%0 Journal Article
%T Overexpression of the Orotate Phosphoribosyl-Transferase Gene Enhances the Effect of 5-Fluorouracil in Head and Neck Squamous Cell Carcinoma In Vitro
%A Ryuji Yasumatsu
%A Torahiko Nakashima
%A Shizuo Komune
%J Journal of Oncology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/649605
%X 5-Fluorouracil (5-FU) is a widely used drug in head and neck squamous cell carcinoma (HNSCC). In the anabolic pathway of 5-FU, the first step in activation of the drug is phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT), which directly metabolizes 5-FU to 5-fluorouridine monophosphate (FUMP) in the presence of 5-phosphoribosyl-1-pyrophosphate. To date, OPRT expression in the tumors has been related to the clinical response or survival of cancer patients receiving 5-FU-based chemotherapy. In this study, we examined whether OPRT expression correlates with the chemosensitivity to 5-FU and cell proliferation in HNSCC. We constitutively expressed an OPRT cDNA in an HNSCC cell line. The effects of OPRT expression on in vitro cell growth and 5-FU cytotoxicity were examined. OPRT transfection increases the cytotoxicity of 5-FU without affecting cell proliferation of HNSCC cells in vitro. These results indicate that OPRT expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy. 1. Introduction 5-Fluorouracil (5-FU) has been used most frequently for treating head and neck squamous cell carcinoma (HNSCC) in a form of single agent or in combination with cisplatin [1] and the drug of choice for systemic therapy in colorectal cancer [2]. However, nowadays 5-FU resistance during the course of treatment has become common, which is an important cause of failure for cancer therapies [3]. It has been reported that response rate of 5-FU and its derivatives are due to interindividual difference in the enzyme activities for anabolism and catabolism. In the anabolic pathway of 5-FU, the first step in activation of the drug is phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT), which directly metabolizes 5-FU to 5-fluorouridine monophosphate (FUMP) in the presence of 5-phosphoribosyl-1-pyrophosphate [4]. This step is the most important mechanism of 5-FU activation. To date, OPRT expression in the tumors has been related to the clinical response or survival of cancer patients receiving 5-FU-based chemotherapy [5, 6]. However, no study has confirmed directly whether the regulation of intratumoral OPRT expression level affects the efficacy of 5-FU and the cell activity in HNSCC. We therefore investigated whether overexpression of the OPRT enhances sensitivity to 5-FU. In this study, to assess the role of OPRT in the biological regulation of HNSCC, we constitutively expressed the OPRT complementary DNA (cDNA) in HNSCC cell line. The effect of OPRT on in vitro cell growth and 5-FU cytotoxicity was examined. 2. Materials
%U http://www.hindawi.com/journals/jo/2012/649605/