Author(s): Tuccillo C, Romano M, Troiani T, Martinelli E, Morgillo F, , Tuccillo C, Romano M, Troiani T, Martinelli E, Morgillo F,
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Abstract PURPOSE: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. Enhanced cyclooxygenase-2 (COX-2) expression has been linked to cancer cell proliferation, EGFR activation, VEGF secretion, and tumor-induced angiogenesis. ZD6474 is an orally available, small molecule, dual VEGF receptor-2 (VEGFR-2) and EGFR tyrosine kinase inhibitor. We investigated the activity of ZD6474 in combination with SC-236, a selective COX-2 inhibitor, to determine the antitumor activity of the simultaneous blockade of EGFR, COX-2, and VEGF functions. EXPERIMENTAL DESIGN: The antitumor activity in vitro and in vivo of ZD6474 and/or SC-236 was tested in human cancer cell lines with a functional EGFR autocrine pathway. RESULTS: The combination of ZD6474 and SC-236 determined supra-additive growth inhibition in all cancer cell lines tested. In nude mice bearing established human colon (GEO) or lung adenocarcinoma (A549) cancer xenografts and treated with ZD6474 and/or SC-236 for 3 weeks, a reversible tumor growth inhibition was seen with each agent, whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents. A long-term, 10-week treatment with ZD6474 plus SC-236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor-bearing mice and in 4 of 10 A549 tumor-bearing mice. CONCLUSIONS: This study provides a rationale for evaluating the simultaneous blockade of EGFR, COX-2, and VEGF signaling as cancer therapy in a clinical setting.
This article was published in Clin Cancer Res
and referenced in Journal of Cancer Science & Therapy