5'-Deoxy-5-fluorouridine increases daunorubicin uptake in multidrug-resistant cells and its activity is related with P-gp 170 expression.

Abstract

Most anticancer agents fail to induce clear responses in the treatment of colorectal cancer. This can be explained by involvement of overexpression of the membrane glycoprotein, P‐gp 170, which is associated with multidrug resistance (MDR), and/or with involvement of ras. Fluoropyrimidines are amongst the few options in the chemotherapeutic treatment of colorectal cancers. 5′‐Deoxy‐5‐fluorouridine (dFUrd) needs intracellular activation via 5‐fluorouracil into 5‐fluoro‐2′‐deoxyuridine‐5′‐monophosphate and 5‐fluorouridine‐S′‐triphosphate. In the present study, the cytotoxic activity of dFUrd in vitro and dFUrd combined with daunorubicin (DNR) was assessed with the (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium) bromide assay in cells with increased P‐gp 170 expression versus controls. Surprisingly, dFUrd was most active in cells with high P‐gp 170 expression, a finding which can not be explained by intracellular metabolic activity only. The results also show that dFUrd improves the DNR uptake in MDR‐positive cells, and this is related with increased cyto‐toxicity of the anthracycline.