Enhancement of the anti-tumor effect of 5 '-deoxy-5-fluorouridine by transfection of thymidine phosphorylase gene into human colon cancer cells

Thymidine phosphorylase (dThdPase) is an enzyme that converts 5'-deoxy-5-fl uorouridine (5' DFUR) to the toric substance 5-fluorouracil (5-FU); it is a lso known to he a platelet-derived endothelial cell growth factor In order to investigate the feasibility of suicide gene therapy against colorectal c ancer by means of the combination of 5' DFUR and the converting enzyme dThd Pase, we transfected the dThdPase gene into the human colon cancer cell lin e SW480 and analyzed the growth pattern as well as the sensitivity to 5-FU or 5' DFUR of the dThdPase-transfected cells. The 50% inhibition (IC50) val ues of 5-FU against the SW480 parental cells, control vector transfected ce lls SW480/V1, and dThdPase-transfected cells SW480/dThdPase were approximat ely 4.9. 6.3 and 2.9 mu M respectively. The IC50 of SW480/dThdPase was lowe r than that of SW480 or SW480/V1, although the differences were not statist ically significant. The IC50 values of 5' DFUR for SW480, SW480/V1, and SW4 80/dThdPase were approximately 300, 330, and 3.2 mu M, respectively, The se nsitivity to 5' DFUR of SW480/dThdPase was increased by about 100-fold comp ared with that of SW480 or SW480/V1. With only. 10% transfection efficacy, a high enough sensitivity to 5' DFUR was obtained to suppress the cell grow th. indicating that a strong bystander effect was induced by this system. T he in vivo growth of the s,c, transplanted SW480/dThdPase tumor in nude mic e was significantly suppressed by i,p, injection of 5' DFUR compared with t hat in control mice that received phosphate-buffered saline (PBS) treatment , These results suggest that gene therapy using the combination of 5' DFUR and the dThdPase gene may he a useful approach for treatment of colon cance r.