Neural Stem Cell-Mediated Delivery of Irinotecan-Activating Carboxylesterases to Glioma: Implications for Clinical Use

Abstract

CPT-11 (irinotecan) has been investigated as a treatment for malignant brain tumors. However, limitations of CPT-11 therapy include low levels of the drug entering brain tumor sites and systemic toxicities associated with higher doses. Neural stem cells (NSCs) offer a novel way to overcome these obstacles because of their inherent tumor tropism and ability to cross the blood-brain barrier, which enables them to selectively target brain tumor sites. Carboxylesterases (CEs) are enzymes that can convert the prodrug CPT-11 (irinotecan) to its active metabolite SN-38, a potent topoisomerase I inhibitor. We have adenovirally transduced an established clonal human NSC line (HB1.F3.CD) to express a rabbit carboxylesterase (rCE) or a modified human CE (hCE1m6), which are more effective at converting CPT-11 to SN-38 than endogenous human CE. We hypothesized that NSC-mediated CE/CPT-11 therapy would allow tumor-localized production of SN-38 and significantly increase the therapeutic efficacy of irinotecan. Here, we report that transduced NSCs transiently expressed high levels of active CE enzymes, retained their tumor-tropic properties, and mediated an increase in the cytotoxicity of CPT-11 toward glioma cells. CE-expressing NSCs (NSC.CEs), whether administered intracranially or intravenously, delivered CE to orthotopic human glioma xenografts in mice. NSCdelivered CE catalyzed conversion of CPT-11 to SN-38 locally at tumor sites. These studies demonstrate the feasibility of NSC-mediated delivery of CE to glioma and lay the foundation for translational studies of this therapeutic paradigm to improve clinical outcome and quality of life in patients with malignant brain tumors. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:983-992

Non-methylated MGMT as Predictive Factor in Newly Diagnosed Glioblastoma Multiforme Treated with Bevacizumab Concurrent with Radiotherapy Followed by Adjuvant Bevacizumab plus Irinotecan versus Temozolomide Concurrent with Radiotherapy Followed by Adjuvant Temozolomide

“…It resulted in improvement in progression of survival not translated in improvement of overall survival [15]. Irinotecan has marginal activity in recurrent glioblastoma multiforme with progression free survival at 6 months 16% [16]. Irinotecan active metabolite (100-1000 times more active inhibitor of topoisomerse) is 7-ethyl-10-hydroxycamptothecin (SN-38).…”

Clinically applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem gliomas

“…The level of SN-38 (14.28 nM) in this study is the concentration that could reduce the cell viability in vitro, but it may not be enough in vivo. [49][50][51] The low efficacy of the CE gene in vivo may be caused by the low activity of the human enzyme. In contrast to CE, the therapeutic gene, sTRAIL, was successfully expressed in hAT-MSCs, and the protein was secreted into conditioned media in vitro.…”

Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level

“…Since mesenchymal stem cells and neural stem cells can be used in therapeutic delivery for GBM, there is a need to further study the mechanism by which miR-9 is involved in GBM resistance [20–22]. This study reports on the molecular mechanisms by which TMZ-induced miR-9 in GBM cells.…”