Enzyme/prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line.
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.[1]References
- Enzyme/prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line. Trinh, Q.T., Austin, E.A., Murray, D.M., Knick, V.C., Huber, B.E. Cancer Res. (1995) [Pubmed]
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