Experimental Gene Therapy for Brain Tumors Using Adenovirus-Mediated Transfer of Cytosine Deaminase Gene and Uracil Phosphoribosyltransferase Gene with 5-Fluorocytosine
- 1 January 2000
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 11 (1) , 77-89
- https://doi.org/10.1089/10430340050016175
Abstract
Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD+ UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD+ UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.Keywords
This publication has 26 references indexed in Scilit:
- Tissue-Specific, Cell Cycle-Regulated Chimeric Transcription Factors for the Targeting of Gene Expression to Tumor CellsHuman Gene Therapy, 1998
- Regional ‘pro-drug’ gene therapy: intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinomaGene Therapy, 1998
- Regression of Experimental Brain Tumors with 6-Thioxanthine andEscherichia coli gptGene TherapyHuman Gene Therapy, 1997
- Regional Delivery of an Adenovirus Vector Containing the Escherichia coli Cytosine Deaminase Gene to Provide Local Activation of 5-Fluorocytosine to Suppress the Growth of Colon Carcinoma Metastatic to LiverHuman Gene Therapy, 1996
- In VivoAdenovirus-Mediated Gene Transfer of theEscherichia coliCytosine Deaminase Gene to Human Colon Carcinoma-Derived Tumors Induces Chemosensitivity to 5-FluorocytosineHuman Gene Therapy, 1995
- Experimental Tumor Therapy in Mice Using the Cyclophosphamide-Activating Cytochrome P450 2B1 GeneHuman Gene Therapy, 1994
- Gene Transfer into Experimental Brain Tumors Mediated by Adenovirus, Herpes Simplex Virus, and Retrovirus VectorsHuman Gene Therapy, 1994
- An experimental model of retrovirus gene therapy for malignant brain tumorsJournal of Neurosurgery, 1993
- Efficient selection for high-expression transfectants with a novel eukaryotic vectorGene, 1991
- Lymphoma Regression Induced by Ganciclovir in Mice Bearing a Herpes Thymidine Kinase TransgeneHuman Gene Therapy, 1990