尿路上皮癌中 5-氟尿嘧啶代谢相关酶的预后意义及 5-氯-2,4-二羟基吡啶增强对 5-氟尿嘧啶的化疗敏感性。
Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma.
机构信息
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
出版信息
BMC Cancer. 2012 Sep 22;12:420. doi: 10.1186/1471-2407-12-420.
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.
背景
最近，S-1 是一种新型的 5-氟尿嘧啶（5-FU）为基础的药物，含有强二氢嘧啶脱氢酶（DPD）抑制剂 5-氯-2,4-二氢嘧啶（CDHP），已被临床用于治疗各种非尿路上皮癌（UC）。胸苷酸合成酶（TS）水平较高，是 5-FU 和 DPD 的靶酶，5-FU 和 DPD 可降解大部分 5-FU，与某些癌症的不良预后相关。然而，仅有少数报告涉及 UC 中的这一点。本研究旨在探讨 TS 和 DPD 在尿路上皮癌（UTUC）中的临床意义，并评估 TS 和 DPD 对 UC 细胞系中 5-FU 敏感性的作用以及 S-1 在 UC 异种移植模型中的抗肿瘤作用。
方法
首先，我们评估了 176 例 UTUC 患者中 TS 和 DPD 的免疫组织化学表达，以确定其预后意义。其次，通过 ELISA 和实时 PCR 测量 UC 细胞系中 TS 和 DPD 的水平。此外，使用针对 TS 和 DPD 的小干扰 RNA（siRNA）检查其水平与 5-FU 敏感性之间的关联。最后，评估 S-1 在 UC 异种移植模型中的抗肿瘤作用。
结果
UTUC 人样本中 TS 和 DPD 的免疫组织化学评估表明，TS 表达与分期、分级和血管淋巴管浸润显著相关，而 DPD 表达与分级显著相关。多变量分析表明，高 TS 表达是它们疾病特异性生存的独立预测因子。在使用 UC 细胞系进行的体外研究中，高水平的 TS 和 DPD 与对 5-FU 的低反应相关，这些关联通过针对 TS 和 DPD 的 siRNA 得到证实。在使用 UC 异种移植模型进行的体内研究中，与对照组、替加氟或 UFT 相比，S-1 治疗可显著抑制 UC 肿瘤的生长，特别是 DPD 水平较高的肿瘤。
结论
TS 在 UTUC 的预后中起重要作用，S-1 可能是 UC 肿瘤的关键药物，特别是对于 DPD 水平较高的肿瘤。
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