Kornmann Marko, Schwabe Wolfgang, Sander Silvia, Kron Martina, Sträter Jörn, Polat Sucan, Kettner Erika, Weiser Hans F, Baumann Wolfram, Schramm Harald, Häusler Peter, Ott Kati, Behnke Detlev, Staib Ludger, Beger Hans G, Link Karl H
Department of General Surgery, University of Ulm, Steinhövelstrasse 9, 89075 Ulm, Germany.
Clin Cancer Res. 2003 Sep 15;9(11):4116-24.
Despite adjuvant 5-fluorouracil (5-FU) therapy, approximately 30% of patients with International Union against Cancer stage II and III colorectal cancer develop recurrence. In this study, we determined the prognostic value of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression in colorectal cancer patients treated with adjuvant 5-FU.
A real-time reverse transcription-PCR technique for quantitation of relative gene expression from paraffin-embedded specimen was established first. In a second step, archival paraffin-embedded primary tumor tissue of 309 patients who participated in adjuvant colorectal cancer trials was analyzed for TS and DPD mRNA expression.
TS mRNA expression determined by real-time reverse transcription-PCR correlated with TS protein levels determined by TS immunoblot and immunohistochemistry in cultured colon cancer cell lines and paraffin-embedded primary tumor tissue. TS mRNA levels in fresh-frozen tissues also correlated with TS mRNA levels in corresponding paraffin sections. Among the patients receiving adjuvant 5-FU therapy, those with high TS survived longer than those with low TS, and in each TS subgroup, the ones with low DPD survived longer than the ones with high DPD levels. Multiple Cox regression analysis showed that besides tumor stage (P = 0.010), only the combination of TS and DPD expression turned out to be an independent prognostic factor for survival (P = 0.030).
This suggests that TS and DPD quantitation may be helpful to evaluate prognosis of patients receiving adjuvant 5-FU and that patients with high TS and low DPD may benefit from adjuvant 5-FU chemotherapy.
尽管采用了辅助性5-氟尿嘧啶（5-FU）治疗，但国际抗癌联盟II期和III期结直肠癌患者中仍约有30%会出现复发。在本研究中，我们确定了胸苷酸合成酶（TS）和二氢嘧啶脱氢酶（DPD）表达在接受辅助性5-FU治疗的结直肠癌患者中的预后价值。
首先建立了一种用于定量石蜡包埋标本中相对基因表达的实时逆转录PCR技术。第二步，分析了参与辅助性结直肠癌试验的309例患者的存档石蜡包埋原发性肿瘤组织中的TS和DPD mRNA表达。
通过实时逆转录PCR测定的TS mRNA表达与通过TS免疫印迹和免疫组织化学测定的培养结肠癌细胞系和石蜡包埋原发性肿瘤组织中的TS蛋白水平相关。新鲜冷冻组织中的TS mRNA水平也与相应石蜡切片中的TS mRNA水平相关。在接受辅助性5-FU治疗的患者中，TS高表达者比TS低表达者存活时间更长，并且在每个TS亚组中，DPD低表达者比DPD高表达者存活时间更长。多因素Cox回归分析表明，除了肿瘤分期（P = 0.010）外，只有TS和DPD表达的组合被证明是生存的独立预后因素（P = 0.030）。
这表明TS和DPD定量可能有助于评估接受辅助性5-FU治疗患者的预后，并且TS高表达和DPD低表达的患者可能从辅助性5-FU化疗中获益。
