Abstract
BackgroundRecently, 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.MethodsFirstly, 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.ResultsImmunohistochemical 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.ConclusionsTS 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.
Highlights
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)
The clinical role of thymidylate synthase (TS) and DPD expression in upper tract urothelial carcinoma (UTUC) human samples TS and DPD expression in UTUC All the specimens were fixed in 10% formalin and embedded in paraffin, and all slides were re-reviewed by genitourinary pathologists
To elucidate the clinical significance of TS and DPD in UTUC, we examined the immunohistochemical expression of TS and DPD (Figure 1A-D)
Summary
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). The prognosis of UC patients with metastasis is poor and 5year survival rates for bladder cancer with lymph node metastasis and UTUC with it were reported to be 1829% and 35%, respectively [2,3]. Systemic chemotherapy with a cisplatin-containing regimen is often proposed for patients with metastatic UC. Cisplatin-based chemotherapy has a short-term therapeutic effect against metastatic UC with a response rate of about 50%, longer survival after receiving systemic chemotherapy is low, with a 5-year survival rate of only 13-15% [4,5,6]. A novel chemotherapeutic regimen for treating highly aggressive UC is urgently needed
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