Abstract
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.
Highlights
Intestinal mucositis is a common side effect of clinical chemotherapy for patients with cancer [1, 2], and includes symptoms such as severe diarrhea and dehydration
Apoptosis is a critical event in the occurrence of 5-FU-induced intestinal mucositis [1, 5, 10, 11], since many apoptotic cells are observed in intestinal crypts before serious mucosal destruction in mice and humans [1, 12, 13]
We investigated the effect of saireito on 5-FU-induced intestinal mucositis in mice in comparison with daikenchuto, especially focusing on its relationship with cytokine-mediated apoptosis in the intestinal crypt
Summary
Intestinal mucositis is a common side effect of clinical chemotherapy for patients with cancer [1, 2], and includes symptoms such as severe diarrhea and dehydration. These symptoms can lead to worsened systemic conditions [2,3,4]. We found that 5-FU-induced apoptosis in the crypt was dependent on the upregulation of these cytokines, since 5-FU-induced apoptosis was potently attenuated by inhibiting cytokine expression [14] These findings suggest that cytokine-mediated apoptosis may play a critical role in the pathogenesis of 5-FU-induced intestinal mucositis. Apoptosis may induce intestinal crypt hypoplasia, leading to increased permeability via the destruction of the mucosal barrier. This destruction may lead to increased susceptibility to infection against intestinal bacteria
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