Schedule-dependent cytotoxicity of 5-fluorouracil and irinotecan in a colon cancer cell line

Yasuhiro Inoue, Chikao Miki, Hideki Watanabe, Junichiro Hiro, Yuji Toiyama, Eiki Ojima, Hidenori Yanagi, Masato Kusunoki

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11 Citations (Scopus)


Background: Our aim was to clarify the significance of widely accepted irinotecan (CPT-11)/5-fluorouracil (5-FU) combinations in colon cancer by investigating their sequential effect. Methods: The sequential effect of CPT-11/5-FU in two colon cancer cell lines, LoVo and SW480, was evaluated by WST-8 colorimetric assay. The cell cycle distributions of each drug were analyzed by flow cytometry, and then the chemoresistant mechanisms and expression of a drug transporter (MDR1), the bcl-2 apoptotic pathway, metabolizing enzymes [carboxylesterase (CE), dihydropyrimidine dehydrogenase], and target enzymes (topoisomerase I, thymidine synthase) associated with sequence-dependent cytotoxicity were examined. Results: The cytotoxicity of 5-FU (10, 100, 1000 μM) followed by CPT-11 (1 μM) was significantly greater than that of CPT-11 (1 μM) followed by 5-FU (10, 100, 1000 μM) (P < 0.05). Reverse transcription-polymerase chain reaction analysis revealed that exposure to 5-FU downregulated both MDR1 and bcl-2 mRNA and simultaneously upregulated CE2 mRNA expression, suggesting enhancement of subsequent CPT-11 cytotoxicity. Conclusions: The cytotoxic effects of the CPT-11/5-FU combinations were shown to be schedule-dependent in human colon cancer cells. The findings suggest that 5-FU followed by CPT-11 administration might be the optimal sequence for CPT-11/5-FU treatment of advanced colon cancer.

Original languageEnglish
Pages (from-to)1149-1157
Number of pages9
JournalJournal of Gastroenterology
Issue number12
Publication statusPublished - 12-2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Gastroenterology


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