ENHANCEMENT OF DRUG-SENSITIVITY AND A BYSTANDER EFFECT IN PC-9 CELLS TRANSFECTED WITH A PLATELET-DERIVED ENDOTHELIAL CELL GROWTH-FACTOR THYMIDINE PHOSPHORYLASE CDNA

5'-Deoxy-5-fluoroundine (5'-DFUR) and 1-(tetrahydro-2-furyl)-5-fluorou racil (tegafur), prodrugs of 5-fluorouracil (5-FU), are anticancer age nts activated by thymidine phosphorylase (dThdPase). As it is well kno wn that the levels of dThdPase are higher in tumours than in normal ti ssue, it should be advantageous to use such pyrimidine antimetabolites for the selective inhibition of tumour growth. However, tumours are n ot necessarily sensitive to 5'-DFUR and tegafur because their levels o f dThdPase vary. In this study, we examined whether transfection of tu mour cells with a human platelet-derived endothelial cell growth facto r (PD-ECGF) complementary DNA (cDNA) expressing dThdPase would sensiti ze the cells to the cytotoxic effects of pyrimidine antimetabolites in vitro. A cDNA encoding PD-ECGF was transfected into PC-9 cells (human lung adenocarcinoma). The transfected cells, PC9-DPE2, had a more tha n 50 times higher activity of dThdPase than the parental PCS cells or control PC-9 cells transfected with the pcDNA3 vector alone (PCS-D1). They were more sensitive than parental PC-9 or PCS-D 1 cells not only to 5'-DFUR and tegafur but also to 5-FU. In addition, we demonstrated that PC9-DPE2 cells are able to potentiate the cytotoxic effects of 5' -DFUR towards co-cultured parental PC-9 cells. This 'bystander effect' did not require cell-cell contact. These results suggest that transfe ction of PD-ECGF (dThdPase) genes may be useful as a gene therapy stra tegy for cancer treatment.