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Synergistic Antitumor Activity of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib and IFN- in Head and Neck Cancer Cells In vitro and In vivo

Authors' Affiliations: ¹ Experimental Pharmacology Unit, Department of Experimental Oncology, ² Division of Medical Oncology A, and ³ Animal Facility, National Cancer Institute G. Pascale; ⁴ Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Naples, Italy; and ⁵ Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy

Requests for reprints: Alfredo Budillon, Experimental Pharmacology Unit, Department of Experimental Oncology, National Cancer Institute G. Pascale, via M. Semmola 80131, Naples, Italy. Phone: 39-815903292; Fax: 39-815903813; E-mail: budillon{at}fondazionepascale.it.

Purpose: Epidermal growth factor receptor (EGFR) overexpression has been implicated in the development of head and neck squamous cell carcinomas (HNSCC) and represents a potential therapeutic target for this disease. We have reported previously that growth inhibitory concentrations of IFN- enhance the expression and activity of EGFR and that this effect could represent an escape mechanism to the growth inhibition and apoptotic cell death induced by IFN-. In this study, we investigate whether the combination of IFN- and gefitinib (Iressa, AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom), a selective EGFR tyrosine kinase inhibitor, might have a cooperative antitumor effect on HNSCC-derived cell lines.

Experimental Design: The interaction of IFN- and gefitinib was evaluated in vitro on HNSCC-derived cell lines by median drug effect analysis calculating a combination index with CalcuSyn software and in vivo by using HNSCC xenografts in nude mice. The mechanism of gefitinib and IFN- interactions was also studied by analysis of cell cycle kinetics, apoptosis assays, and Western blotting of EGFR signal transduction components.

Results: Simultaneous exposure to gefitinib and IFN- produced synergistic antiproliferative and proapoptotic effects compared with single drug treatment. Furthermore, daily treatment of gefitinib (50 mg/kg p.o.) in combination with an IFN- regimen (50,000 units s.c. three times weekly) induced tumor growth delay and increased survival rate on established HNSCC xenografts in nude mice. Moreover, the concomitant treatment with gefitinib suppressed the stimulation of extracellular signal-regulated kinase phosphorylation/activity induced by IFN- both in vitro and in vivo.

Conclusion: The observed cooperative antitumor effects could be, at least in part, explained by the inhibition exerted by gefitinib of an IFN--induced EGF-dependent survival pathway, which involves extracellular signal-regulated kinase activation. These results provide a rationale for the clinical evaluation of gefitinib in combination with IFN- in HNSCC.

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