title: Antitumor effects of genetically engineered stem cells expressing yeast             cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties.
abstract: Although mortality related with primary tumors is approximately 10%, metastasis             leads to 90% of cancer-associated death. The majority of brain metastases result             from lung cancer, but the metastatic mechanism remains unclear. In general, chemotherapy             for treating brain diseases is disrupted by the brain blood barrier (BBB). As             an approach to improve treatment of lung cancer metastasis to the brain, we employed             genetically engineered stem cells (GESTECs), consisting of neural stem cells (NSCs)             expressing a suicide gene. Cytosine deaminase (CD), one of the suicide genes,             originating from bacterial (bCD) or yeast (yCD), which can convert the non-toxic             prodrug, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU), can inhibit cancer             cell growth. We examined the therapeutic efficacy and migratory properties of             GESTECs expressing yCD, designated as HB1.F3.yCD, in a xenograft mouse model of             lung cancer metastasis to the brain. In this model, A549 lung cancer cells were             implanted in the right hemisphere of the mouse brain, while CM-DiI pre-stained             HB1.F3.yCD cells were implanted in the contralateral brain. Two days after the             injection of stem cells, 5-FC was administered via intraperitoneal injection.             The tumor-tropic effect of HB1.F3.yCD was evident by fluorescent analysis, in             which red-colored stem cells migrated to the lung tumor mass of the contralateral             brain. By histological analysis of extracted brain, the therapeutic efficacy of             HB1.F3.yCD in the presence of 5-FC was confirmed by the reduction in density and             aggressive tendency of lung cancer cells following treatment with 5-FC, compared             to a negative control or HB1.F3.yCD injection without 5-FC. Taken together, these             results indicate that HB1.F3.yCD expressing a suicide gene may be a new therapeutic             strategy for lung cancer metastases to the brain in the presence of a prodrug.
authors.affiliation: Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Bo-Rim
authors.initials: BR
authors.lastname: Yi
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Yun-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Hong Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary / Q000628:therapy*; D002470:Cell Survival / Q000187:drug effects; D043525:Cytosine Deaminase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D005437:Flucytosine / Q000008:administration & dosage / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology*; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000637:transplantation*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil