Tohoku J. Exp. Med., 2017 August, 242(4)

Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

TAKAYUKI SHIINA,¹ GAKU SAITO,¹ TAKAO SAKAIZAWA,¹ HIROYUKI AGATSUMA,¹ YOSHIAKI TOMINAGA,¹ AKIRA HYOGOTANI,¹ KAZUTOSHI HAMANAKA,¹ MASAYUKI TOISHI,¹ KEIICHIRO TAKASUNA,¹ RYOICHI KONDO,¹ KAZUO YOSHIDA¹ and KEN-ICHI ITO¹

¹Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery (II), Shinshu University School of Medicine, Matsumoto, Nagano, Japan

Thymidylate synthase (TS) is essential in thymidylate biosynthesis and DNA replication. Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in pyrimidine catabolism and is important in catabolism of 5-fluorouracil (5-FU). The significance of TS and DPD expressed in lung cancer remains controversial. Here we analyzed the relationship between TS and DPD expression and clinicopathological features of lung cancer. Enzyme-linked immunosorbent assays (ELISAs) were used to measure TS and DPD levels in paired tumor and non-tumor lung tissues obtained from 168 patients (107 adenocarcinomas, 39 squamous cell carcinomas, and 22 others), who had operations at the Shinshu University Hospital from 2004 to 2007 and were followed up for a median of 57.0 months. TS and DPD expression levels were higher in tumor tissues, and TS expression levels were significantly lower in adenocarcinomas than those in other subtypes. In addition, patients with low TS levels survived longer compared with patents with high TS levels. By contrast, DPD expression levels were not correlated with overall patient survival. Importantly, patients with low TS and DPD levels exhibited significantly prolonged survival than those with high TS and DPD. Among the 168 patients, 59 patients were treated with tegafur-uracil (UFT), a DPD-inhibitory fluoropyrimidine, and the UFT-treated patients with high TS and high DPD levels showed worst prognosis. Our study demonstrates a significant correlation between low TS expression levels and long-term prognosis of patients with lung cancer. Thus, ELISA is a clinically useful method to measure TS and DPD expression in lung cancer tissues.

keywords —— dihydropyrimidine dehydrogenase, ELISA, fluoropyrimidines, lung cancer, thymidylate synthase

© 2017 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2017, 242, 303-316

Correspondence: Ken-ichi Ito, Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery (II), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

e-mail: kenito@shinshu-u.ac.jp