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Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor

¹ Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F Magrassi e A Lanzara," Seconda Università degli Studi di Napoli; ² Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università degli Studi di Napoli Federico II, Naples, Italy; and ³ Istituto di Anatomia Patologica, Università degli Studi di Pisa, Pisa, Italy

Requests for reprints: Fortunato Ciardiello, Cattedra di Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Via S. Pansini 5, 80131 Naples, Italy. Phone: 39-081-5666713; Fax: 39-081-5666728; E-mail: fortunato.ciardiello{at}unina2.it.

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.

Key Words: Epidermal growth factor receptor • vascular endothelial growth factor receptor • cyclooxygenase-2 • small molecule tyrosine kinase inhibitors • combination therapy

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