Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor

The transforming growth factor-alpha /epidermal growth factor receptor (TGF -ol-EGFR) autocrine pathway, which is involved in the development and the p rogression of human epithelial cancers, controls, in part, the production o f angiogenic factors, These angiogenic factors, including vascular endothel ial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are sec reted by cancer cells to stimulate normal endothelial cell growth through p aracrine mechanisms. ZD1839 (Iressa) is a p,o,-active, selective EGFR-tyros ine kinase inhibitor (TKI) in clinical trials in cancer patients. In this s tudy, we evaluated the antiangiogenic and antitumor activity of ZD1839 in h uman colon (GEO, SW480, and CaCo2), breast (ZR-75-1 and MCF-7 ADR), ovarian (OVCAR-3), and gastric (KATO III and N87) cancer cells that coexpress TGF- alpha and EGFR, ZD1839 treatment determined a dose- and time-dependent grow th inhibition accompanied by the decrease of VEGF, bFGF and TGF-alpha produ ction in vitro. Treatment of immunodeficient mice bearing well-established, palpable GEO xenografts with ZD1839 determined a cytostatic dose-dependent tumor growth inhibition. Immunohistochemical analysis of GEO tumor xenogra fts after ZD1839 treatment revealed a significant dose-dependent reduction of TGF-a, bFGF, and VEGF expression in cancer cells and of neoangiogenesis, as determined by microvessel count. Furthermore, the antitumor activity of ZD1839 was potentiated in combination with the cytotoxic drug paclitaxel i n GEO tumor xenografts, Tumor regression was observed in all mice after tre atment with ZD1839 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of TGF-a, VEGF, and bFGF expression with a few or no microvessels, Furthermore, 6 of 16 mice bearing well-established, pal pable GEO xenografts had no histological evidence of GEO tumors at the end of treatment with ZD1839 plus paclitaxel, These results demonstrate that th e antitumor effect of ZD1839 is accompanied by inhibition in the production of autocrine and paracrine growth factors that sustain autonomous local gr owth and facilitate angiogenesis, and that this effect can be potentiated b y the combined treatment with certain cytotoxic drugs, such as paclitaxel.