Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, Hubei 430030, PR China.
Department of Pharmacy, The Central Hospital of Wuhan Affiliated with Tongji Medical College, Huazhong University of Science and Technology, No. 26 Shengli Road, Wuhan, Hubei 430030, PR China.
Biomed Pharmacother. 2018 Oct;106:910-916. doi: 10.1016/j.biopha.2018.07.029. Epub 2018 Jul 12.
5-Fluorouracil (5-FU) is the most frequently prescribed anti-tumor drug, but has been reported to result in intestinal injury. Although some progress has been made in understanding the intestinal toxicity of 5-FU, confusion remains about animal models of 5-FU-induced intestinal injury, especially the dosage of 5-FU. This study aims to assess the dose-response relationship between the severity of intestinal injury and different doses of 5-FU, and to determine a proper dosing for the murine model. We found that mice in the 5-FU groups gradually lost body weight over time. Increasing doses of 5-FU resulted in more severe diarrhea, with a concomitant increase in mortality. Histopathological damage was more severe in mice that received higher doses of 5-FU. In addition, plasma diamine oxidase (DAO) activity decreased in experimental mice with intestinal injury in a dose-dependent way. TUNEL and western blot analysis showed cell apoptosis in the ileum and colon related to 5-FU dosage. However, administration of 200 and 400 mg/kg 5-FU caused extremely high mortality, severe diarrhea and histopathological damage, but 25 mg/kg 5-FU did not result in significant intestinal injury. The severity of intestinal injury induced by 5-FU appeared to be dose-dependent and we concluded that the proper dosage of 5-FU to induce a murine model with intestinal mucositis ranged from 50 mg/kg to 100 mg/kg.
5-氟尿嘧啶（5-FU）是最常被开的抗肿瘤药物，但已被报道会导致肠道损伤。虽然人们在理解 5-FU 的肠道毒性方面已经取得了一些进展，但对于 5-FU 诱导的肠道损伤的动物模型仍然存在混淆，尤其是 5-FU 的剂量。本研究旨在评估肠道损伤严重程度与 5-FU 不同剂量之间的剂量反应关系，并确定用于小鼠模型的适当剂量。我们发现，5-FU 组小鼠的体重逐渐减轻。随着 5-FU 剂量的增加，腹泻更加严重，死亡率也随之增加。接受更高剂量 5-FU 的小鼠的组织病理学损伤更严重。此外，血浆二胺氧化酶（DAO）活性在肠道损伤的实验小鼠中呈剂量依赖性下降。TUNEL 和 Western blot 分析显示，与 5-FU 剂量相关的回肠和结肠细胞凋亡。然而，给予 200 和 400mg/kg 5-FU 会导致极高的死亡率、严重的腹泻和组织病理学损伤，但给予 25mg/kg 5-FU 不会导致明显的肠道损伤。5-FU 诱导的肠道损伤似乎呈剂量依赖性，我们得出结论，诱导肠道黏膜炎的小鼠模型的 5-FU 适当剂量范围为 50mg/kg 至 100mg/kg。
