title: Determining the mechanisms of lapatinib-induced diarrhoea using a rat model.
abstract: BACKGROUND
  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
  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.
authors: School of Medical Sciences, University of Adelaide, Adelaide, 5005, Australia, joanne.bowen@adelaide.edu.au.
authors: Joanne M
authors: JM
authors: Bowen
authors: Bronwen J
authors: BJ
authors: Mayo
authors: Erin
authors: E
authors: Plews
authors: Emma
authors: E
authors: Bateman
authors: Anthony
authors: A
authors: Wignall
authors: Andrea M
authors: AM
authors: Stringer
authors: Frances M
authors: FM
authors: Boyle
authors: Dorothy M K
authors: DM
authors: Keefe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D003967:Diarrhea / Q000139:chemically induced* / Q000473:pathology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D020397:Goblet Cells / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D000077341:Lapatinib; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C483803:Egfr protein, rat; C483804:Erbb2 protein, rat