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Determining the mechanisms of lapatinib-induced diarrhoea using a rat model
Joanne M Bowen1, Bronwen J Mayo, Erin Plews
1School of Medical Sciences, University of Adelaide, Adelaide, 5005, Australia, joanne.bowen@adelaide.edu.au.
Introduction:
Diarrhoea caused by treatment with receptor tyrosine kinase inhibitors (TKI) targeting Epidermal Growth Factor Receptors (EGFR) is an important clinical toxicity in oncology that remains poorly understood. This study aimed to identify histological and molecular changes within the intestine following lapatinib to elucidate mechanisms of diarrhoea related to treatment with this dual EGFR TKI.
Methods And Materials:
Male albino Wistar rats were orally gavaged lapatinib at 100, 240 or 500 mg/kg daily for 4 weeks and assessed for indicators of gastrointestinal injury at the end of each week. Lapatinib in combination with weekly paclitaxel (9 mg/kg i.p.) was also assessed for cumulative injury. At each time point, blood was collected for biochemical analysis. Sections or jejunum and colon were also collected and underwent immunohistochemistry and RT-PCR to detect markers of EGFR pathway signalling, and morphometric analysis to assess changes in mucosal architecture.
Results:
Lapatinib (with or without paclitaxel co-treatment) caused dose-dependent changes in crypt length, mitotic rate and goblet cell morphology. Jejunal crypt expression of EGFR and ErbB2 were decreased, whilst no changes in Erk1/2 were observed. Markers of apoptosis (caspase-3) and proliferation (Ki-67) were only significantly altered in rats treated with both lapatinib and paclitaxel.
Conclusions:
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.
Insights
Lapatinib treatment caused dose-dependent intestinal changes in rats, impacting EGFR signaling and leading to diarrhoea. These findings highlight the need for new interventions to prevent this common side effect in cancer patients.
Area of Science:
- Oncology
- Pharmacology
- Gastroenterology
Background:
- Diarrhoea is a significant toxicity of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) in cancer treatment.
- The precise mechanisms underlying TKI-induced diarrhoea remain poorly understood.
- Lapatinib, a dual EGFR TKI, is associated with this adverse effect.
Purpose of the Study:
- To investigate the histological and molecular changes in the intestine induced by lapatinib.
- To elucidate the mechanisms of diarrhoea associated with dual EGFR TKI treatment.
Main Methods:
- Rats were treated with varying doses of lapatinib, with and without paclitaxel.
- Gastrointestinal injury indicators, biochemical markers, and mucosal architecture were assessed.
- Immunohistochemistry and RT-PCR were used to analyze EGFR pathway signaling and proliferation markers.
Main Results:
- Lapatinib induced dose-dependent alterations in intestinal crypt length, mitotic rate, and goblet cell morphology.
- Jejunal EGFR and ErbB2 expression decreased, while Erk1/2 remained unchanged.
- Apoptosis and proliferation markers were significantly altered only with combination therapy.
Conclusions:
- A novel rat model demonstrated that lapatinib-induced diarrhoea is linked to changes in small intestinal structure and EGFR expression.
- Further research is needed to develop preventative strategies for TKI-induced diarrhoea.
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