Adenoviral-mediated transfer of Escherichia coli uracil phosphoribosyltransferase (UPRT) gene to modulate the sensitivity of the human colon cancer cells to 5-fluorouracil

5-Fluorouracil (5-FU) has been used as a chemotherapeutic drug for colorect al cancer. Escherichia coil uracil phosphoribosyltransferase (UPRT), a pyri midine salvage enzyme, converts 5-FU into 5-fluorouridine monophosphate (5- FUMP) at the initial step of 5-FU activation. WI: investigated the effects of adenoviral-mediated transfer of the E. coli UPRT gene into human colon c ancer cells on 5-FU metabolism and 5-FU chemosensitivity. Three cell lines were used (HT29, KM12 and SW1116). The intracellular levels of 5-fluorodeox yuridine monophosphate (5-FdUMP) and 5-FU incorporated into RNA after 5-FU treatment in cells infected with adenovirus containing the UPRT gene (AdCA- UPRT) were significantly higher than those of non-infected cells. This was accompanied by marked inhibition of thymidylate synthase (TS) in all cell l ines. Furthermore, HT29, KM12 and SW1116 infected with AdCA-UPRT were, resp ectively, 13.1-, 30.2- and 70.5-fold more sensitive to 5-FU than non-infect ed cells. Most importantly, treatment with AdCA-UPRT and 5-FU effectively i nhibited the: growth of HT29-xenografted subcutaneous tumours in nude mice. Therefore, AdCA-UPRT/5-FU treatment had the potential to enhance the actio ns of 5-FU at both the DNA and RNA levels. Treatment augmented the sensitiv ity of human colon cancer cells to 5-FU both in vitro and in vivo. We concl ude that adenoviral-mediated transfer of the E. coli UPRT gene into colon c ancer cells can achieve biochemical modulation of 5-FU and this provides a new approach in the treatment of colorectal cancer. (C) 2000 Elsevier Scien ce Ltd. All rights reserved.