Background/Objectives.Damage of the gastrointestinal mucosa is a major side effect of the anticancer drug 5-fluorouracil (5-FU). Insight into the molecular pathogenesis of 5-FU-induced gut mucositis is expected to justify the strategies of prophylaxis.Methods.We analyzed intestinal specimens obtained from Balb/c mice treated with 70 mg/kg 5-FU daily for up to 6 days.Results.Manifestations of mucositis in the ileum and the colon included diarrhea, weight loss, and morphological lesions. The proteomic analysis revealed dozens of differentially expressed proteins governed by a set of master regulator proteins that regulated downstream pathways culminating in the complexes of specific transcription factors. Among the most important mechanisms of 5-FU-induced gut damage predicted by bioinformatics tools was stimulation of insulin-like growth factor 1 concomitant with inhibition of insulin receptor substrate 1, suggesting an involvement of the insulin pathway. Furthermore, the levels of 14-3-3γ protein and epinephrin B2 tyrosine kinase were interpreted as key inhibitory effects of 5-FU. These changes were detectable in the ileum as well as in the colon, pointing to the commonality of 5-FU responses across the gut.Conclusion.These results demonstrated a hierarchical network of gut injury mechanisms differentially regulated in the course of the emergence of 5-FU-induced mucositis.
背景/目的。胃肠道黏膜损伤是抗癌药物5-氟尿嘧啶（5-FU）的主要副作用。深入了解5-FU诱导肠道黏膜炎的分子发病机制，有望为预防策略提供依据。方法。我们分析了每日给予70 mg/kg 5-FU处理长达6天的Balb/c小鼠的肠道标本。结果。回肠和结肠黏膜炎的表现包括腹泻、体重减轻和形态学损伤。蛋白质组学分析揭示了数十种差异表达蛋白，这些蛋白受一组主调控蛋白调控，进而调控下游通路，最终形成特定转录因子复合物。通过生物信息学工具预测，5-FU诱导肠道损伤最重要的机制之一是胰岛素样生长因子1的刺激伴随胰岛素受体底物1的抑制，提示胰岛素通路参与其中。此外，14-3-3γ蛋白和肾上腺素B2酪氨酸激酶的水平被解释为5-FU的关键抑制作用。这些变化在回肠和结肠中均可检测到，表明5-FU在整个肠道中的反应具有共性。结论。这些结果揭示了在5-FU诱导黏膜炎发生过程中差异调控的肠道损伤机制层级网络。
Proteomic Analysis Identifies Multiple Mechanisms of 5-Fluorouracil-Induced Gut Mucositis in Mice
肿瘤(癌症)患者之家