title: 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. NSC-delivered 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.
authors.affiliation: Department of Neurosciences.
authors.forename: Marianne Z
authors.initials: MZ
authors.lastname: Metz
authors.forename: Margarita
authors.initials: M
authors.lastname: Gutova
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
authors.forename: Yelena
authors.initials: Y
authors.lastname: Abramyants
authors.forename: Tien
authors.initials: T
authors.lastname: Vo
authors.forename: Megan
authors.initials: M
authors.lastname: Gilchrist
authors.forename: Revathiswari
authors.initials: R
authors.lastname: Tirughana
authors.forename: Lucy Y
authors.initials: LY
authors.lastname: Ghoda
authors.forename: Michael E
authors.initials: ME
authors.lastname: Barish
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.forename: Joseph
authors.initials: J
authors.lastname: Najbauer
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.forename: Jana
authors.initials: J
authors.lastname: Portnow
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001711:Biotransformation; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D043182:Carboxylesterase / Q000172:deficiency / Q000235:genetics; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005822:Genetic Vectors; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D058953:Neural Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation*; D011817:Rabbits; D013997:Time Factors; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D014161:Transduction, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C469486:Ces1c protein, mouse; D002166:Camptothecin
keywords: CPT-11; Cancer therapy; Carboxylesterase; Glioma; Immunogenicity; Irinotecan; Microdialysis; Neural stem cells