5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells

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 (50mg center dot kg1) for 5 days. Effects of 5-HT3 receptor antagonists, ramosetron (0.010.1mg center dot kg1) and ondansetron (5mg center dot kg1), 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-, IL-1 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.