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Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity.

Abstract
To ascertain whether concomitant expression of Escherichia coli deaminase (CD) and herpes simplex virus type-1 thymidine kinase (HSV-1 TK) could mediate greater levels of cytotoxicity beyond that observed with either suicide gene alone, 9L gliosarcoma cells were transduced with a retrovirus encoding a CD/HSV-1 TK fusion gene. The resultant CD/HSV-1 TK fusion protein (CDglyTK) was found to be bifunctional via CD and HSV-1 TK enzymatic assays, and conferred upon cells prodrug sensitivities equivalent to or better than that observed for each enzyme independently (ganciclovir [GCV] and bromovinyldeoxyuridine [BVdU] for HSV-1 TK and 5-fluorocytosine [5-FC] for CD). Simultaneous treatment of CDglyTK-expressing cells with prodrugs specific for HSV-1 TK and CD (GCV/5-FC or BVdU/5-FC) resulted in slight synergistic toxicity, two- to three-fold greater than that expected if the cytotoxic effects of each prodrug were purely additive. More importantly, co-treatment with HSV-1 TK- and CD-specific prodrugs was found to increase greatly the radiosensitivity of CDglyTK-expressing cells. Sensitivity enhancement ratios of 2.44 (GCV/5-FC) and 3.90 (BVdU/5-FC) were achieved. The results suggest that double suicide gene therapy, using a bifunctional CD/HSV-1 TK fusion gene, coupled with radiotherapy may provide a highly efficient means of selectively treating cancer.
AuthorsK R Rogulski, J H Kim, S H Kim, S O Freytag
JournalHuman gene therapy (Hum Gene Ther) Vol. 8 Issue 1 Pg. 73-85 (Jan 01 1997) ISSN: 1043-0342 [Print] United States
PMID8989997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Enzyme Inhibitors
  • Prodrugs
  • Recombinant Fusion Proteins
  • brivudine
  • Cytosine
  • Flucytosine
  • Thymidine Kinase
  • Nucleoside Deaminases
  • Cytosine Deaminase
  • Bromodeoxyuridine
  • Ganciclovir
  • Deoxyuridine
Topics
  • Blotting, Western
  • Bromodeoxyuridine (analogs & derivatives, pharmacology, toxicity)
  • Cytosine (metabolism)
  • Cytosine Deaminase
  • Deoxyuridine (metabolism)
  • Enzyme Inhibitors (pharmacology, toxicity)
  • Escherichia coli (enzymology)
  • Flucytosine (pharmacology, toxicity)
  • Ganciclovir (pharmacology, toxicity)
  • Gene Expression Regulation, Viral (genetics)
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors (genetics)
  • Gliosarcoma (metabolism)
  • Humans
  • Nucleoside Deaminases (genetics, metabolism)
  • Prodrugs (pharmacology, toxicity)
  • Radiation Tolerance (physiology)
  • Recombinant Fusion Proteins (genetics, isolation & purification, metabolism)
  • Simplexvirus (enzymology)
  • Thymidine Kinase (genetics, metabolism)
  • Tumor Cells, Cultured

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