Document Detail


Effect and risk of AEE788, a dual tyrosine kinase inhibitor, on regeneration in a rat liver resection model.
MedLine Citation:
PMID:  20090347     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: AEE788, a dual tyrosine kinase inhibitor, has antiproliferative effects on diverse tumor models in mice. We aimed to investigate whether AEE788 blocks liver regeneration and causes drug-related side effects. METHODS: Rats treated orally with 50 mg/kg AEE788 or solvent every 2 days were subjected to 70% partial hepatectomy (PH) and sacrificed on postoperative days 1, 2, 7, and 28. Liver regeneration was evaluated using liver weight to body weight ratio, BrdU-staining, mitotic index, and PCR for PCNA (proliferating cell nuclear antigen). Side effects on the gastrointestinal system and liver were assessed using clinical chemistry, histology, silver staining, and immunohistochemistry. Plasma and liver tissue levels of AEE788 were measured using spectrometry. RESULTS: AEE788 treatment did not inhibit liver regeneration. No obvious drug-related systemic or hepatic side effects were observed. Restoration of liver architecture during liver regeneration was not obviously impaired, even after 4 weeks' AEE788 treatment. After a 1-week treatment, AEE788 concentrations in plasma and liver tissue in the PH group were 3-fold and 8-fold higher than the non-PH group, respectively. CONCLUSION: Its antiproliferative properties, good tolerance, and lack of inhibition on liver regeneration make AEE788 a potential candidate for clinical study with oncological PH, but one that carries the risk of overexposure in the early postoperative phase.
Authors:
M Deng; H Huang; O Dirsch; U Dahmen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-19
Journal Detail:
Title:  European surgical research. Europ?ische chirurgische Forschung. Recherches chirurgicales europ?ennes     Volume:  44     ISSN:  1421-9921     ISO Abbreviation:  Eur Surg Res     Publication Date:  2010  
Date Detail:
Created Date:  2010-02-26     Completed Date:  2010-05-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0174752     Medline TA:  Eur Surg Res     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  82-95     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2010 S. Karger AG, Basel.
Affiliation:
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstrasse 55, Essen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Body Weight
Cell Division / drug effects*
Colorectal Neoplasms / complications
Hepatectomy
Injections, Intravenous
Liver Neoplasms / secondary,  surgery*
Liver Regeneration / drug effects*
Male
Mice
Mitotic Index
Neoplasm Metastasis
Organ Size
Phosphorylation
Protein-Tyrosine Kinases / antagonists & inhibitors*
Purines / administration & dosage,  adverse effects*,  pharmacology*,  therapeutic use
Rats
Rats, Inbred Lew
Receptor, Epidermal Growth Factor / antagonists & inhibitors*,  metabolism
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/AEE 788; 0/Purines; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/Receptors, Vascular Endothelial Growth Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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