Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil
Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil
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DOI：
10.1159/000098110
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发表时间：
2006-01-01
期刊：
影响因子：
3.5
通讯作者：
Barone, C.
中科院分区：
文献类型：
--
作者：
Ciaparrone, M.;Quirino, M.;Barone, C.
目的：胸苷酸合成酶（TS），二氢嘧啶脱氢酶（DPD）和胸苷磷酸化酶（TP）基因表达的联合评估转移性结直肠癌已被报道能够预测疗效的氟嘧啶为基础的化疗。为了评估辅助治疗中的预后作用，我们研究了5-氟尿嘧啶（5-FU）治疗的结直肠癌患者原发肿瘤中TS、DPD和TP的表达。研究方法：采用免疫组化法检测62例Dukes'B、C期结直肠癌患者手术切除并接受5-FU辅助化疗后石蜡包埋的原发肿瘤组织中TS、DPD和TP的表达水平。中位随访时间为90个月（范围17-127）。结果如下：Dukes'C期癌症和高TS表达是无病生存期（DFS;分别为p = 0.0009和p = 0.007）和总生存期（OS;分别为p = 0.0005和p = 0.011）预后不良的独立标志物。通过多变量分析，与DPD低表达患者相比，DPD高表达患者的DFS（p = 0.007）和OS（p = 0.005）显著缩短。在2种标志物的联合分析中，低TS和低DPD的患者在DFS（p = 0.007）和OS（p = 0.03）方面具有最佳结局。所有3种蛋白质的分析显示，所有3种标志物低表达的患者的DFS（p = 0.04）和OS（p = 0.01）显著长于任何一种蛋白质表达高值的患者。然而，与2种标志物的分析（TS-/DPD-组）相比，3种标志物的联合分析（TS-/DPD-/TP-组）不能识别具有更好预后的患者亚组。对Dukes'C期癌症患者的分析证实，当所有3种标志物均具有低表达时，在DFS和OS方面具有显著益处（分别为p = 0.001和p = 0.006）。我们还发现TS和TP蛋白表达之间存在显著正相关（p = 0.033）。结论：本回顾性研究提示TS和DPD联合评估对Dukes' B和C期结肠癌患者接受5-FU辅助化疗的预后有一定的参考价值。TP作为5-FU为基础的治疗的预测作用需要进一步调查。版权所有（c）2006 S. Karger AG，巴塞尔。
Objective: The combined assessment of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene expressions in metastatic colorectal cancer has been reported to be able to predict the efficacy of fluoropyrimidine-based chemotherapy. In order to evaluate the prognostic role in the adjuvant setting, we investigated the TS, DPD and TP expression in primary tumors of colorectal cancer patients treated with 5-fluorouracil (5-FU). Methods: TS, DPD and TP expression levels were determined by immunohistochemistry in paraffin-embedded primary tumor tissues from 62 patients with Dukes' stage B and C colorectal cancers who underwent surgery and received adjuvant systemic chemotherapy with 5-FU. The median follow-up was 90 months ( range 17-127). Results: Dukes' stage C cancer and high TS expression were independent markers of poor prognosis for disease-free survival (DFS; p = 0.0009 and p = 0.007, respectively) and overall survival ( OS; p = 0.0005 and p = 0.011, respectively). By multivariate analysis, patients with high DPD expression had significantly shorter DFS ( p = 0.007) and OS ( p = 0.005) compared to patients with low DPD expression. In the combined analysis of 2 markers, patients with low TS and low DPD had the best outcome in terms of DFS ( p = 0.007) and OS ( p = 0.03). The analysis of all 3 proteins showed that the patients with low expression of all 3 markers had significantly longer DFS ( p = 0.04) and OS ( p = 0.01) than patients with a high value of any one of the protein expressions. However, the joint analysis of 3 markers ( group with TS-/DPD-/TP-) could not identify a subgroup of patients with a better prognosis compared to the analysis of 2 markers ( group with TS-/DPD-). The analysis of Dukes' stage C cancer patients confirmed a significant benefit in terms of DFS and OS ( p = 0.001 and p = 0.006, respectively) when all 3 markers had low expression. We also found a positive significant correlation between TS and TP protein expression ( p = 0.033). Conclusions: This retrospective investigation suggests that the combined assessment of TS and DPD may be useful to evaluate the prognosis of patients with Dukes' B and C colon carcinoma receiving 5-FU adjuvant chemotherapy. The role of TP as a predictor for 5-FU-based therapy needs further investigations. Copyright (c) 2006 S. Karger AG, Basel.