eight gain and caused significant changes in left ventricular wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers BMS-540215 VEGFR inhibitor of TUNEL positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.
Keywords Animal model, growth factors, EGFR, cardiotoxicity Introduction The epidermal growth factor receptor is the prototypical member of the ERBB family of receptor tyrosine kinases, which also includes ERBB2, ERBB3 and ERBB4. Correspondence: David Threadgill, Department of Genetics, CB#7264, University of North CHIR-124 405168-58-3 Carolina, Chapel Hill, NC 27599, Tel: 919 843 6472, Fax: 919 966 3292, E mail: E mail: [email protected]. Conflict of interest The authors have no conflicts to declare. Publisher,s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Toxicol Appl Pharmacol. Author manuscript, available in PMC 2009 May 18. Published in final edited form as: Toxicol Appl Pharmacol. 2008 May 1, 228: 315 325. doi:10.1016/j.taap.2007.12.012. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Ligand binding induces receptor homo or heterodimerization with subsequent phosphorylation of tyrosine residues in the carboxy terminal tail creating docking sites that initiates intracellular signaling cascades.
It has been estimated that increased or constitutive signaling through EGFR occurs in approximately one third of all human neoplasms, moreover, aberrant signaling is associated with poor prognosis including non responsiveness to traditional chemotherapy and decreased survival. Since the EGFR was first proposed as a cancer drug target almost twenty years ago, advances in drug discovery have produced a plethora of inhibitors targeting the receptor. In particular, tyrosine kinase inhibitors, which block EGFR activity by competing with adenosine triphosphate for binding to the receptor,s kinase pocket, have shown efficacy for several cancer types. Two EGFR TKIs, Gefitinib/Iressa, and Erlotinib/Tarceva,, have received regulatory approval for use in cancer patients while several others are being evaluated in ongoing clinical trials as mono or combinatorial therapies. With the enormous strides that have been made in cancer therapy, and the resultant increases in life expectancy after diagnoses, certain cancers are now perceived