title: Neural stem cell-mediated CE/CPT-11 enzyme/prodrug therapy in transgenic mouse model of intracerebellar medulloblastoma.
abstract: Medulloblastoma is a heterogeneous diffuse neoplasm that can be highly disseminated, and is the most common malignant childhood brain tumor. Although multimodal treatments have improved survival rates for patients with medulloblastoma, these tumors are associated with high morbidity and mortality. New treatment strategies are urgently needed to improve cure rates and, importantly, to spare normal brain tissue from neurotoxicity and patients from life-long cognitive and functional deficits associated with current therapies. In numerous preclinical brain tumor models, neural stem cells (NSCs) have shown great promise as delivery vehicles for therapeutic genes. Here, we have used an established, genetically modified human NSC line (HB1.F3.CD) to deliver carboxylesterase (CE) to cerebellar tumor foci and locally activate the prodrug camptothecin-11 (CPT-11) (Irinotecan) to the potent topoisomerase I inhibitor SN-38. HB1.F3.CD NSC tumor tropism, intratumoral distribution and therapeutic efficacy were investigated in clinically relevant experimental models. Magnetic resonance imaging was used for in vivo tracking of iron nanoparticle-labeled NSCs, and to assess the therapeutic efficacy of CE-expressing HB1.F3.CD cells. As compared with controls, a significant decrease in tumor growth rate was seen in mice that received both NSCs and CPT-11 as their treatment regimen. Thus, this study provides proof-of-concept for NSC-mediated CE/CPT-11 treatment of medulloblastoma, and serves as a foundation for further studies toward potential clinical application.
authors.affiliation: Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010-3000, USA. mgutova@coh.org
authors.forename: M
authors.initials: M
authors.lastname: Gutova
authors.forename: G M
authors.initials: GM
authors.lastname: Shackleford
authors.forename: V
authors.initials: V
authors.lastname: Khankaldyyan
authors.forename: K A
authors.initials: KA
authors.lastname: Herrmann
authors.forename: X-H
authors.initials: XH
authors.lastname: Shi
authors.forename: K
authors.initials: K
authors.lastname: Mittelholtz
authors.forename: Y
authors.initials: Y
authors.lastname: Abramyants
authors.forename: M S
authors.initials: MS
authors.lastname: Blanchard
authors.forename: S U
authors.initials: SU
authors.lastname: Kim
authors.forename: A J
authors.initials: AJ
authors.lastname: Annala
authors.forename: J
authors.initials: J
authors.lastname: Najbauer
authors.forename: T W
authors.initials: TW
authors.lastname: Synold
authors.forename: M
authors.initials: M
authors.lastname: D'Apuzzo
authors.forename: M E
authors.initials: ME
authors.lastname: Barish
authors.forename: R A
authors.initials: RA
authors.lastname: Moats
authors.forename: K S
authors.initials: KS
authors.lastname: Aboody
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D043182:Carboxylesterase / Q000235:genetics*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D000077146:Irinotecan; D008527:Medulloblastoma / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000201:enzymology; D011355:Prodrugs / Q000627:therapeutic use*; D033581:Stem Cell Transplantation; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin