Van Sebille Ysabella Z A, Gibson Rachel J, Wardill Hannah R, Secombe Kate R, Ball Imogen A, Keefe Dorothy M K, Finnie John W, Bowen Joanne M
Cancer Treatment Toxicities Group, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
Division of Health Sciences, University of South Australia, Adelaide, Australia.
Int J Cancer. 2017 Jun 15;140(12):2820-2829. doi: 10.1002/ijc.30699. Epub 2017 Mar 28.
Dacomitinib-an irreversible pan-ErbB tyrosine kinase inhibitor (TKI)-causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1-4 μM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays. Rats were treated with 7.5 mg/kg dacomitinib daily via oral gavage for 7 or 21 days (n = 6/group). Weights, and diarrhoea incidence were recorded daily. Rats were administered FITC-dextran 2 hr before cull, and serum levels of FITC-dextran were measured and serum biochemistry analysis was conducted. Detailed histopathological analysis was conducted throughout the gastrointestinal tract. Gastrointestinal expression of ErbB1, ErbB2 and ErbB4 was analysed using RT-PCR. The ileum and the colon were analysed using multiplex for expression of various cytokines. T84 cells treated with dacomitinib showed no alteration in TEER or cell viability. Rats treated with dacomitinib developed severe diarrhoea, and had significantly lower weight gain. Further, dacomitinib treatment led to severe histopathological injury localised to the ileum. This damage coincided with increased levels of MCP1 in the ileum, and preferential expression of ErbB1 in this region compared to all other regions. This study showed dacomitinib induces severe ileal damage accompanied by increased MCP1 expression, and gastrointestinal permeability in rats. The histological changes were most pronounced in the ileum, which was also the region with the highest relative expression of ErbB1.
达可替尼——一种不可逆的泛表皮生长因子受体（ErbB）酪氨酸激酶抑制剂（TKI）——导致75%的患者出现腹泻。此前尚未对达可替尼所致腹泻进行过研究，其机制仍知之甚少。本研究旨在建立达可替尼所致腹泻的体外和体内模型，以探究潜在机制。用1 - 4μM达可替尼处理T84细胞，使用跨上皮电阻（TEER）和XTT试验测量其抗性和活力。大鼠每天经口灌胃给予7.5mg/kg达可替尼，持续7天或21天（每组n = 6）。每天记录体重和腹泻发生率。在处死前2小时给大鼠注射异硫氰酸荧光素（FITC）标记的葡聚糖，测量血清中FITC - 葡聚糖水平并进行血清生化分析。对整个胃肠道进行详细的组织病理学分析。使用逆转录聚合酶链反应（RT - PCR）分析胃肠道中ErbB1、ErbB2和ErbB4的表达。使用多重分析法分析回肠和结肠中各种细胞因子的表达。用达可替尼处理的T84细胞的TEER或细胞活力无变化。用达可替尼处理的大鼠出现严重腹泻，体重增加显著降低。此外，达可替尼治疗导致回肠出现严重的组织病理学损伤。这种损伤与回肠中单核细胞趋化蛋白1（MCP1）水平升高以及该区域与所有其他区域相比ErbB1的优先表达相一致。本研究表明，达可替尼可诱导大鼠回肠严重损伤，伴有MCP1表达增加和胃肠道通透性增加。组织学变化在回肠最为明显，而回肠也是ErbB1相对表达最高的区域。
