Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant.

Background: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats.

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model.

Background: The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity.

Objectives: The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model.

Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model.

Purpose: 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.

Irinotecan disrupts tight junction proteins within the gut : implications for chemotherapy-induced gut toxicity.

Chemotherapy for cancer causes significant gut toxicity, leading to severe clinical manifestations and an increased economic burden. Despite much research, many of the underlying mechanisms remain poorly understood hindering effective treatment options. Recently there has been renewed interest in the role tight junctions play in the pathogenesis of chemotherapy-induced gut toxicity.