Dihydropyrimidine dehydrogenase overexpression correlates with potential resistance to 5-fluorouracil-based treatment in head and neck squamous cell carcinoma

Over the past several decades, the 5-year survival for head and neck squamous cell carcinoma (HNSCC) patients has not improved despite advances in treatment (1). One of the reasons for this is treatment failure due to resistance to chemotherapy and/or radiotherapy (2). 5-Fluorouracil (5-FU) has been widely used for HNSCC patients either in chemotherapy alone or in combination with radiotherapy, as several studies have shown that 5-FU-based chemotherapy or chemoradiotherapy improved survival in HNSCC patients (3,4). However, patients with advanced or recurrent HNSCC frequently showed chemotherapeutic resistance to 5-FU, resulting in poor outcomes (5,6). Thus, identifying biomarkers of chemotherapeutic resistance to 5-FU is crucial to improve survival among HNSCC patients. To date, a variety of candidates have been reported as predictive markers for 5-FU response (7,8), including the tumor expression level of dihydropyrimidine dehydrogenase (DPD), an initial and rate-limiting enzyme for degrading 5-FU, in colorectal (9,10), gastric (11-14), and breast cancer (15). However, the relationship between DPD expression levels and chemotherapeutic resistance to 5-FU remains unclear in HNSCC. We therefore hypothesized that DPD overexpression increases 5-FU resistance in HNSCC cells and that overexpression of DPD in cancer cells predicts shorter overall survival of HNSCC patients who are treated with 5-FU-based chemotherapy in this study. The purpose of the present study is to evaluate the significance of DPD expression on 5-FU sensitivity and survival of HNSCC patients who receive 5-FU based treatment