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Advances in Brief

Enzyme/Prodrug Gene Therapy: Comparison of Cytosine Deaminase/5-Fluorocytosine Versus Thymidine Kinase/Ganciclovir Enzyme/Prodrug Systems in a Human Colorectal Carcinoma Cell Line

Quynh T. Trinh, Elizabeth A. Austin, Doris M. Murray, Vincent C. Knick and Brian E. Huber
Quynh T. Trinh
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Elizabeth A. Austin
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Doris M. Murray
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Vincent C. Knick
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Brian E. Huber
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DOI:  Published November 1995
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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 µm in WiDr/TK cells, while the IC50 for 5-FCyt was approximately 27 µm 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.

Footnotes

  • ↵1 To whom requests for reprints should be addressed, at Division of Cell Biology, Wellcome Research Laboratories, 3030 Cornwallis Road, Research Triangle Park, NC 27709.

  • Received July 27, 1995.
  • Accepted September 19, 1995.
  • ©1995 American Association for Cancer Research.
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November 1995
Volume 55, Issue 21
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Enzyme/Prodrug Gene Therapy: Comparison of Cytosine Deaminase/5-Fluorocytosine Versus Thymidine Kinase/Ganciclovir Enzyme/Prodrug Systems in a Human Colorectal Carcinoma Cell Line
Quynh T. Trinh, Elizabeth A. Austin, Doris M. Murray, Vincent C. Knick and Brian E. Huber
Cancer Res November 1 1995 (55) (21) 4808-4812;

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Enzyme/Prodrug Gene Therapy: Comparison of Cytosine Deaminase/5-Fluorocytosine Versus Thymidine Kinase/Ganciclovir Enzyme/Prodrug Systems in a Human Colorectal Carcinoma Cell Line
Quynh T. Trinh, Elizabeth A. Austin, Doris M. Murray, Vincent C. Knick and Brian E. Huber
Cancer Res November 1 1995 (55) (21) 4808-4812;
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