Determining the mechanisms of lapatinib-induced diarrhoea using a rat model

Bowen, Joanne M.; Mayo, Bronwen J.; Plews, Erin; Bateman, Emma; Wignall, Anthony; Stringer, Andrea M.; Boyle, Frances M.; Keefe, Dorothy

doi:10.1007/s00280-014-2519-4

Cited by 27 publications

(24 citation statements)

References 28 publications

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“…In a previous rat model of lapatinib‐induced diarhroea, blood biochemistry showed a significant decrease in serum chloride. This decrease coincided with diarrhoea in rats treated with high‐dose lapatinib, suggesting a possible secretory diarrhoea phenotype . However, in the current study we saw no changes in serum chloride suggesting negligible secretory processes.…”

Section: Discussioncontrasting

confidence: 40%

Dacomitinib‐induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats

Sebille

Gibson

Wardill

et al. 2017

Intl Journal of Cancer

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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.

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Section: Discussioncontrasting

confidence: 40%

Dacomitinib‐induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats

Sebille

Gibson

Wardill

et al. 2017

Intl Journal of Cancer

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“…No significant changes were noted in intestinal weights and no significant histopathology was noted in the jejunum or colon, indicating that no significant pathology in the intestines occurred as a result of lapatinib treatment [51]. In fact, it was found that jejunum crypts were significantly longer, and contained increased mitotic cells in rats treated with lapatinib [52]. This is in stark contrast to what is noted in mucositis models of rats treated with chemotherapeutic agents such as irinotecan causing severe intestinal damage and atrophy [14,53].…”

Section: Erbb Tkis and Diarrhoeamentioning

confidence: 78%

“…This is therefore highly suggestive that the mechanism of ErbB TKI-induced diarrhoea is profoundly different from chemotherapy-induced diarrhoea. Further investigation found that serum biochemistry levels of chloride were decreased in rats treated with high dose lapatinib, correlating with diarrhoea incidence, suggesting that chloride loss via the intestinal lumen may be involved in the manifestation of small molecule ErbB TKI induced diarrhoea [52]. However, this was inconclusive.…”

Section: Erbb Tkis and Diarrhoeamentioning

confidence: 97%

ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis

Sebille

Gibson

Wardill

et al. 2015

Cancer Treatment Reviews

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“…34 Furthermore, there were alterations in electrolytes, and a lengthened crypt compartment in the jejunum in a rat lapatinib-induced diarrhoea model. 35 Compromising alterations in the villus–crypt structure are common in weaned pigs. Consistent with previous experiments, our current findings showed that intestine VH was significantly lower and that CD was increased in stress diarrhoea mice compared to control animals.…”

Section: Discussionmentioning

confidence: 99%

The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice

et al. 2016

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Diarrhoea is a common cause of death in children and weaned animals. Recent research has found that serotonin (5-HT) in the gastrointestinal tract plays an important role in regulating growth and the maintenance of mucosa, which protect against diarrhoea. To determine the influence of 5-HT on intestinal epithelium cell renewal under weaned stress diarrhoea, a weaned-stress diarrhoea mouse model was established with senna infusion (15 mL/Kg) via intragastric administration and stress restraint (SR). Mice with an increase in 5-HT were induced by intraperitoneal injection with citalopram hydrobromide (CH, 10 mg/Kg). The results demonstrated that compared with the control animals, diarrhoea appeared in weaned stress mice and the 5-HT content in the small intestine was significantly increased (P<0.05). Further, the caspase-3 cells and cells undergoing apoptosis in the small intestine were significantly increased, but the VH (villus height), V/C (villus height /crypt depth), and PCNA-positive rate significantly decreased. Compared with the control animals, CH increased the intestinal 5-HT content, caspase-3 cells and cells undergoing apoptosis but decreased the VH and V/C. Compared with both control and weaned stress animals, weaned stress animals that were pre-treated with CH showed higher 5-HT concentrations, positive caspase-3 cells and cells undergoing apoptosis but lower VH, V/C and PCNA-positive rate. In vitro, a low concentration of 5-HT inhibit, IEC-6 cell line apoptosis but a higher concentration of 5-HT promoted it. Therefore, weaned stress diarrhoea mice were accompanied by a 5-HT increase in the small intestine and vice versa, and the increase in 5-HT induced by CH caused diarrhoea. In brief, 5-HT and diarrhoea slowed the intestinal epithelium cell renewal and injured the abortion function and mucosal barrier by decreasing VH, V/C and proliferation and increasing epithelium cell apoptosis.

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Determining the mechanisms of lapatinib-induced diarrhoea using a rat model

Abstract: In our novel rat model of lapatinib-induced diarrhoea we have shown that changes in small intestinal morphometry and expression of EGFR are associated with diarrhoea. Further research is required to test intervention agents for the prevention of diarrhoea.

Cited by 27 publications

References 28 publications

Dacomitinib‐induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats

Dacomitinib‐induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats

ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis

The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice

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