Expression of CYP2A6 in tumor cells augments cellular sensitivity to tegafur

To examine the role of cytochrome P450 2A6 (CYP2A6) in the cellular sensitivity to an anti-tumor prodrug, tegafur (FT), a CYP2A6 cDNA construct was transfected into cells of a colon cancer cell line, DLD-1. CYP2A6-expressing cells (DLD-1 / CYP2A6 cells) more efficiently catalyzed the conversion of FT to 5-fluorouracil (5-FU) (2.6-fold) and the 7-hydroxylation of coumarin (7.9-fold) than cells transfected with a null construct (DLD-1 / null cells). These results indicated that the expressed CYP2A6 was functionally active. The extent of growth inhibition of the DLD-1 / CYP2A6 cells by FT was greater than that of DLD-1 / null cells; the difference between the DLD-1 / CYP2A6 and DLD-1 / null cells was statistically significant at the concentrations of 250, 500 and 1000 mM. 5-FU, an active metabolite of FT, inhibited the growth of both types of cells to the same extent. Thus, intracellular expression of CYP2A6 can sensitize cells to FT.