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Type: Journal article
Title: Determining the mechanisms of lapatinib-induced diarrhoea using a rat model
Author: Bowen, J.
Mayo, B.
Plews, E.
Bateman, E.
Wignall, A.
Stringer, A.
Boyle, F.
Keefe, D.
Citation: Cancer Chemotherapy and Pharmacology, 2014; 74(3):617-627
Publisher: Springer-Verlag
Issue Date: 2014
ISSN: 0344-5704
Statement of
Joanne M. Bowen, Bronwen J. Mayo, Erin Plews, Emma Bateman, Anthony Wignall, Andrea M. Stringer, Frances M. Boyle, Dorothy M. K. Keefe
Abstract: 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.
Keywords: Intestines
Intestinal Mucosa
Goblet Cells
Rats, Wistar
Disease Models, Animal
Receptor, erbB-2
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Protein Kinase Inhibitors
ErbB Receptors
Rights: © Springer-Verlag Berlin Heidelberg 2014
DOI: 10.1007/s00280-014-2519-4
Appears in Collections:Aurora harvest 2
Medical Sciences publications

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