Radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells in culture transduced with cytosine deaminase gene.

Abstract

Recently, use of the suicide gene, cytosine deaminase (CD), has shown a selective antitumor activity of 5-fluorocytosine (5-FC) on human colorectal carcinoma cells grown in vitro and in vivo. We hypothesized that the radiosensitivity of human colorectal carcinoma cells transduced with a retroviral vector encoding the bacterial CD gene would be selectively enhanced by the nontoxic prodrug 5-FC. The radiobiological rationale of using suicide gene therapy is based on the fact that a toxic metabolite of 5-FC, 5-fluorouracil, is a well-known radiation enhancer for the treatment of gastrointestinal and other tumors. 5-FC was found to enhance selectively the radiation cytotoxicity of human colorectal carcinoma cells expressing the CD gene. Colorectal carcinoma cells transduced with the CD gene (WiDr-CD) were highly sensitive to radiation compared with parental cells (WiDr) when exposed to 20 microgram/ml 5-FC for 72 h prior to irradiation. The sensitization enhancement ratio was 2.38. This magnitude of radiation enhancement is comparable to that obtained with 5-fluorouracil. These results suggest that the addition of radiation would substantially improve the therapeutic potential of CD gene therapy for the treatment of locally advanced colorectal carcinomas.