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Research Articles: Therapeutics, Targets, and Development

Tetrathiomolybdate promotes tumor necrosis and prevents distant metastases by suppressing angiogenesis in head and neck cancer

¹ Department of Otolaryngology-Head and Neck Surgery and ² Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Theodoros N. Teknos, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, 1500 East Medical Centre Drive, 1904 Taubman Center, Ann Arbor, MI 48109. Phone: 734-936-3172; Fax: 734-936-9625. E-mail: teknos{at}med.umich.edu

Abstract

Angiogenesis is well recognized as an essential process that influences not only the growth of head and neck squamous cell carcinoma (HNSCC) but also promotes its invasive and metastatic behavior. The critical role of copper in multiple facets of angiogenesis makes it an important therapeutic target. Tetrathiomolybdate is a potent copper chelator, which has shown remarkable ability to suppress angiogenesis. Although this may involve multiple mechanisms, the effects on vascular endothelial growth factor (VEGF) are pivotal. In previous work, tetrathiomolybdate suppressed production of several proangiogenic cytokines by HNSCC cell lines. Given these results, we hypothesized that tetrathiomolybdate would impair tumor growth and metastasis by HNSCC. To test this concept, we evaluated the effects of long-term tetrathiomolybdate treatment on the growth and metastatic progression of HNSCC using a xenograft animal model. The results showed that tetrathiomolybdate treatment is able to maintain effective inhibition of angiogenesis. There was a significant reduction in the tumor size and vascularity with evident gross necrosis in the tetrathiomolybdate-treated animals. These effects were highly correlated with suppression of human VEGF expressed in the developing tumors as well as the mouse VEGF levels detected in the plasma. Moreover, tetrathiomolybdate treatment drastically suppressed the development of lung metastases. Taken together, these results show that tetrathiomolybdate can act long-term as a suppressor of vascularity and inhibit the growth of metastasis in this model of HNSCC. [Mol Cancer Ther 2007;6(3):1039–45]

Grant support: National Cancer Institute Specialized Programs in Research Excellence grants (T.N. Teknos and S.D. Merajver) and Canadian Institute of Health Research Award (B Hassouneh).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: B. Hassouneh and M. Islam contributed equally to this work.

S.D. Merajver is a consultant and holds a financial interest in Attenuon Corp., LLC, a company that has licensed tetrathiomolybdate for antineoplastic application from the University of Michigan.

³ http://www.cytokinelab.com

Received 8/25/06; revised 11/13/06; accepted 1/23/07.

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