SELECTIVE IN-VIVO RADIOSENSITIZATION BY 5-FLUOROCYTOSINE OF HUMAN COLORECTAL-CARCINOMA CELLS TRANSDUCED WITH THE ESCHERICHIA-COLI CYTOSINE DEAMINASE (CD) GENE

Purpose: The E. coil cytosine deaminase (CD) gene encodes an enzyme ca pable of converting the nontoxic prodrug 5-fluorocytosine (5-FC) to 5- fluorouracil (5-FU), a known radiosensitizer. Having previously shown that combined CD suicide gene therapy and radiation (RT) results in pr onounced radiosensitization in vitro, we progressed to in vivo studies of combined therapy. Methods and Materials: WiDr human colon cancer c ells were transduced in vitro with the CD gene and cells expressing CD were selected for use as xenografts in a nude mouse model. After admi nistration of 5-FC, tumors received 10-30 Gy local field radiation (RT ) and tumor growth delay was compared to control animals receiving eit her 5-FU, 5-FC, or RT alone. Results: Maximal growth delay was seen in mice treated with 5-FC for 6 consecutive days prior to RT, Combined t reatment with 15 Gy radiation resulted in a dose-modifying factor (DMF ) of 1.50, and a greater DMF was observed with higher doses of radiati on. There was no appreciable toxicity using this new approach. In cont rast, a similar treatment of combined 5-FU and radiation resulted in c onsiderable toxicity and no appreciable radiosensitization, Conclusion : The present results show that combined suicide gene therapy and RT r esults in pronounced antitumor effect without any notable toxicity. Th is indicates that the CD gene may be useful in the development of nove l treatment strategies combining radiation and gene therapy in the tre atment of locally advanced cancers. (C) 1998 Elsevier Science Inc.