5-FC and MSC/CD can be used in patients with GBM during the immediate postoperative period to sensitize tumors to subsequent adjuvant chemo- and radiotherapy.