title: Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.
abstract: High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in-human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma.
authors: Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA. kaboody@coh.org
authors: Karen S
authors: KS
authors: Aboody
authors: Joseph
authors: J
authors: Najbauer
authors: Marianne Z
authors: MZ
authors: Metz
authors: Massimo
authors: M
authors: D'Apuzzo
authors: Margarita
authors: M
authors: Gutova
authors: Alexander J
authors: AJ
authors: Annala
authors: Timothy W
authors: TW
authors: Synold
authors: Larry A
authors: LA
authors: Couture
authors: Suzette
authors: S
authors: Blanchard
authors: Rex A
authors: RA
authors: Moats
authors: Elizabeth
authors: E
authors: Garcia
authors: Soraya
authors: S
authors: Aramburo
authors: Valerie V
authors: VV
authors: Valenzuela
authors: Richard T
authors: RT
authors: Frank
authors: Michael E
authors: ME
authors: Barish
authors: Christine E
authors: CE
authors: Brown
authors: Seung U
authors: SU
authors: Kim
authors: Behnam
authors: B
authors: Badie
authors: Jana
authors: J
authors: Portnow
mesh_terms: D000818:Animals; D002460:Cell Line; D043525:Cytosine Deaminase / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005437:Flucytosine / Q000378:metabolism / Q000627:therapeutic use; D005472:Fluorouracil / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil
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