PMID- 15660382
OWN - NLM
STAT- MEDLINE
DCOM- 20050310
LR  - 20220330
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 41
IP  - 2
DP  - 2005 Feb
TI  - Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in 
      the rat liver with cirrhosis.
PG  - 307-14
AB  - Epidermal growth factor receptor (EGFR) binds transforming growth factor alpha 
      (TGF-alpha) which is mitogenic for hepatocytes. Diverse lines of evidence suggest 
      that activation of the TGF-alpha /EGFR pathway contributes to hepatocellular 
      carcinoma (HCC) formation. Herein, we developed an experimental model of 
      cirrhosis giving rise to HCC and tested the antitumoral effect of gefitinib, a 
      selective EGFR tyrosine kinase inhibitor, in this model. Rats received weekly 
      intraperitoneal injections of diethylnitrosamine (DEN) followed by a 2-week 
      wash-out period that caused cirrhosis in 14 weeks and multifocal HCC in 18 weeks. 
      Hepatocyte proliferation was increased in diseased tissue at 14 weeks compared 
      with control liver and at even higher levels in HCC nodules compared with 
      surrounding diseased tissues at 18 weeks. Increased proliferation was paralleled 
      by upregulation of TGF-alpha messenger RNA expression. A group of DEN-treated 
      rats received daily intraperitoneal injections of gefitinib between weeks 12 and 
      18. In rats treated with gefitinib, the number of HCC nodules was significantly 
      lower than in untreated rats (18.1 +/- 2.4 vs. 3.7 +/- 0.45; P < .05), while EGFR 
      was activated to a lesser extent in the diseased and tumoral tissues of these 
      animals compared with untreated rats. HCC nodules from both untreated and 
      gefitinib-treated animals displayed insulin-like growth factor 2 overexpression 
      that contributed to tumor formation in treated animals. In conclusion, the 
      blockade of EGFR activity by gefitinib has an antitumoral effect on the 
      development of HCC in DEN-exposed rats, suggesting that it may provide benefit 
      for the chemoprevention of HCC.
FAU - Schiffer, Eduardo
AU  - Schiffer E
AD  - INSERM Unit 402, Faculte de Medecine Saint-Antoine et Universite Pierre et Marie 
      Curie, Paris, France.
FAU - Housset, Chantal
AU  - Housset C
FAU - Cacheux, Wulfran
AU  - Cacheux W
FAU - Wendum, Dominique
AU  - Wendum D
FAU - Desbois-Mouthon, Christele
AU  - Desbois-Mouthon C
FAU - Rey, Colette
AU  - Rey C
FAU - Clergue, Francois
AU  - Clergue F
FAU - Poupon, Raoul
AU  - Poupon R
FAU - Barbu, Veronique
AU  - Barbu V
FAU - Rosmorduc, Olivier
AU  - Rosmorduc O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Alkylating Agents)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - 0 (Transforming Growth Factor alpha)
RN  - 3IQ78TTX1A (Diethylnitrosamine)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Alkylating Agents
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Hepatocellular/*prevention & control
MH  - Diethylnitrosamine
MH  - ErbB Receptors/*antagonists & inhibitors/metabolism
MH  - Gefitinib
MH  - Liver Cirrhosis/chemically induced/*complications/pathology/physiopathology
MH  - Liver Neoplasms/*etiology/*prevention & control
MH  - Male
MH  - Quinazolines/*pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction
MH  - Transforming Growth Factor alpha/metabolism
EDAT- 2005/01/22 09:00
MHDA- 2005/03/11 09:00
CRDT- 2005/01/22 09:00
PHST- 2005/01/22 09:00 [pubmed]
PHST- 2005/03/11 09:00 [medline]
PHST- 2005/01/22 09:00 [entrez]
AID - 10.1002/hep.20538 [doi]
PST - ppublish
SO  - Hepatology. 2005 Feb;41(2):307-14. doi: 10.1002/hep.20538.