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- Title
Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model.
- Authors
Secombe, Kate R.; Ball, Imogen A.; Shirren, Joseph; Wignall, Anthony D.; Finnie, John; Keefe, Dorothy; Avogadri-Connors, Francesca; Olek, Elizabeth; Martin, David; Moran, Susan; Bowen, Joanne M.
- Abstract
<bold>Purpose: </bold>Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use is associated with the development of severe diarrhea in up to 40% of patients in the absence of proactive management. We previously developed a rat model of neratinib-induced diarrhea and found inflammation and anatomical disruption in the ileum and colon. Here we tested whether anti-diarrheal interventions, budesonide and colesevelam, can reduce neratinib-induced diarrhea and intestinal pathology.<bold>Methods: </bold>Rats were treated with 50 mg/kg neratinib via oral gavage for 14 or 28 days (total n = 64). Body weight and diarrhea severity were recorded daily. Apoptosis was measured using immunohistochemistry for caspase-3. Inflammation was measured via a multiplex cytokine/chemokine assay. ErbB levels were measured using PCR and Western Blot.<bold>Results: </bold>Budesonide co-treatment caused rats to gain significantly less weight than neratinib alone from day 4 of treatment (P = 0.0418). Budesonide (P = 0.027) and colesevelam (P = 0.033) each reduced the amount of days with moderate diarrhea compared to neratinib alone. In the proximal colon, rats treated with neratinib had higher levels of apoptosis compared to controls (P = 0.0035). Budesonide reduced histopathological injury in the proximal (P = 0.0401) and distal colon (P = 0.027) and increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) compared to rats treated with neratinib alone. In the distal ileum, while budesonide decreased ErbB1 mRNA expression compared to controls (P = 0.018) (PCR), an increase in total ErbB1 protein was detected (P = 0.0021) (Western Blot).<bold>Conclusion: </bold>Both budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.
- Subjects
DIARRHEA; BUDESONIDE; RATS; BREAST cancer; HISTOPATHOLOGY
- Publication
Cancer Chemotherapy & Pharmacology, 2019, Vol 83, Issue 3, p531
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-018-3756-8