5'-DEOXY-5-FLUOROURIDINE INCREASES DAUNORUBICIN UPTAKE IN MULTIDRUG-RESISTANT CELLS AND ITS ACTIVITY IS RELATED WITH P-GP-170 EXPRESSION

Most anticancer agents fail to induce clear responses in the treatment of colorectal cancer. This can be explained by involvement of overexp ression of the membrane glycoprotein, P-gp 170, which is associated wi th multidrug resistance (MDR), and/or with involvement of ras. Fluorop yrimidines are amongst the few options in the chemotherapeutic treatme nt of colorectal cancers. 5'-Deoxy-5-fluorouridine (dFUrd) needs intra cellular activation via 5-fluorouracil into 5-fluoro-2'-deoxyuridine-5 '-monophosphate and 5-fluorouridine-5'-triphosphate. In the present st udy, the cytotoxic activity of dFUrd in vitro and dFUrd combined with daunorubicin (DNR) was assessed with the 4,5-dimethylthiazol-2-yl]-2,5 -diphenyltetrazolium) bromide assay in cells with increased P-gp 170 e xpression versus controls. Surprisingly, dFUrd was most active in cell s with high P-gp 170 expression, a finding which can not be explained by intracellular metabolic activity only. The results also show that d FUrd improves the DNR uptake in MDR-positive cells, and this is relate d with increased cytotoxicity of the anthracycline.