Synergistic antitumor effect of combined 5-fluorouracil (5-FU) with 5-chloro-2,4-dihydroxypyridine on 5-FU-resistant gastric cancer cells: possible role of a dihydropyrimidine dehydrogenase-independent mechanism.

Abstract

BACKGROUND:

S-1 is an oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur, a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase (DPD); and potassium oxonate, an agent included to reduce gastrointestinal toxicity. S-1 has a potent antitumor effect on gastric cancer, even in 5-FU-refractory cases. However, there is a lack of basic information to account for this clinical outcome. This study was performed to determine the differences in antitumor effects of combined administration of 5-FU and CDHP between NUGC-3 cells and NUGC-3/5FU/L cells, which are resistant to 5-FU (established by repeated cultures of NUGC-3 with escalating concentrations of 5-FU), and to determine the mechanisms involved.

METHODS:

Both cell lines were incubated with various concentrations of 5-FU and/or CDHP. The antitumor effect was assessed using an MTS assay and cell counts. DPD levels were assayed by using enzyme-linked immunosorbent assay. Expression of DPD and thymidylate synthase (TS) mRNA was quantified using real-time quantitative polymerase chain reaction analysis.

RESULTS:

The combination of 5-FU (IC15) with CDHP exerted a synergistic antitumor effect on NUGC-3/5FU/L, but not on NUGC-3, while CDHP by itself did not affect cell growth in either cell line. Expression of DPD was not detected in NUGC-3/5FU/L. In NUGC-3/5FU/L, 5-FU-enhanced expression of TS mRNA was inhibited by the addition of CDHP. In contrast, in NUGC-3, administration of 5-FU with or without CDHP did not alter TS mRNA expression.

CONCLUSIONS:

The inhibitory mechanism of CDHP, which is independent of DPD, may in part contribute to the antitumor effect of S-1 even in 5-FU-resistant gastric cancer cases.

• Authors: Eiji Sasaki, Kazunari Tominaga, Hikaru Kuwamura, Toshio Watanabe, Yasuhiro Fujiwara, Nobuhide Oshitani, Kazuhide Higuchi, Tetsuo Arakawa
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 42 Issue 10 Pg. 816-22 (Oct 2007) ISSN: 0944-1174 [Print] Japan
• PMID: 17940834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-chlorodihydroxypyridine
• Drug Combinations
• Pyridines
• RNA, Messenger
• S 1 (combination)
• Tegafur
• Oxonic Acid
• Dihydrouracil Dehydrogenase (NADP)
• Thymidylate Synthase
• Fluorouracil

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Dihydrouracil Dehydrogenase (NADP) (drug effects, genetics)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Drug Synergism
• Enzyme-Linked Immunosorbent Assay
• Fluorouracil (administration & dosage, pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• Oxonic Acid (pharmacology)
• Pyridines (administration & dosage, pharmacology)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms (drug therapy, genetics)
• Tegafur (pharmacology)
• Thymidylate Synthase (drug effects, genetics)