Global Research Center for Innovative Life Science, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Int J Mol Sci. 2018 Jan 6;19(1):170. doi: 10.3390/ijms19010170.
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.
伊立替康（CPT-11）具有很强的抗癌作用，但也会引起严重的腹泻等不良反应。本研究通过关注结肠中的水通道水通道蛋白-3（AQP3），分析了 CPT-11 引起迟发性腹泻的发病机制。当大鼠接受 CPT-11 时，严重腹泻时 AQP3 的表达水平降低。研究发现，给予 CPT-11 时，结肠中炎症细胞因子的表达水平升高，隐窝细胞丢失。同时给予抗炎药塞来昔布时，CPT-11 引起的腹泻和 AQP3 表达降低均受到抑制。CPT-11 通过激活巨噬细胞引起大鼠结肠炎症。这些结果表明，CPT-11 给药时，结肠中 AQP3 的表达水平降低，通过阻止水从肠道转运导致迟发性腹泻。此外，AQP3 表达降低可能是由于结肠隐窝细胞丢失引起的炎症以及 CPT-11 直接激活巨噬细胞造成的损伤所致。因此，认为抑制 AQP3 表达降低的抗炎药物可能预防 CPT-11 引起的迟发性腹泻。
