Gastrointestinal toxicities of 5-fluorouracil increase the proportion of regulatory T cells in intestinal tract: advantages of alternate-day S-1 administration

Taiki Kajiwara, Koh Miura, Shinobu Ohnuma, Miki Shimada, Toshihiro Komura, Masahide Toshima, Atsushi Kohyama, Katsuyoshi Kudoh, Sho Haneda, Hiroaki Musha, Takeshi Naitoh, Tetsuhiko Shirasaka, Michiaki Unno

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Background: 5-Fluorouracil (5-FU), a core anticancer agent for malignancies, induces gastrointestinal (GI) toxicities. Despite recent advances in tumor immunology, it still remains unknown how GI toxicities affect antitumor immunity. S-1 is a tegafur-based oral 5-FU prodrug which has been widely introduced in Japan and other countries. The alternate-day S-1 administration has been proposed to minimize its GI and other toxicities without reducing its anticancer efficacy. Methods: In this study, two S-1 administration regimens were compared in mice to evaluate their impact of GI toxicities on immunity. In the daily group as a standard administration model, S-1 was administered for 14 days on and 14 days off, and in the alternate-day group as a non-GI toxicity model, S-1 was administered every other day for 28 days. As well as physical findings, regulatory T cells, Th1 cells and other cells in murine lymphoid tissues were analyzed with flow cytometry. Results: Only the daily group exhibited body weight loss and GI toxicities. In the daily group, a proportion of regulatory T cells in the intestinal lymphoid tissue were demonstrated to be six-fold higher than in the control without S-1, and the proportion of Th1 cells showed a decreasing trend. However, the alternate-day group exhibited almost no change in T-cell subsets. Conclusion: GI toxicities of 5-FU may have a negative influence on antitumor immunity due to increased proportions of regulatory T cells and decreased proportions of Th1 cells. The alternate-day S-1 administration may be a useful regimen with its minimal influence on T-cell subsets.

Original languageEnglish
Pages (from-to)913-921
Number of pages9
JournalInternational Journal of Clinical Oncology
Issue number5
Publication statusPublished - 2015 Oct 3


  • 5-FU
  • Alternate-day administration
  • Gastrointestinal toxicity
  • Regulatory T cell
  • S-1

ASJC Scopus subject areas

  • Surgery
  • Hematology
  • Oncology


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