van Triest B, Pinedo H M, Blaauwgeers J L, van Diest P J, Schoenmakers P S, Voorn D A, Smid K, Hoekman K, Hoitsma H F, Peters G J
Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Clin Cancer Res. 2000 Mar;6(3):1063-72.
5-Fluorouracil (5FU)-based therapy is given to patients with advanced colorectal cancer and as adjuvant treatment. Thymidylate synthase (TS) is the target for 5FU, and may have a prognostic role for the outcome of 5FU-based therapy together with proliferation markers such as p53 and Ki67. Thymidine phosphorylase (TP, also known as platelet-derived endothelial cell growth factor) may be of importance both in the 5FU drug activation pathway and in tumor angiogenesis, similar to vascular endothelial growth factor (VEGF). TS and TP levels were determined biochemically in fresh-frozen tumor specimens of 32 untreated patients with colorectal cancer, whereas in paraffin-embedded tissue samples, immunohistochemistry was performed for TS, TP, and additional prognostic markers such as p53, Ki67, and VEGF as well as microvessel density. All factors were correlated with patient characteristics such as age, gender, Dukes' stage, angio-invasion, and differentiation grade. TS and TP as measured by various assays were correlated with overall and disease-free survival in this patient group. TP enzyme activity and protein expression correlated with each other. A significant correlation was found between TP enzyme activity and 5-fluoro-2'-deoxyuridine-5'-monophosphate binding activity. VEGF expression correlated significantly with TP immunostaining and Ki67 index. Survival analysis revealed a significant relation of TS levels to the overall survival in this small patient group and a significant correlation between TP activity and disease-free survival. TS and TP both were of prognostic significance in these patients with colorectal cancer. The interesting relationship of TS and TP with angiogenesis and proliferation needs further investigation.
以5-氟尿嘧啶（5FU）为基础的疗法用于晚期结直肠癌患者并作为辅助治疗。胸苷酸合成酶（TS）是5FU的作用靶点，与p53和Ki67等增殖标志物一起，可能对以5FU为基础的治疗结果具有预后作用。胸苷磷酸化酶（TP，也称为血小板衍生内皮细胞生长因子）在5FU药物激活途径和肿瘤血管生成中可能都很重要，类似于血管内皮生长因子（VEGF）。对32例未经治疗的结直肠癌患者的新鲜冷冻肿瘤标本进行生化测定TS和TP水平，而在石蜡包埋组织样本中，对TS、TP以及其他预后标志物如p53、Ki67和VEGF以及微血管密度进行免疫组织化学检测。所有因素均与患者特征如年龄、性别、Dukes分期、血管侵犯和分化程度相关。通过各种检测方法测得的TS和TP与该患者组的总生存期和无病生存期相关。TP酶活性与蛋白表达相互关联。发现TP酶活性与5-氟-2'-脱氧尿苷-5'-单磷酸结合活性之间存在显著相关性。VEGF表达与TP免疫染色和Ki67指数显著相关。生存分析显示，在这个小患者组中TS水平与总生存期存在显著关系，TP活性与无病生存期存在显著相关性。TS和TP在这些结直肠癌患者中均具有预后意义。TS和TP与血管生成及增殖之间有趣的关系需要进一步研究。
