Antitumor effect of gefitinib ('Iressa') on esophageal squamous cell carcinoma cell lines in vitro and in vivo.
High expression of epidermal growth factor receptor (EGFR) is thought to be correlated with cell proliferation, invasion, metastasis, resistance to chemoradiotherapy, and poor prognosis in various kinds of human cancers. Blockade of EGFR signal transduction can be a promising strategy for cancer therapy. Approximately 40-70% of esophageal squamous cell carcinomas (ESCCs) show high expression of EGFR. In this study, we examined the antitumor effect of gefitinib, an EGFR tyrosine kinase inhibitor, against ESCC cells in vitro and in vivo. In three ESCC cell lines (TE8, T.T and T.Tn), cell proliferation had been inhibited in a dose-dependent manner and IC(50) values (respectively, 8.49, 18.9 and 17.3muM). Gefitinib inhibited EGF-induced autophosphorylation of EGFR and its downstream signaling pathways, Ras/Raf/MAPK and PI3K/Akt, and caused G(1) arrest of cell cycle and apoptosis confirmed with flow cytometry. We examined the effect of gefitinib on nude mice bearing established TE8 and T.T xenografts. Gefitinib (100 or 200mg/kg once-daily, p.o.) showed antitumor activity in a dose-dependent manner, resulting in a significantly improved survival of treated mice as compared with untreated mice. Immunohistochemical examination of the harvested tumor was performed to examine the status of phosphorylated EGFR, PCNA, Factor VIII and apoptosis. We found inhibition of EGFR phosphorylation, cell cycle arrest (by PCNA staining), decrease of microvessel density (Factor VIII) and induction of apoptosis by TUNEL staining. In conclusion, our findings demonstrate that gefitinib is effective for growth inhibition of ESCC cell lines in vitro and in vivo and suggest that gefitinib may be one of the new therapeutic options for ESSC.
Hara
Fumikata
F
Department of Cancer and Thoracic Surgery, Okayama University Graduate School Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. fumikata@jf6.so-net.ne.jp
Aoe
Motoi
M
Doihara
Hiroyoshi
H
Taira
Naruto
N
Shien
Tadahiko
T
Takahashi
Hirotoshi
H
Yoshitomi
Seiji
S
Tsukuda
Kazunori
K
Toyooka
Shinichi
S
Ohta
Tetsuya
T
Shimizu
Nobuyoshi
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000096:biosynthesis; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib