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 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-5'-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 cytotoxicity of the anthracycline.
van der Heyden
S
S
Laboratory of Cancer Research & Clinical Oncology, Antwerp University, Wilrijk, Belgium.
Gheuens
E
E
van de Vrie
W
W
Van Bockstaele
D
D
Van Oosterom
A
A
Eggermont
A
A
De Bruijn
E A
EA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004351:Drug Resistance; D005434:Flow Cytometry; D005467:Floxuridine / Q000378:metabolism / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011355:Prodrugs; D051381:Rats; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011355:Prodrugs; D005467:Floxuridine; C025034:doxifluridine; D003630:Daunorubicin