Theranostics 2016; 6(10):1477-1490. doi:10.7150/thno.14158

Research Paper

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

Taemoon Chung1,2,3,4*, Juri Na1,2,3,4*, Young-il Kim1,5, Da-Young Chang7,8, Young Il Kim4,6, Hyeonjin Kim2,4,6, Ho Eun Moon9, Keon Wook Kang1,2,3, Dong Soo Lee1,5, June-Key Chung1,2,3✉, Sung-Soo Kim8, Haeyoung Suh-Kim8, Sun Ha Paek9, Hyewon Youn1,3,6✉

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.
5. Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea,
6. Cancer Imaging Center, Seoul National University Hospital, Seoul, Korea.
7. Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.
8. Department of Anatomy, Ajou University School of Medicine, Suwon, Korea.
9. Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.
*These authors contributed equally to this research.

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.

Keywords: Dihydropyrimidine dehydrogenase (DPD), 5-Fluorouracil (5-FU), 5-Fluorocytosine (5-FC), mesenchymal stem cells (MSC), cytosine deaminase (CD), gene therapy.

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How to cite this article:
Chung T, Na J, Kim Yi, Chang DY, Kim YI, Kim H, Moon HE, Kang KW, Lee DS, Chung JK, Kim SS, Suh-Kim H, Paek SH, Youn H. 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. Theranostics 2016; 6(10):1477-1490. doi:10.7150/thno.14158. Available from http://www.thno.org/v06p1477.htm