Gefitinib (’Iressa’, ZD1839) inhibits the expression of COX-2 and the growth of experimental head and neck squamous-cell carcinoma

4645 Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are believed to contribute to the growth of head and neck squamous-cell carcinoma (HNSCC). In this study, we investigated the antitumor properties of gefitinib (‘Iressa’, ZD1839), an orally active EGFR-TKI (EGFR tyrosine kinase inhibitor), in experimental HNSCC. Studies were carried out in 1483 cells, an EGFR overexpressing human HNSCC cell line. Initially, we evaluated whether gefitinib inhibited the growth of 1483 xenografts in nude mice. Gefitinib at doses of 10, 50, and 100 mg/kg/day administered by oral gavage caused dose-dependent inhibition of tumor growth. Tumor growth was almost completely inhibited by 100 mg/kg/day gefitinib. To determine whether growth inhibition reflected a change in cell proliferation, immunohistochemistry for Ki-67 was carried out. Treatment with 100 mg/kg/day gefitinib caused more than a 60% decrease in cell proliferation in 1483 xenografts. Subsequently, in vitro studies were performed to further elucidate the mechanism underlying the growth inhibitory effect of gefitinib. Gefitinib caused dose- and time-dependent inhibition of 1483 cell growth with an IC50 of 1 μM. Growth inhibition was a consequence of reduced DNA synthesis and a G0/G1 cell cycle arrest. These inhibitory effects were associated with a marked reduction in levels of phospho-Rb and cyclin D1. Selective inhibitors of COX-2 also suppress the growth of HNSCC. Activation of EGFR signaling has been observed to induce COX-2 in vitro. It was of interest, therefore, to determine whether treatment with gefitinib suppressed the expression of COX-2 in vitro and in vivo. Gefitinib caused dose-dependent inhibition of EGF-mediated induction of COX-2 in 1483 cells in vitro. Moreover, acute treatment of mice bearing 1483 xenografts caused nearly complete suppression of intratumoral COX-2 expression. Taken together, these results support the evaluation of gefitinib in the treatment of HNSCC. Inhibition of COX-2 expression is likely to contribute to the antitumor activity of gefitinib.