5‐HT3 receptor antagonists ameliorate 5‐fluorouracil‐induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells. (25th February 2013)

• Record Type: Journal Article
• Authors: Yasuda, M; Kato, S; Yamanaka, N; Iimori, M; Matsumoto, K; Utsumi, D; Kitahara, Y; Amagase, K; Horie, S; Takeuchi, K
• Is Part Of: British journal of pharmacology. Volume 168:Number 6(2013:Mar.)
• Page Start: 1388
• Page End: 1400
• Publication Date: 2013-02-25
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12019
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12019-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Chemotherapeutic agents, including 5‐fluorouracil (5‐FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5‐HT<sub>3</sub> receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5‐HT<sub>3</sub> receptor antagonists on 5‐FU‐induced intestinal mucositis in mice.</p> </sec> <sec id="bph12019-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Intestinal mucositis was induced in male C57BL/6 mice by daily administration of 5‐FU (50 mg·kg<sup>−1</sup>) for 5 days. Effects of 5‐HT<sub>3</sub> receptor antagonists, ramosetron (0.01–0.1 mg·kg<sup>−1</sup>) and ondansetron (5 mg·kg<sup>−1</sup>), on the accompanying histology, cytokine production and apoptosis were assessed.</p> </sec> <sec id="bph12019-sec-0003" sec-type="section"> <title>Key Results</title> <p>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.</p> </sec> <sec id="bph12019-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>5‐HT<sub>3</sub> 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‐HT<sub>3</sub> receptor antagonists may be useful for preventing not only nausea and emesis but also intestinal mucositis during 5‐FU chemotherapy.</p> </sec> </abstract>