Abstract
While irinotecan (CPT-11) has a potent anti-cancer effect, it also causes serious diarrhea as an adverse reaction. In this study, we analyzed the pathogenic mechanism of CPT-11-induced delayed diarrhea by focusing on water channel aquaporin-3 (AQP3) in the colon. When rats received CPT-11, the expression level of AQP3 was reduced during severe diarrhea. It was found that the expression levels of inflammatory cytokines and the loss of crypt cells were increased in the colon when CPT-11 was administered. When celecoxib, an anti-inflammatory drug, was concomitantly administered, both the diarrhea and the reduced expression of AQP3 induced by CPT-11 were suppressed. The inflammation in the rat colon during diarrhea was caused via activated macrophage by CPT-11. These results showed that when CPT-11 is administered, the expression level of AQP3 in the colon is reduced, resulting in delayed diarrhea by preventing water transport from the intestinal tract. It was also suggested that the reduced expression of AQP3 might be due to the inflammation that occurs following the loss of colonic crypt cells and to the damage caused by the direct activation of macrophages by CPT-11. Therefore, it was considered that anti-inflammatory drugs that suppress the reduction of AQP3 expression could prevent CPT-11-induced delayed diarrhea.
Highlights
Irinotecan (CPT-11) is an anticancer agent that is widely used in the treatment of colon cancer, gastric cancer, pulmonary cancer, and cervical cancer
When CPT-11 was administered via the tail vein at various doses and schedules, early-onset diarrhea was observed within 3 h immediately after administration
The results indicated that diarrhea did not develop in rats receiving CPT-11 at 60 or 80 mg/kg/day for four days, soft stool was observed
Summary
Irinotecan (CPT-11) is an anticancer agent that is widely used in the treatment of colon cancer, gastric cancer, pulmonary cancer, and cervical cancer. After being excreted into the bile, SN-38-glu is deconjugated by enteric bacteria-derived β-glucuronidase in the intestinal tract and is re-converted into the active SN-38 [9,10] This SN-38 is believed to induce severe, persistent diarrhea by damaging the intestinal mucosa and by accumulating in the body via the enterohepatic circulation [11]. We discovered that AQP3 is expressed at significant levels in colonic mucosal epithelial cells and that AQP3 plays a major role in the development of diarrhea and constipation [24,25,26,27] These results led us to consider the possibility that AQP3 in the colon is involved in CPT-11-induced delayed diarrhea and that diarrhea may be prevented from becoming severe by controlling AQP3 expression, thereby preventing dehydration. We investigated the mechanism of the development of CPT-11-induced delayed diarrhea by focusing on AQP3 to discover new preventive methods and/or treatments for CPT-11-induced delayed diarrhea
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