Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma

BMC Cancer

Mototsugu Oya¹  Akira Miyajima¹  Takeo Kosaka¹  Norihide Kozakai¹  Masanori Hasegawa¹  Eiji Kikuchi¹  Hiroki Ide¹ 

[1]Department of Urology, Keio University School of Medicine, Tokyo, Japan

关键词: Dihydropyrimidine dehydrogenase;    Thymidylate synthase;    5-fluorouracil;    S-1;    Urothelial carcinoma;   

Others  :  1080189
DOI  :  10.1186/1471-2407-12-420

 received in 2012-02-04, accepted in 2012-09-19,  发布年份 2012

【 摘 要 】

Background

Recently, S-1, a novel 5-fluorouracil (5-FU)-based agent containing the strong dihydropyrimidine dehydrogenase (DPD) inhibitor, 5-chloro-2,4-dihydropyrimidine (CDHP) has been clinically used to treat various non-urothelial carcinomas (UC). High levels of thymidylate synthase (TS), the target enzyme of 5-FU and DPD which degrades the majority of 5-FU, are associated with poor prognosis in some cancers. However, only a few reports have dealt with this in UC. The aim of this study was to investigate the clinical significance of TS and DPD in upper tract urothelial carcinoma (UTUC) and evaluate the role of TS and DPD on the sensitivity of 5-FU in UC cell lines and the anti-tumor effect of S-1 in UC xenograft model.

Methods

Firstly, we evaluated the immunohistochemical expression of TS and DPD in 176 patients with UTUC to determine their prognostic significance. Secondly, the levels of TS and DPD in UC cell lines were measured by ELISA and real-time PCR. Furthermore, the association between their levels and the sensitivity to 5-FU was examined using the small interfering RNA (siRNA) specific for TS and DPD. Thirdly, the anti-tumor effect of S-1 was evaluated in UC xenograft model.

Results

Immunohistochemical evaluation of TS and DPD in UTUC human samples revealed that TS expression was significantly associated with stage, grade, and lymphovascular invasion and DPD expression was significantly associated with grade. Multivariate analysis revealed that high TS expression was an independent predictor of disease-specific survival in them. In in vitro study using UC cell lines, high levels of TS and DPD were associated with low response to 5-FU and these associations were confirmed with siRNA specific for TS and DPD. In in vivo study using UC xenograft model, S-1 treatment dramatically inhibited tumor growth compared to controls, tegafur, or UFT in UC tumor with a high level of DPD.

Conclusions

TS plays an important role in the prognosis of UTUC and S-1 may be a key agent for UC tumor, especially with a high level of DPD.

【 授权许可】

   
2012 ide et al.; licensee BioMed Central Ltd.

【 图 表 】

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