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

• Published in: Theranostics 2016-01, Vol.6 (10), p.1477-1490
• Main Authors: Chung, Taemoon, Na, Juri, Kim, Young-Il, Chang, Da-Young, Kim, Young Il, Kim, Hyeonjin, Moon, Ho Eun, Kang, Keon Wook, Lee, Dong Soo, Chung, June-Key, Kim, Sung-Soo, Suh-Kim, Haeyoung, Paek, Sun Ha, Youn, Hyewon
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Biomarkers - analysis; Cell Line, Tumor; Cytosine Deaminase - metabolism; Dihydrouracil Dehydrogenase (NADP) - analysis; Disease Models, Animal; Flucytosine - therapeutic use; Glioma - therapy; Humans; Mesenchymal Stromal Cells - enzymology; Mice; Prodrugs - therapeutic use; Prognosis; Recurrence; Research Paper; Stem Cell Transplantation - methods; Treatment Outcome
• ISSN: 1838-7640
• DOI: 10.7150/thno.14158

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.