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Transduction of cytosine deaminase gene makes rat glioma cells highly sensitive to 5-fluorocytosine.

Abstract
To investigate the potential use of E. coli cytosine deaminase (CD) gene instead of the commonly used HSV-TK gene in the gene therapy of brain tumors, we constructed a retrovirus vector carrying the CD gene. We then transduced a rat glioma cell line C6 with CD gene by the retrovirus vector. Transduction of the CD gene made C6 cells become highly sensitive to the anti-fungi drug 5-fluorocytosine (5FC). IC50 for 5FC was 6,000 microM in CD-negative cells, while it was 3 microM in CD-positive cells. Mixed cellular assay showed that CD-positive cells had a strong "bystander effect" on CD-negative cells when exposed to 5FC. Significant anti-tumor effects were observed in nude mice bearing s.c. tumors derived from CD-positive cells when these animals were given 250 mg/kg 5FC twice a day for 20 consecutive days. A marked decrease in tumor weight occurred when a mixture containing 50% CD-positive and 50% CD-negative C6 cells was injected s.c., followed by 5FC treatment, suggesting the bystander effect in vivo. Concerning the pharmacokinetics of 5FC, especially its high oral bio-availability and good penetration into cerebrospinal fluid, we suppose that the combination of CD-gene transfer and 5FC oral administration may have potential use in the gene therapy of brain tumors.
AuthorsK Ge, L Xu, Z Zheng, D Xu, L Sun, X Liu
JournalInternational journal of cancer (Int J Cancer) Vol. 71 Issue 4 Pg. 675-9 (May 16 1997) ISSN: 0020-7136 [Print] United States
PMID9178825 (Publication Type: Journal Article)
Chemical References
  • Antimetabolites, Antineoplastic
  • Recombinant Fusion Proteins
  • Flucytosine
  • Nucleoside Deaminases
  • Cytosine Deaminase
Topics
  • Animals
  • Antimetabolites, Antineoplastic (pharmacology, therapeutic use)
  • Brain Neoplasms (drug therapy, enzymology, pathology)
  • Cytosine Deaminase
  • Drug Resistance, Neoplasm (genetics)
  • Flucytosine (pharmacology, therapeutic use)
  • Genetic Therapy
  • Genetic Vectors (administration & dosage)
  • Glioma (drug therapy, enzymology, pathology)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Nucleoside Deaminases (genetics, metabolism)
  • Rats
  • Recombinant Fusion Proteins (metabolism)
  • Single-Blind Method
  • Transfection
  • Tumor Cells, Cultured (drug effects)

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