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.
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Authors | K R Rogulski, J H Kim, S H Kim, S O Freytag |
Journal | Human gene therapy
(Hum Gene Ther)
Vol. 8
Issue 1
Pg. 73-85
(Jan 01 1997)
ISSN: 1043-0342 [Print] United States |
PMID | 8989997
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Enzyme Inhibitors
- Prodrugs
- Recombinant Fusion Proteins
- brivudine
- Cytosine
- Flucytosine
- Thymidine Kinase
- Nucleoside Deaminases
- Cytosine Deaminase
- Bromodeoxyuridine
- Ganciclovir
- Deoxyuridine
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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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