title: Dihydropyrimidine Dehydrogenase Is a Prognostic Marker for Mesenchymal Stem Cell-Mediated Cytosine Deaminase Gene and 5-Fluorocytosine Prodrug Therapy for the Treatment of Recurrent Gliomas.
abstract: We investigated a therapeutic strategy for recurrent malignant gliomas using mesenchymal stem cells (MSC), expressing cytosine deaminase (CD), and prodrug 5-Fluorocytosine (5-FC) as a more specific and less toxic option. MSCs are emerging as a novel cell therapeutic agent with a cancer-targeting property, and CD is considered a promising enzyme in cancer gene therapy which can convert non-toxic 5-FC to toxic 5-Fluorouracil (5-FU). Therefore, use of prodrug 5-FC can minimize normal cell toxicity. Analyses of microarrays revealed that targeting DNA damage and its repair is a selectable option for gliomas after the standard chemo/radio-therapy. 5-FU is the most frequently used anti-cancer drug, which induces DNA breaks. Because dihydropyrimidine dehydrogenase (DPD) was reported to be involved in 5-FU metabolism to block DNA damage, we compared the survival rate with 5-FU treatment and the level of DPD expression in 15 different glioma cell lines. DPD-deficient cells showed higher sensitivity to 5-FU, and the regulation of DPD level by either siRNA or overexpression was directly related to the 5-FU sensitivity. For MSC/CD with 5-FC therapy, DPD-deficient cells such as U87MG, GBM28, and GBM37 showed higher sensitivity compared to DPD-high U373 cells. Effective inhibition of tumor growth was also observed in an orthotopic mouse model using DPD- deficient U87MG, indicating that DPD gene expression is indeed closely related to the efficacy of MSC/CD-mediated 5-FC therapy. Our results suggested that DPD can be used as a biomarker for selecting glioma patients who may possibly benefit from this therapy.
authors.affiliation: 1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.; 2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.; 3. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.; 4. Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.
authors.forename: Taemoon
authors.initials: T
authors.lastname: Chung
authors.affiliation: 1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.; 2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.; 3. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.; 4. Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.
authors.forename: Juri
authors.initials: J
authors.lastname: Na
authors.affiliation: 1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.; 5. Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Kim
authors.affiliation: 7. Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.; 8. Department of Anatomy, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Da-Young
authors.initials: DY
authors.lastname: Chang
authors.affiliation: 4. Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.; 6. Cancer Imaging Center, Seoul National University Hospital, Seoul, Korea.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Kim
authors.affiliation: 2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.; 4. Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.; 6. Cancer Imaging Center, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hyeonjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: 9. Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ho Eun
authors.initials: HE
authors.lastname: Moon
authors.affiliation: 1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.; 2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.; 3. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.affiliation: 1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.; 5. Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: 1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.; 2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.; 3. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.affiliation: 8. Department of Anatomy, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: 8. Department of Anatomy, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Haeyoung
authors.initials: H
authors.lastname: Suh-Kim
authors.affiliation: 9. Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Paek
authors.affiliation: 1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.; 3. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.; 6. Cancer Imaging Center, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Youn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis*; D004195:Disease Models, Animal; D005437:Flucytosine / Q000627:therapeutic use*; D005910:Glioma / Q000628:therapy*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000201:enzymology*; D051379:Mice; D011355:Prodrugs / Q000627:therapeutic use*; D011379:Prognosis; D012008:Recurrence; D033581:Stem Cell Transplantation / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D011355:Prodrugs; D005437:Flucytosine; D042943:Dihydrouracil Dehydrogenase (NADP); D043525:Cytosine Deaminase
keywords: 5-Fluorocytosine (5-FC); 5-Fluorouracil (5-FU); Dihydropyrimidine dehydrogenase (DPD); cytosine deaminase (CD); gene therapy.; mesenchymal stem cells (MSC)