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High Expression of Dihydropyrimidine Dehydrogenase in Lung Adenocarcinoma is Associated With Mutations in Epidermal Growth Factor Receptor: Implications for the Treatment of Non–Small-Cell Lung Cancer Using 5-Fluorouracil


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Title: High Expression of Dihydropyrimidine Dehydrogenase in Lung Adenocarcinoma is Associated With Mutations in Epidermal Growth Factor Receptor: Implications for the Treatment of Non–Small-Cell Lung Cancer Using 5-Fluorouracil
Authors: Mochinaga, Koji / Tsuchiya, Tomoshi / Nagasaki, Toshiya / Arai, Junichi / Tominaga, Tetsuro / Yamasaki, Naoya / Matsumoto, Keitaro / Miyazaki, Takuro / Nanashima, Atsushi / Hayashi, Tomayoshi / Tsukamoto, Kazuhiro / Nagayasu, Takeshi
Issue Date: Mar-2014
Publisher: Elsevier
Citation: Clinical Lung Cancer, 15(2), pp.136–144; 2014
Abstract: Background It has been shown that 5-fluorouracil (5-FU) sensitivity in patients with non–small-cell lung cancer (NSCLC) is associated with epidermal growth factor receptor (EGFR) mutation status. However, the relationship between dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, and EGFR mutation status is unknown. Here, we focus on clinicopathologic factors and in vitro correlations between DPD expression and EGFR mutation status. Patients and Methods EGFR mutations and messenger RNA (mRNA) levels of DPD and thymidylate synthase (TS) were analyzed in 47 resected NSCLC tumors by laser-capture microdissection. In addition, relationships between EGFR mutation status and the immunohistochemical expression of DPD and TS in 49 patients with primary NSCLC who were treated with a 5-FU derivative of S-1 postoperatively were examined. Correlations among clinicopathologic factors were evaluated. The effect of epidermal growth factor on DPD expression was also investigated in vitro in various cell lines. Results Adenocarcinoma in situ showed significantly higher DPD mRNA levels and more EGFR mutation frequency than other histological types (P < .05). DPD immunopositive cases were more frequently observed in adenocarcinoma, in females, and in nonsmokers. DPD immunopositive cases were correlated with EGFR mutation status (P < .003). The prognoses of wild-type EGFR and mutated EGFR populations were similarly favorable with postoperative S-1 treatment, which overcomes the problem of 5-FU degradation in mutated EGFR. In vitro, EGFR-mutated cell lines showed high DPD mRNA and protein expression. Conclusion High DPD expression was shown to be correlated with EGFR mutation in adenocarcinoma cells and tissues. Clinicians should take this finding into consideration when using 5-FU to treat patients with NSCLC.
Keywords: Adenocarcinoma in situ / Dihydropyrimidine dehydrogenase / epidermal growth factor receptor mutation / epidermal growth factor receptor tyrosine kinase inhibitor
URI: http://hdl.handle.net/10069/34284
ISSN: 15257304
DOI: 10.1016/j.cllc.2013.09.002
Rights: © 2014 Elsevier Inc. All rights reserved. / NOTICE: this is the author’s version of a work that was accepted for publication in Clinical Lung Cancer. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Clinical Lung Cancer, 15, 2, (2014)
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/34284

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