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


METHODS
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.


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
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.
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
M
M
Yasuda
S
S
Kato
N
N
Yamanaka
M
M
Iimori
K
K
Matsumoto
D
D
Utsumi
Y
Y
Kitahara
K
K
Amagase
S
S
Horie
K
K
Takeuchi
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003967:Diarrhea / Q000209:etiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005472:Fluorouracil / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052016:Mucositis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017294:Ondansetron / Q000009:adverse effects / Q000627:therapeutic use; D058827:Serotonin 5-HT3 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D001562:Benzimidazoles; D016207:Cytokines; D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D017294:Ondansetron; C071315:ramosetron; D005472:Fluorouracil