Kajiwara Taiki, Miura Koh, Ohnuma Shinobu, Shimada Miki, Komura Toshihiro, Toshima Masahide, Kohyama Atsushi, Kudoh Katsuyoshi, Haneda Sho, Musha Hiroaki, Naitoh Takeshi, Shirasaka Tetsuhiko, Unno Michiaki
Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Department of Surgery, Miyagi Cancer Center, 47-1 Nodayama, Medeshima-Shiote, Natori, Miyagi, 981-1293, Japan.
Int J Clin Oncol. 2015 Oct;20(5):913-21. doi: 10.1007/s10147-015-0791-x. Epub 2015 Feb 5.
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.
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.
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.
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.
5-氟尿嘧啶（5-FU）是恶性肿瘤的核心抗癌药物，会引发胃肠道（GI）毒性。尽管肿瘤免疫学最近取得了进展，但胃肠道毒性如何影响抗肿瘤免疫力仍不清楚。S-1是一种基于替加氟的口服5-FU前体药物，已在日本和其他国家广泛应用。有人提出隔日给予S-1可在不降低其抗癌疗效的情况下将其胃肠道及其他毒性降至最低。
在本研究中，对两种S-1给药方案在小鼠中的应用进行了比较，以评估其胃肠道毒性对免疫的影响。在作为标准给药模型的每日给药组中，S-1给药14天，停药14天；在作为非胃肠道毒性模型的隔日给药组中，S-1隔日给药，共28天。除了体格检查结果外，还通过流式细胞术分析了小鼠淋巴组织中的调节性T细胞、Th1细胞和其他细胞。
只有每日给药组出现体重减轻和胃肠道毒性。在每日给药组中，肠道淋巴组织中调节性T细胞的比例被证明比未给予S-1的对照组高六倍，Th1细胞的比例呈下降趋势。然而，隔日给药组的T细胞亚群几乎没有变化。
5-FU的胃肠道毒性可能由于调节性T细胞比例增加和Th1细胞比例降低而对抗肿瘤免疫力产生负面影响。隔日给予S-1可能是一种有用的给药方案，因其对T细胞亚群的影响最小。
