title: Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis.
abstract: 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.
authors.affiliation: INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Schiffer
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.forename: Wulfran
authors.initials: W
authors.lastname: Cacheux
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.forename: Christèle
authors.initials: C
authors.lastname: Desbois-Mouthon
authors.forename: Colette
authors.initials: C
authors.lastname: Rey
authors.forename: François
authors.initials: F
authors.lastname: Clergue
authors.forename: Raoul
authors.initials: R
authors.lastname: Poupon
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbu
authors.forename: Olivier
authors.initials: O
authors.lastname: Rosmorduc
mesh_terms: D000477:Alkylating Agents; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control*; D004052:Diethylnitrosamine; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D004052:Diethylnitrosamine; D066246:ErbB Receptors; D000077156:Gefitinib