TY - JOUR
T1 - Gastrointestinal toxicities of 5-fluorouracil increase the proportion of regulatory T cells in intestinal tract
T2 - advantages of alternate-day S-1 administration
AU - Kajiwara, Taiki
AU - Miura, Koh
AU - Ohnuma, Shinobu
AU - Shimada, Miki
AU - Komura, Toshihiro
AU - Toshima, Masahide
AU - Kohyama, Atsushi
AU - Kudoh, Katsuyoshi
AU - Haneda, Sho
AU - Musha, Hiroaki
AU - Naitoh, Takeshi
AU - Shirasaka, Tetsuhiko
AU - Unno, Michiaki
N1 - Funding Information:
We are grateful to Prof. Naoto Ishii and Dr. Takeshi Kawabe (Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine) for their helpful discussions and technical advice. We also thank Prof. Hiroki Yamaue and Dr. Masaji Tani (Second Department of Surgery, Wakayama Medical University) for their thoughtful comments toward the improvement of the manuscript. The present study was financially supported by the Setsuro Fujii Memorial Osaka Basic Medical Research Foundation (Osaka, Japan), the HIROMI Medical Research Foundation (Sendai, Japan) and the Grant-in-Aid for Scientific Research (KAKENHI) (26461967 and 24591895).
Publisher Copyright:
© 2015, Japan Society of Clinical Oncology.
PY - 2015/10/3
Y1 - 2015/10/3
N2 - 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.
AB - 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.
KW - 5-FU
KW - Alternate-day administration
KW - Gastrointestinal toxicity
KW - Regulatory T cell
KW - S-1
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U2 - 10.1007/s10147-015-0791-x
DO - 10.1007/s10147-015-0791-x
M3 - Article
C2 - 25652909
AN - SCOPUS:84942987191
VL - 20
SP - 913
EP - 921
JO - International Journal of Clinical Oncology
JF - International Journal of Clinical Oncology
SN - 1341-9625
IS - 5
ER -