Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa)

Abstract

ZD1839 ("Iressa") is an orally-active, selective epidermal growth factor receptor-tyrosinekinase inhibitor. We evaluated the antitumor activity of ZD1839 in combination with radiation in human squamous cell carcinomas (SCCs) of the head and neck. ZD1839 produced a dose-dependent inhibition of cellular proliferation in human SCCs grown in culture. Flow cytometry analysis of cell cycle progression confirmed the accumulation of cells in G(1) phase after exposure to ZD1839. Clonogenic analysis demonstrated that treatment of SCCs with ZD1839 reduced cell survival after radiation exposure. Flow cytometric analysis further demonstrated that treatment of SCCs with ZD1839 amplified radiation-induced apoptosis. Tumor xenograft studies confirmed that oral administration of ZD1839, or focal radiation, resulted in partial and transient tumor regression in both SCC-1 and SCC-6 xenografts. In contrast, profound tumor regression and regrowth delay was observed in mice treated with the combination of ZD1839 and radiation. To examine antiangiogenic effects, we studied the impact of ZD1839 on human umbilical vascular endothelial cells (HUVECs). In the presence of reconstituted Matrigel matrix, HUVECs established a capillary-like network structure (tube formation). Treatment with ZD1839 reduced the cell-to-cell interaction of HUVECs, resulting in disruption of tube formation. The effect of ZD1839 was further examined using an in vivo tumor xenograft model of angiogenesis (Matrigel plug) in athymic mice. Systemic treatment with ZD1839 significantly inhibited tumor-induced neovascularization across the Matrigel plug. Taken together, these results suggest that the antitumor activity of ZD1839 in combination with radiation appears to derive from not only proliferative growth inhibition (with associated cell cycle arrest and enhancement of radiation-induced apoptosis) but also from inhibition of tumor angiogenesis.