Saireito (TJ-114), a Japanese traditional herbal medicine, reduces 5-fluorouracil-induced intestinal mucositis in mice by inhibiting cytokine-mediated apoptosis in intestinal crypt cells.

Clinical chemotherapy frequently causes intestinal mucositis as a side effect, which is accompanied by severe diarrhea. We recently showed that the cytokine-mediated apoptotic pathway might be important for the development of intestinal mucositis induced by 5-fluorouracil (5-FU). Saireito, the traditional Japanese herbal (Kampo) medicine, is widely used to treat diarrhea and various inflammatory diseases in Japan. In the present study, we investigated the effect of saireito on 5-FU-induced intestinal mucositis in mice, especially in relation to apoptosis in the intestinal crypt. Male C57BL/6 mice were given 5-FU (50 mg/kg), i.p. once daily for 6 days. Intestinal mucositis was evaluated histochemically. Saireito (100-1000 mg/kg) was administered p.o. twice daily for 6 days. Repeated 5-FU treatment caused severe intestinal mucositis including morphological damage, which was accompanied by body weight loss and diarrhea. Daily administration of saireito reduced the severity of intestinal mucositis in a dose-dependent manner. Body weight loss and diarrhea during 5-FU treatment were also significantly attenuated by saireito administration. The number of apoptotic and caspase-3-activated cells in the intestinal crypt was increased, and was accompanied by up-regulated tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA within 24 h of the first 5-FU injection. However, all of these measures were significantly lower after saireito administration. These results suggest that saireito attenuates 5-FU-induced intestinal mucositis. This action may come from the reduction of apoptosis in the intestinal crypt via suppression of the up-regulation of inflammatory cytokines. Therefore, saireito may be clinically useful for the prevention of intestinal mucositis during cancer chemotherapy

Effect of saireito on apoptosis and caspase-3 activation in the intestinal crypt induced by 5-fluorouracil (5-FU).

<p>5-FU (50 mg/kg) was injected i.p. while saireito (1000 mg/kg) was administered p.o. twice, 30 min before and 8 h after 5-FU injection. The jejunum was excised 24 h after 5-FU injection, sectioned, and TUNEL assay (A, 400×) and cleaved-caspases-3 immunostaining (B, 400×) were performed. The number of apoptotic (C) and caspase-3-activated cells (D) were counted. Data are presented as the mean ± SEM of 6 mice. *<i>P < 0.05</i>, versus control (vehicle alone); ^#<i>P < 0.05</i>, versus normal (5-FU-untreated).</p

Effect of saireito on the anti-tumor action, body weight loss, and diarrhea induced during 5-fluorouracil (5-FU) treatment in Colon 38 tumor-implanted mice.

<p>5-FU (20 mg/kg) was injected i.p. once daily for 6 days (days 7–12), while saireito (1000 mg/kg) was administered p.o. twice daily for 14 days (days 7–21), starting 7 day after tumor implantation. The volume (mm³) of solid tumor (A), body weight (B), and diarrhea score (C) were determined every 2 or 3 days, starting 7 days after the implantation. Data are presented as the mean ± SEM of 6–8 mice. *<i>P < 0.05</i>, versus control (vehicle alone); ^#<i>P < 0.05</i>, versus normal (5-FU-untreated).</p

Three-dimensional high-performance liquid chromatograph pattern of saireito (TJ-114).

<p>Three-dimensional high-performance liquid chromatograph pattern of saireito (TJ-114).</p

Effect of saireito and daikenchuto on changes in body weight and diarrhea during 5-fluorouracil (5-FU) treatment.

<p>5-FU (50 mg/kg) was injected i.p. once daily while saireito (100–1000 mg/kg) and daikenchuto (2700 mg/kg) were administered p.o. twice daily for 6 days (days 0–5). Body weight is shown as a percentage of initial body weight (A), whereas the severity of diarrhea is scored using the four-grade scale (0 to 3) (B). Data are presented as the mean ± SEM of 6–8 mice. *<i>P < 0.05</i> versus control (vehicle alone), ^#<i>P < 0.05</i> versus normal (5-FU-untreated).</p