title: Targeted inhibition of osteosarcoma tumor growth by bone marrow-derived mesenchymal stem cells expressing cytosine deaminase/5-fluorocytosine in tumor-bearing mice.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) are considered as an attractive approach for gene or drug delivery in cancer therapy. In the present study, the ability of human bone marrow-derived MSCs expressing the cytosine deaminase/5-fluorocytosine prodrug (CD/5-FC MSCs) to target the human osteosarcoma cell line Cal72 was evaluated.
  
  
  METHODS
  The stable CD/5-FC MSC cell line was established by transfection of pEGFP containing the cytosine deaminase gene into MSCs with G418 selection. The anti-tumor effect was verified by a bystander effect assay in vitro and co-injection of Cal72 and CD/5-FC MSCs in cancer-bearing mice.
  
  
  RESULTS
  The therapeutic CD/5-FC MSCs retained the characteristics of multipotent cells, such as differentiation into adipocytes/osteocytes and expression of mesenchymal markers (CD90 and CD44), and showed migration toward Cal72 cells to a greater extent than the native MSCs. The bystander effect assay showed that the CD/5-FC MSCs significantly augmented Cal72 cytotoxicity in direct co-culture and in the presence of 5-FC through the application of conditioned medium. In osteosarcoma-bearing mice, the CD/5-FC MSCs inhibited tumor growth compared to control mice subcutaneously injected with only Cal72 cells.
  
  
  CONCLUSIONS
  Taken together, these findings suggest that CD/5-FC MSCs may be suitable for targeting human osteosarcoma.
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Quynh-Anh
authors: QA
authors: NguyenThai
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Neelesh
authors: N
authors: Sharma
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Do Huynh
authors: do H
authors: Luong
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Simrinder Singh
authors: SS
authors: Sodhi
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Jeong-Hyun
authors: JH
authors: Kim
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Nameun
authors: N
authors: Kim
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Sung-Jong
authors: SJ
authors: Oh
authors: Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju Si, Jeju-do, South Korea.
authors: Dong Kee
authors: DK
authors: Jeong
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D024201:Bystander Effect / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D043525:Cytosine Deaminase / Q000378:metabolism*; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use*; D041722:Genes, Transgenic, Suicide; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy*; D064209:Phytochemicals / Q000494:pharmacology; D019076:Transgenes
chemical_list: D064209:Phytochemicals; D005437:Flucytosine; D043525:Cytosine Deaminase
keywords: bystander effect; cytosine deaminase; mesenchymal stem cell; osteosarcoma; prodrug; tumor tropism