1. ¹Department of Neurosurgery, Sungkyunkwan University School of Medicine, Seoul, Korea
2. ²Cancer Stem Cell Research Center, Samsung Medical Center and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
3. ³Institute for Regenerative Medicine, Gachon University Gil Hospital, Inchon, Korea
4. ⁴Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence: Seung U. Kim, Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia V6T2B5, Canada. E-mail: sukim@interchange.ubc.ca; Do-Hyun Nam, Department of Neurosurgery, Samsung Medical Center and Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku,50 Ilwon-dong, Kangnam-gu, Seoul 135-710, Korea. E-mail: nsnam@skku.edu

The first two authors contributed equally to this work.

Received 27 March 2008; Accepted 25 November 2008; Published online 6 January 2009.

Abstract

The tumor-tropic properties of neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to tumors in the brain. To apply this strategy to the treatment of brain metastases, we made a human NSC line expressing cytosine deaminase (F3.CD), which converts 5-fluorocytosine (5-FC) into 5-fluorouracil, an anticancer agent. In vitro, the F3.CD cells significantly inhibited the growth of tumor cell lines in the presence of the prodrug 5-FC. In vivo, MDA-MB-435 human breast cancer cells were implanted into the brain of immune-deficient mouse stereotactically, and F3.CD cells were injected into the contralateral hemisphere followed by systemic 5-FC administration. The F3.CD cells migrated selectively into the brain metastases located in the opposite hemisphere and resulted in significantly reduced volumes. The F3.CD and 5-FC treatment also decreased both tumor volume and number of tumor mass significantly, when immune-deficient mouse had MDA-MB-435 cells injected into the internal carotid artery and F3.CD cells were transplanted into the contralateral brain hemisphere stereotactically. Taken together, brain transplantation of human NSCs, encoding the suicide enzyme CD, combined with systemic administration of the prodrug 5-FC, is an effective treatment regimen for brain metastases of tumors.