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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.

AbstractBACKGROUND:
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.
AuthorsEiji Sasaki, Kazunari Tominaga, Hikaru Kuwamura, Toshio Watanabe, Yasuhiro Fujiwara, Nobuhide Oshitani, Kazuhide Higuchi, Tetsuo Arakawa
JournalJournal of gastroenterology (J Gastroenterol) Vol. 42 Issue 10 Pg. 816-22 (Oct 2007) ISSN: 0944-1174 [Print] Japan
PMID17940834 (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)

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