The role of dihydropyrimidine dehydrogenase expression in resistance to 5-fluorouracil in head and neck squamous cell carcinoma cells.
5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic drugs to treat cancer patients. However, the presence of drug resistant tumor cells may cause a poor response to 5-FU based chemotherapy. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and is also responsible for the degradation of 5-FU. In this study, we examined whether DPD expression affects the cytotoxic activity of 5-FU against head and neck squamous cell carcinoma (HNSCC) and the role of DPD in the biological regulation of HNSCC. We constitutively expressed the DPD cDNA in a HNSCC cell line. The effect of DPD expression on in vitro cell growth, cell cycle and 5-FU cytotoxicity was examined. In addition, we also evaluated the association between DPD expression and the proliferation of tumor cells in surgical specimens, and prognosis of the patients with HNSCC. DPD overexpression decreases the cytotoxicity of 5-FU. CDHP, a strong DPD inhibitor, enhances the cytotoxic effect of 5-FU in HNSCC cells in vitro. DPD expression level does not effect cell proliferation and does not seem to have prognostic value in HNSCC. The present results strongly indicate that DPD expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy, suggesting the possibility of personalized chemotherapy including the prediction of response and adverse effects.
Yasumatsu
Ryuji
R
Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. yasuryuj@qent.med.kyushu-u.ac.jp
Nakashima
Torahiko
T
Uryu
Hideoki
H
Masuda
Muneyuki
M
Hirakawa
Naoya
N
Shiratsuchi
Hideki
H
Tomita
Kichinobu
K
Fukushima
Masakazu
M
Komune
Shizuo
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil