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Antitumor efficiency of the cytosine deaminase/5-fluorocytosine suicide gene therapy system on malignant gliomas: an in vivo study.

AbstractBACKGROUND:
Suicide gene therapy, particularly that utilizing the cytosine deaminase/5-fluorocytosine (CD/5-FC) system, represents a novel and attractive methodology of cancer research. Mechanistically, the CD enzyme can convert the antifungal agent 5-FC into the antimetabolite agent 5-fluorouracil (5-FU), thereby killing tumor cells. The purpose of this study was to investigate the antitumor efficiency of the CD/5-FC system in malignant gliomas using a nude mouse model.
MATERIAL/METHODS:
The eukaryotic expression plasmid pCMV-CD was transfected into U251 malignant glioma cells. Resistant clones (labeled U251/CD cells) were subsequently isolated and further confirmed by reverse transcription polymerase chain reaction (RT-PCR), immunofluoroscence, and immunoblot. Then U251/CD cells were incubated with 5-FC at various concentrations to measure viability ratios as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. 5-FU concentrations in the media were measured by high-performance liquid chromatography (HPLC). Finally, the volumes and weights of tumors from glioma-bearing nude mice after 5-FC intervention were evaluated.
RESULTS:
The results revealed that the untreated U251 cells were insensitive to 5-FC whereas the U251/CD cells were highly sensitive. Apoptosis and cell death were observed on the U251/CD cells after 5-FC administration. HPLC analysis showed that 5-FU was detected in the U251/CD cell media. These in vivo animal data showed that the volumes and weights of the implanted tumors were dramatically decreased due to cell apoptosis and tumor necrosis.
CONCLUSIONS:
The in vivo results encourage a further investigation in a controlled trial on the treatment of malignant gliomas via the CD/5-FC gene therapy system.
AuthorsSheng-Qing Lv, Ke-Bin Zhang, Eric E Zhang, Fang-You Gao, Chang-Lin Yin, Chun-Ji Huang, Jia-Quan He, Hui Yang
JournalMedical science monitor : international medical journal of experimental and clinical research (Med Sci Monit) Vol. 15 Issue 1 Pg. BR13-20 (Jan 2009) ISSN: 1643-3750 [Electronic] United States
PMID19114960 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA Primers
  • Tetrazolium Salts
  • Thiazoles
  • Flucytosine
  • Cytosine Deaminase
  • thiazolyl blue
  • Fluorouracil
Topics
  • Animals
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Cytosine Deaminase (genetics, metabolism)
  • DNA Primers (genetics)
  • Escherichia coli
  • Flucytosine (metabolism)
  • Fluorescent Antibody Technique
  • Fluorouracil (metabolism, therapeutic use)
  • Genetic Therapy (methods)
  • Glioma (drug therapy, genetics, therapy)
  • Immunoblotting
  • Mice
  • Mice, Nude
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetrazolium Salts
  • Thiazoles

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