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Arch Otolaryngol Head Neck Surg. 2005 Mar;131(3):204-11.

The effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth in squamous cell carcinoma of the head and neck.

Author information

  • 1Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, MI 48103, USA. teknos@umich.edu

Abstract

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.

PMID:
15781759
[PubMed - indexed for MEDLINE]
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