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Research Articles: Therapeutics, Targets, and Development

Arsenic trioxide enhances the therapeutic efficacy of radiation treatment of oral squamous carcinoma while protecting bone

Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan

Requests for reprints: Pawan Kumar, Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1011 North University Avenue, Room no. 5205, Ann Arbor, MI 48109. Phone: 734-647-7599; Fax: 734-647-2110. E-mail: pksuri{at}umich.edu or Peter J. Polverini, University of Michigan School of Dentistry, 1011 North University Avenue, Room no. 1234, Ann Arbor, MI 48109. Phone: 734-763-3311; Fax: 734-763-5142. E-mail: neovas{at}umich.edu

Abstract

Therapeutic radiation is commonly used in the treatment of squamous cell carcinoma of the oral cavity and pharynx. Despite the proven efficacy of this form of anticancer therapy, high-dose radiation treatment is invariably associated with numerous unwanted side effects. This is particularly true for bone, in which radiation treatment often leads to osteoradionecrosis. The aim of this study was to investigate if treatment with arsenic trioxide (As₂O₃) could enhance the antitumor effect of radiotherapy whereas minimizing the destructive effects of radiation on bone. As₂O₃ treatment induced a dose-dependent (1–20 µmol/L) inhibition of endothelial and tumor cell (OSCC-3 and UM-SCC-74A) survival and significantly enhanced radiation-induced endothelial cell and tumor cell death. In contrast, As₂O₃ treatment (0.5–7.5 µmol/L) induced the proliferation of osteoblasts and also protected osteoblasts against radiation-induced cell death. Furthermore, As₂O₃ treatment was able to significantly enhance radiation-induced inhibition of endothelial cell tube formation and tumor cell colony formation. To test the effectiveness of As₂O₃ and radiation treatment in vivo, we used a severe combined immunodeficiency mouse model that has a bone ossicle and tumor growing side by side subcutaneously. Animals treated with As₂O₃ and radiation showed a significant inhibition of tumor growth, tumor angiogenesis, and tumor metastasis to the lungs as compared with As₂O₃ treatment or radiation treatment alone. In contrast, As₂O₃ treatment protected bone ossicles from radiation-induced bone loss. These results suggest a novel strategy to enhance the therapeutic efficacy of radiation treatment while protecting bone from the adverse effects of therapeutic radiation. [Mol Cancer Ther 2008;7(7):2060–9]

Grant support: University of Michigan's Head and Neck Cancer Specialized Programs of Research Excellence grant 5 P50 CA097248 (P. Kumar).

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: Present address Q. Gao: Department of Oral and Maxillofacial Surgery, SiChuan University, ChengDu, Sichuan, China.

Received 8/29/07; revised 3/24/08; accepted 5/20/08.