title: Gastrointestinal toxicities of 5-fluorouracil increase the proportion of regulatory T cells in intestinal tract: advantages of alternate-day S-1 administration.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Taiki
authors: T
authors: Kajiwara
authors: Department of Surgery, Miyagi Cancer Center, 47-1 Nodayama, Medeshima-Shiote, Natori, Miyagi, 981-1293, Japan. kou-miura@miyagi-pho.jp.
authors: Koh
authors: K
authors: Miura
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Shinobu
authors: S
authors: Ohnuma
authors: Pharmaceutical Department, Tottori University Hospital, Yonago, Tottori, 683-8504, Japan.
authors: Miki
authors: M
authors: Shimada
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Toshihiro
authors: T
authors: Komura
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Masahide
authors: M
authors: Toshima
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Atsushi
authors: A
authors: Kohyama
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Katsuyoshi
authors: K
authors: Kudoh
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Sho
authors: S
authors: Haneda
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Hiroaki
authors: H
authors: Musha
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Takeshi
authors: T
authors: Naitoh
authors: Kitasato Institute for Life Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors: Tetsuhiko
authors: T
authors: Shirasaka
authors: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors: Michiaki
authors: M
authors: Unno
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D004195:Disease Models, Animal; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000276:immunology*; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010094:Oxonic Acid / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D005641:Tegafur / Q000008:administration & dosage*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil
keywords: 5-FU; Alternate-day administration; Gastrointestinal toxicity; Regulatory T cell; S-1
references: N Engl J Med. 2005 Dec 22;353(25):2654-66
references: 16371631
references: Curr Opin Immunol. 2009 Apr;21(2):200-8
references: 19285848
references: Int J Clin Oncol. 2004 Jun;9(3):143-8
references: 15221596
references: Anticancer Res. 2008 Nov-Dec;28(6A):3785-91
references: 19189665
references: Int J Cancer. 2010 Aug 15;127(4):759-67
references: 20518016
references: Cancer Sci. 2010 Sep;101(9):1947-54
references: 20550524
references: Lancet Oncol. 2010 Sep;11(9):853-60
references: 20708966
references: Biosci Biotechnol Biochem. 2009 Aug;73(8):1732-40
references: 19661699
references: Cancer Res. 2011 Nov 15;71(22):6915-20
references: 22068034
references: Int J Clin Oncol. 2015 Feb;20(1):117-25
references: 24802097
references: Anticancer Res. 2008 Jan-Feb;28(1B):373-8
references: 18383872
references: Hepatogastroenterology. 2011 Mar-Apr;58(106):352-8
references: 21661395
references: J Clin Oncol. 2011 Dec 20;29(36):4828-36
references: 22042955
references: Immunol Rev. 2011 May;241(1):241-59
references: 21488901
references: Cancer Sci. 2013 Jan;104(1):116-23
references: 23066919
references: Cancer Chemother Pharmacol. 2011 Sep;68(3):713-20
references: 21153821
references: Scand J Gastroenterol. 2012 Apr;47(4):367-77
references: 22229663
references: Cancer Res. 1996 Jun 1;56(11):2602-6
references: 8653704
references: Cancer Chemother Pharmacol. 2006 Aug;58(2):183-8
references: 16317557
references: Science. 2006 Sep 29;313(5795):1960-4
references: 17008531
references: Cancer Chemother Pharmacol. 2014 Jan;73(1):97-102
references: 24146260
references: Cancer Res. 2011 Feb 15;71(4):1263-71
references: 21303976
references: Nat Rev Immunol. 2006 Apr;6(4):295-307
references: 16557261
references: PLoS One. 2006 Dec 27;1:e129
references: 17205133
references: J Clin Oncol. 2009 Jan 10;27(2):186-92
references: 19064967
references: J Immunol. 2013 Jun 1;190(11):5788-98
references: 23610141
references: N Engl J Med. 2007 Nov 1;357(18):1810-20
references: 17978289
references: JPEN J Parenter Enteral Nutr. 2005 Nov-Dec;29(6):395-400
references: 16224030
references: Eur J Immunol. 2010 Jul;40(7):1830-5
references: 20583029
references: Jpn J Clin Oncol. 2009 Jan;39(1):2-15
references: 19052037
references: Int J Clin Oncol. 2008 Dec;13(6):515-20
references: 19093179
references: Nature. 2011 Dec 21;480(7378):480-9
references: 22193102
references: Gastric Cancer. 2014;17(3):508-13
references: 23948997
references: Semin Immunol. 2011 Dec;23(6):424-30
references: 22055883
references: Int J Clin Oncol. 2010 Apr;15(2):166-71
references: 20195683
references: Expert Opin Drug Deliv. 2012 Mar;9(3):273-86
references: 22235991
references: Int J Cancer. 2003 Nov 1;107(2):303-8
references: 12949812
references: Int Immunol. 2001 Apr;13(4):519-28
references: 11282991
references: Cancer Res. 2010 Apr 15;70(8):3052-61
references: 20388795