Abstract
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.
Highlights
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]
Several clinical reports have demonstrated a relationship between orotate phosphoribosyltransferase (OPRT) activity in the tumors and clinical response of cancer patients receiving 5-FU-based chemotherapy [5, 6]
The role of OPRT expression in HNSCC has not been established and, to the best of our knowledge, there are no studies investigating the relationship between the in vitro OPRT expression and 5-FU cytotoxicity in HNSCC
Summary
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]. 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. OPRT expression in the tumors has been related to the clinical response or survival of cancer patients receiving. 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. The effect of OPRT on in vitro cell growth and 5-FU cytotoxicity was examined
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