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Antitumor Vascular Strategy for Controlling Experimental Metastatic Spread of Human Small-Cell Lung Cancer Cells with ZD6474 in Natural Killer Cell–Depleted Severe Combined Immunodeficient Mice

Authors' Affiliations: Departments of ¹ Internal Medicine and Molecular Therapeutics and ² Molecular and Environmental Pathology, University of Tokushima School of Medicine, Tokushima, Kuramoto-cho, Tokushima, Japan and ³ AstraZeneca, Macclesfield, United Kingdom

Requests for reprints: Seiji Yano, Department of Internal Medicine and Molecular Therapeutics, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Phone: 81-88-633-7127; Fax: 81-88-633-2134; E-mail: manae{at}clin.med.tokushima-u.ac.jp.

Background: Small-cell lung cancer is often characterized by rapid growth and metastatic spread. Because tumor growth and metastasis are angiogenesis dependent, there is great interest in therapeutic strategies that aim to inhibit tumor angiogenesis.

Methods: The effect of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor tyrosine kinases, was studied in experimental multiple-organ metastasis models with human small-cell lung cancer cell lines (SBC-3 or SBC-5) in natural killer cell–depleted severe combined immunodeficient mice.

Results: Intravenously inoculated SBC-5 cells produced experimental metastases in the liver, lung, and bone whereas SBC-3 cells produced the metastases in the liver, systemic lymph nodes, and kidneys. Daily oral treatment with ZD6474 (50 mg/kg), started on day 14 (after the establishment of micrometastases), significantly reduced the frequency of large (>3 mm) metastatic colonies (in the liver and lymph nodes) and osteolytic bone lesions. ZD6474 treatment did not significantly reduce the frequency of small (<2-3 mm) metastatic lesions found in the lung (SBC-5) or kidney (SBC-3), consistent with an antiangiogenic mechanism of action. Immunohistochemical analysis of SBC-5 metastatic deposits in the liver showed that ZD6474 treatment inhibited VEGFR-2 activation and induced apoptosis of tumor-associated endothelial cells, resulting in decreasing tumor microvessel density. ZD6474 treatment was also associated with a decrease in tumor cell proliferation and an increase in tumor cell apoptosis. The antitumor effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib, a small-molecule inhibitor of epidermal growth factor receptor tyrosine kinase, was inactive in these models.

Conclusions: These results suggest that ZD6474 may be of potential therapeutic value in inhibiting the growth of metastatic small-cell lung cancer in humans. Phase II trials with ZD6474 are currently ongoing in a range of solid tumors.

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