Background and Purpose: Chemotherapeutic agents, including 5‐fluorouracil (5‐FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5‐HT₃ receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5‐HT₃ receptor antagonists on 5‐FU‐induced intestinal mucositis in mice.Experimental Approach: Intestinal mucositis was induced in male C57BL/6 mice by daily administration of 5‐FU (50 mg·kg⁻¹) for 5 days. Effects of 5‐HT₃ receptor antagonists, ramosetron (0.01–0.1 mg·kg⁻¹) and ondansetron (5 mg·kg⁻¹), on the accompanying histology, cytokine production and apoptosis were assessed.Key Results: Continuous administration of 5‐FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea. Daily ramosetron administration dose‐dependently reduced the severity of intestinal mucositis, body weight loss and diarrhoea. Similar beneficial effects were observed with ondansetron. The number of apoptotic, caspase‐3‐ and caspase‐8‐activated cells increased 24 h after the first 5‐FU administration, and these responses were reduced by ramosetron. The up‐regulation of TNF‐α, IL‐1β and IL‐6 following 5‐FU treatment was also attenuated by ramosetron.Conclusions and Implications: 5‐HT₃ receptor antagonists ameliorated 5‐FU‐induced intestinal mucositis in mice, and this action could result from suppression of apoptotic responses in the intestinal crypt cells via inhibition of cytokine expression. Thus, 5‐HT₃ receptor antagonists may be useful for preventing not only nausea and emesis but also intestinal mucositis during 5‐FU chemotherapy.

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.