Gastrointestinal Toxicities Of 5-Fu Increase The Proportion Of Regulatory T Cells In Murine Intestinal Tract: Advantages Of Alternate-Day S-1 Administration

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA [Introduction] 5-fluorouracil (5-FU), a core anticancer agent used for various malignancies, induces gastrointestinal (GI) toxicities. The tegafur-based oral 5-FU prodrug S-1 is recognized to be a key drug for GI and other malignancies in Japan and some Asian countries. S-1 was developed to potentiate antitumor activity of 5-FU and to reduce gastrointestinal toxicities. However, S-1 also causes GI toxicities by the standard daily regimen. On the other hand, the alternate-day administration of S-1 has been proposed to minimize toxicities without reducing the anticancer efficacy of 5-FU. Recently, tumor immunology has greatly advanced, and the role of T cells in antitumor immunity has been well investigated. However, it remains unknown how GI toxicities of 5-FU affect T cell subsets related to antitumor immunity. [Purpose] The purpose of this study is to clarify the influence of 5-FU mediated GI toxicities on T cell subsets related to antitumor immunity. [Methods] Two regimens of S-1 were compared to evaluate the impact of GI toxicities of 5-FU on T cells using Balb/c mice. The first regimen consisted of the daily administration of S-1 (daily group) as a 5-FU GI toxicity model, and the second regimen consisted of the alternate-day administration of S-1 (alternate-day group) as a 5-FU non-GI toxicity model. S-1 was orally administered at a dose of 12 mg/kg as tegafur. We then investigated the degree of GI toxicities and T cell subsets in intra-abdominal lymphoid tissues (spleen, mesenteric lymph node and gut-associated lymphoid tissue). [Results] Only the daily group exhibited body weight loss and GI toxicities. Flow cytometric analyses demonstrated that the proportion of regulatory T cells in the intestinal tissue was 6-fold higher in the daily group than that in the control group, and the proportions of Th1 cells in the daily group showed a decreasing trend. However, the alternate-day group exhibited almost no changes in the proportions of T cell subsets. [Conclusions] GI toxicities of 5-FU increase the proportion of regulatory T cells in intestinal tissue and decrease the proportions of Th1 cells systemically, which suggests that GI toxicities of 5-FU have a negative influence on T cell-dependent antitumor immunity, and the alternate-day administration of S-1 has neither GI toxicities nor the influence on T cell subsets, which suggests that 5-FU regimens without GI toxicities are more useful than those with GI toxicities from the viewpoint of antitumor immunity. Citation Format: Taiki Kajiwara, Koh Miura, Shinobu Ohnuma, Tetsuhiko Shirasaka, Toshihiro Komura, Masahide Toshima, Atsushi Kohyama, Katsuyoshi Kudoh, Sho Haneda, Hiroaki Musha, Fuyuhiko Motoi, Yu Katayose, Takeshi Naitoh, Michiaki Unno. Gastrointestinal toxicities of 5-FU increase the proportion of regulatory T cells in murine intestinal tract: Advantages of alternate-day S-1 administration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 631. doi:10.1158/1538-7445.AM2014-631