Author(s): Trinh QT, Austin EA, Murray DM, Knick VC, Huber BE
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Abstract We have been developing an enzyme/prodrug gene therapy approach for the treatment of primary and metastatic tumors in the liver. This system uses the cytosine deaminase/5-fluorocytosine (CD/5-FCyt) enzyme/prodrug combination. Another system that has received considerable attention is the herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) enzyme/prodrug combination. The purpose of the present study was to compare these two enzyme/prodrug systems. The human colorectal tumor cell line, WiDr, was genetically modified to express either the CD gene (WiDr/CD) or the HSV-TK gene (WiDr/TK). The IC50 (concentration of drug producing 50\% inhibition of cell growth) for GCV was approximately 3.4 microM in WiDr/TK cells, while the IC50 for 5-FCyt was approximately 27 microM in WiDr/CD cells. In vivo antitumor studies were conducted using high but nontoxic levels of GCV (50 mg/kg/day) or 5-FCyt (500 mg/kg/day). When tumor xenografts were composed of 100\% of cells expressing either HSV-TK or CD, 100\% tumor-free animals were observed after GCV or 5-FCyt treatment, respectively. However, when only 10\% of the tumor cells expressed HSV-TK, no antitumor effect by GCV treatment could be observed. In contrast, when tumors were composed of 4\% of the cells expressing CD, 60\% of the animals were tumor-free after 5-FCyt treatment. Transmission electron microscopy of the WiDr solid tumors revealed the presence of desmosomes but no gap junctions.
This article was published in Cancer Res
and referenced in Journal of Genetic Syndromes & Gene Therapy