title: Neural stem cell-based dual suicide gene delivery for metastatic brain tumors.
abstract: In our previous works, we demonstrated that human neural stem cells (NSCs) transduced with the cytosine deaminase (CD) gene showed remarkable 'bystander killer effect' on glioma and medulloblastoma cells after administration of the prodrug 5-fluorocytosine (5-FC). In addition, herpes simplex virus thymidine kinase (TK) is a widely studied enzyme used for suicide gene strategies, for which the prodrug is ganciclovir (GCV). To apply this strategy to brain metastasis treatment, we established here a human NSC line (F3.CD-TK) expressing the dual suicide genes CD and TK. We examined whether F3.CD-TK cells intensified the antitumor effect on lung cancer brain metastases. In vitro studies showed that F3.CD-TK cells exerted a marked bystander effect on human lung cancer cells after treatment with 5-FC and GCV. In a novel experimental brain metastases model, intravenously administered F3 cells migrated near lung cancer metastatic lesions, which were induced by the injection of lung cancer cells via the intracarotid artery. More importantly, F3.CD-TK cells in the presence of prodrugs 5-FC and GCV decreased tumor size and considerably prolonged animal survival. The results of the present study indicate that the dual suicide gene-engineered, NSC-based treatment strategy might offer a new promising therapeutic modality for brain metastases.
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Natsume
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Motomura
authors.forename: Y
authors.initials: Y
authors.lastname: Nishimira
authors.forename: M
authors.initials: M
authors.lastname: Ohno
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Kinjo
authors.forename: H
authors.initials: H
authors.lastname: Momota
authors.forename: K
authors.initials: K
authors.lastname: Iwami
authors.forename: F
authors.initials: F
authors.lastname: Ohka
authors.forename: T
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: S U
authors.initials: SU
authors.lastname: Kim
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001932:Brain Neoplasms / Q000556:secondary* / Q000628:therapy; D024201:Bystander Effect; D002339:Carotid Arteries / Q000378:metabolism; D002465:Cell Movement; D002470:Cell Survival; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D005437:Flucytosine / Q000008:administration & dosage / Q000494:pharmacology; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D005818:Genetic Engineering / Q000379:methods; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy; D058953:Neural Stem Cells / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D049452:Green Fluorescent Proteins; D005437:Flucytosine; D013937:Thymidine Kinase; D043525:Cytosine Deaminase; D015774:Ganciclovir