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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 2/2010

01-07-2010 | Original Article

Enhanced 5-fluorouracil cytotoxicity in high cyclooxygenase-2 expressing colorectal cancer cells and xenografts induced by non-steroidal anti-inflammatory drugs via downregulation of dihydropyrimidine dehydrogenase

Authors: Andrea Réti, Éva Pap, Vilmos Adleff, András Jeney, Judit Kralovánszky, Barna Budai

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2010

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Abstract

Purpose

To prove that 5-FU cytotoxicity could be increased by combination with low-dose non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin or NS-398) in high cyclooxygenase-2- (COX-2) expressing cells and xenografts through the modulation of dihydropyrimidine dehydrogenase (DPD) mRNA expression and/or enzyme activity.

Methods

HT-29 cells were grown on collagen IV coated plates (HT-29-C). The antiproliferative effect of 5-fluorouracil (5-FU) ± NSAIDs was examined on non-COX-2 expressing HT-29 and COX-2-expressing HT-29-C cells by sulphorhodamine B assay. The COX-2 and DPD expressions were visualized by immunofluorescent staining, and prostaglandin E2 levels were measured by ELISA kit. The HT-29 xenograft was established in SCID mice and treated with 5-FU ± NSAIDs for 5 days. The tumor volume, enzyme activity, and DPD mRNA expression were investigated by caliper, radioenzymatic method, and real-time RT-PCR, respectively. The drug interaction was calculated for both combinations (5-FU + indomethacin and 5-FU + NS-398).

Results

Collagen IV up-regulated significantly the COX-2 and DPD mRNA, and protein expressions, and also their enzyme activities in HT-29 cells. NSAIDs enhanced in a synergistic manner the cytotoxic effect of 5-FU treatment both in vitro and in vivo. Downregulation of DPD was observed after 5-FU monotherapy, but the combined effect of NSAIDs and 5-FU on DPD mRNA expression, and enzyme activity was superior to the effect of 5-FU alone.

Conclusions

Since 5-FU + NSAID treatment can alter the DPD enzyme activity resulting in an enhanced cytotoxic effect, further studies in clinical practice are warranted.
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Metadata
Title
Enhanced 5-fluorouracil cytotoxicity in high cyclooxygenase-2 expressing colorectal cancer cells and xenografts induced by non-steroidal anti-inflammatory drugs via downregulation of dihydropyrimidine dehydrogenase
Authors
Andrea Réti
Éva Pap
Vilmos Adleff
András Jeney
Judit Kralovánszky
Barna Budai
Publication date
01-07-2010
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-009-1149-8

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