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: Taemoon Chung, Juri Na, Young-Il Kim, Da-Young Chang, Young Il Kim, Hyeonjin Kim, Ho Eun Moon, Keon Wook Kang, Dong Soo Lee, June-Key Chung, Sung-Soo Kim, Haeyoung Suh-Kim, Sun Ha Paek, Hyewon Youn
• Journal: Theranostics (Theranostics) Vol. 6 Issue 10 Pg. 1477-90 ( 2016) ISSN: 1838-7640 [Electronic] Australia
• PMID: 27446484 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers
• Prodrugs
• Flucytosine
• Dihydrouracil Dehydrogenase (NADP)
• Cytosine Deaminase

Topics

• 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 Stem Cells (enzymology)
• Mice
• Prodrugs (therapeutic use)
• Prognosis
• Recurrence
• Stem Cell Transplantation (methods)
• Treatment Outcome