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5'-Deoxy-5-fluorouridine increases daunorubicin uptake in multidrug-resistant cells and its activity is related with
S van der Heyden1, E Gheuens, W van de Vrie
1Laboratory of Cancer Research & Clinical Oncology, Antwerp University, Wilrijk, Belgium.
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-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.
Insights
Surprisingly, 5'-Deoxy-5-fluorouridine (dFUrd) shows enhanced anticancer activity in colorectal cancer cells with high P-gp 170 expression, improving daunorubicin (DNR) uptake and efficacy in multidrug resistance (MDR) cases.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Colorectal cancer treatment faces challenges due to multidrug resistance (MDR), often mediated by P-glycoprotein (P-gp 170) overexpression.
- Fluoropyrimidines like 5'-Deoxy-5-fluorouridine (dFUrd) are key chemotherapeutics, requiring intracellular activation.
Purpose of the Study:
- To investigate the in vitro cytotoxic activity of dFUrd, alone and in combination with daunorubicin (DNR), in colorectal cancer cells with varying P-gp 170 expression levels.
- To elucidate the mechanisms underlying dFUrd's efficacy in P-gp 170-overexpressing and multidrug-resistant cells.
Main Methods:
- Cytotoxicity was assessed using the MTT assay in cell lines with induced P-gp 170 expression compared to controls.
- Drug uptake studies were performed to evaluate the effect of dFUrd on daunorubicin (DNR) internalization in MDR-positive cells.
Main Results:
- Unexpectedly, dFUrd demonstrated superior cytotoxic activity in cells with high P-gp 170 expression, suggesting mechanisms beyond simple intracellular metabolism.
- dFUrd significantly enhanced daunorubicin (DNR) uptake in multidrug-resistant (MDR) cells.
- The improved DNR uptake correlated with increased cytotoxicity of the anthracycline in MDR-positive colorectal cancer cells.
Conclusions:
- 5'-Deoxy-5-fluorouridine (dFUrd) exhibits potent activity against P-gp 170-overexpressing colorectal cancer cells.
- dFUrd can overcome multidrug resistance (MDR) by enhancing the cellular uptake of co-administered drugs like daunorubicin (DNR).
- This study highlights dFUrd's potential as a therapeutic agent or sensitizer in treating resistant colorectal cancers.