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The Effect of Tetrathiomolybdate on Cytokine Expression, Angiogenesis, and Tumor Growth in Squamous Cell Carcinoma of the Head and Neck
Theodoros N. Teknos, MD;
Mozaffarul Islam, PhD;
Douglas A. Arenberg, MD;
Quintin Pan, PhD;
Shannon L. Carskadon, BS;
Aaron M. Abarbanell, BS;
Benjamin Marcus, MD;
Supriti Paul, MD;
Curtis D. Vandenberg, MD;
Michael Carron, MD;
Jacques E. Nor, DDS, PhD;
Sofia D. Merajver, MD, PhD
Arch Otolaryngol Head Neck Surg. 2005;131:204-211.
Objective To assess the effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth rate in human squamous cell carcinoma (SCC).
Design Three human SCC cell lines were used in this study for both in vitro and in vivo investigations. Conditioned media from untreated and tetrathiomolybdate-treated cell lines were compared with regard to cytokine levels, endothelial cell chemotaxis, endothelial cell tubule formation, and migration and the ability to induce angiogenesis in a rat aortic ring array. In vivo UM-SCC-38 was seeded onto tissue-engineered scaffolds and surgically implanted into the flanks of immunodeficient mice. Tumor growth rates and the level of angiogenesis were compared after 2 weeks of therapy.
Setting A tertiary care facility.
Results In this study, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by head and neck SCC (HNSCC) cell lines in vitro. Furthermore, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by HNSCC cell lines in vitro. Furthermore, tetrathiomolybdate treatment of HNSCC cell lines results in significantly decreased endothelial cell chemotaxis, tubule formation, and neovascularization in a rat aortic ring assay. This in vitro evidence of decreased angiogenesis by tetrathiomolybdate is confirmed in vivo by using a severe combined immunodeficiency disorder mouse model in which tetrathiomolybdate therapy is shown to prevent human blood vessel formation. Finally, human HNSCC implanted into immunodeficient mice grow to a much larger size in untreated mice compared with those treated with 0.7 mL/kg per day of oral tetrathiomolybdate.
Conclusions These findings illustrate the ability of tetrathiomolybdate to down-regulate proinflammatory and proangiogenic cytokines in HNSCC. These observations are potentially exciting from a clinical perspective because a global decrease in these cytokines may decrease tumor aggressiveness and reverse the resistance to chemotherapy and radiation therapy seen in this tumor type.
Author Affiliations: Departments of Otolaryngology–Head and Neck Surgery (Drs Teknos, Islam, Marcus, Paul, and Vandenberg and Mr Abarbanell) and Internal Medicine (Dr Nor), Divisions of Pulmonary Medicine (Dr Arenberg and Ms Carskadon) and Hematology/Oncology (Drs Pan and Merajver), and University of Michigan School of Dentistry (Dr Nor), University of Michigan Medical Center, Ann Arbor.
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