Combined cytosine deaminase expression, 5-fluorocytosine exposure, and radiotherapy increases cytotoxicity to cholangiocarcinoma cells
| Autor: | Matthew S. Mayo, Sreekanth R. Kancharla, David T. Curiel, Murray A. Stackhouse, Donald J. Buchsbaum, Lee C. Pederson, Selwyn M. Vickers |
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| Rok vydání: | 1998 |
| Předmět: |
Antimetabolites
Antineoplastic medicine.medical_treatment Genetic enhancement Cell Genetic Vectors Flucytosine Nucleoside Deaminases law.invention Adenoviridae Cytosine Deaminase Cholangiocarcinoma Radiotherapy High-Energy chemistry.chemical_compound law medicine Tumor Cells Cultured Humans Prodrugs Cytotoxicity business.industry Cytosine deaminase Gastroenterology Genetic Therapy Molecular biology Combined Modality Therapy Radiation therapy Cell killing medicine.anatomical_structure chemistry Bile Duct Neoplasms Recombinant DNA Surgery Fluorouracil business Cytosine |
| Zdroj: | Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2(3) |
| ISSN: | 1091-255X |
| Popis: | Cholangiocarcinoma is a malignancy that is resistant to current therapy. We applied the toxin gene therapy strategy of cytosine deaminase conversion of the nontoxic producing 5-fluorocytosine to 5-fluorouracil combined with radiotherapy to cholangiocarcinoma. The transduction efficiency of SK-ChA-1 cholangiocarcinoma cells was determined by fluorescence-activated cell-sorting analysis following infection with recombinant adenovirus AdCMVLacZ, which encodes thc gene for Beta-galactosidase. To evaluate cytosine deaminase-mediated conversion of 5-fluorocytosine to 5-fluorouracil and subsequent cytotoxicity, SK-ChA-1 cells were infected with the recombinant adenovirus AdCMVCD, which encodes cytosine deaminase, and exposed to 5-fluorocytosine for 6 to 8 days. Additive cytotoxicity of radiation therapy was evaluated by cobalt-60 exposure following AdCMVCD infection and 5-fluorocytosine treatment. SK-ChA-1 cells were transduced (98.4%) by AdCMVLacZ at 100 plaque-forming units per cell. Following infection with AdCMVCD and exposure to 5 to 100 microgram/ml of 5-fluorocytosine, 20% to 64% of SK-ChA-1 cells were killed. A combination of radiation and cytosine deaminase/5-fluorocytosine therapy resulted in enhanced cell killing (83.5% to 91.5%). Cholangiocarcinoma cells were transduced by recombinant adenoviral vectors and were killed by cytosine deaminase-mediated production of 5-fluorouracil. Enhanced cytotoxicity was seen with the addition of external beam radiation. These results provide a foundation for multimodality therapy for human cholangiocarcinoma that combines gene therapy technology with radiation therapy. |
| Databáze: | OpenAIRE |
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