Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors.
Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors.
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发表时间：
1995-04
期刊：
影响因子：
11.2
通讯作者：
P. Johnston;H. Lenz;C. Leichman;K. Danenberg;C. Allegra;P. Danenberg;L. Leichman
中科院分区：
文献类型：
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作者：
P. Johnston;H. Lenz;C. Leichman;K. Danenberg;C. Allegra;P. Danenberg;L. Leichman
胸苷酸合成酶（TS）是5-氟尿嘧啶（5-FU）的靶酶。我们将TS蛋白和基因表达与分别接受5-FU+甲酰四氢叶酸（LV）或5-FU/LV+顺铂输注治疗的结直肠癌（n = 9）和胃癌（n = 12）患者的反应相关。用TS 106单克隆抗体进行Western blot和光密度扫描分析TS蛋白表达。TS基因表达通过使用β-肌动蛋白作为内标物的PCR分析来测量，并表示为TS：β-肌动蛋白mRNA比率。TS蛋白表达和TS基因表达之间存在密切的线性关系（r2 = 0.60）。TS免疫组化染色结果显示，TS染色强度与TS蛋白和mRNA表达密切相关。在两个活检样本中，TS蛋白水平和TS基因表达没有相关性，但是，其中一个表现出局灶性TS染色模式。TS蛋白水平和TS基因表达均与5-FU治疗反应显著相关。有反应的患者平均TS蛋白水平为0.17 +/-0.03任意单位（范围0.05 - 0.38），而在肿瘤无反应的患者中，平均TS蛋白水平显著高于0.60 +/-0.09（范围0.06 - 1.01; P < 0.01）。TS基因表达也有类似的模式。在有反应性疾病的患者中，平均TS：β-肌动蛋白基因比为1.36 +/- 0.3（范围，0.5-3.3 x 10 - 3）。相比之下，无反应性疾病患者的活检组织中TS：β-肌动蛋白基因的平均比值为15.4 +/- 2.6 x 10（-3）（范围，2.7-35.9; P < 0.01）。TS蛋白和TS mRNA表达高度相关，并且各自预测结直肠癌和胃癌患者对基于5-FU/LV的化疗的反应。
Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU). We have correlated TS protein and gene expression with the response in patients with colorectal (n = 9) and gastric cancer (n = 12) treated with infusional 5-FU plus leucovorin (LV) or infusional 5-FU/LV and cisplatin, respectively. TS protein expression was analyzed by Western blot using TS106 monoclonal antibody and densitometry scanning. TS gene expression was measured by PCR analysis using beta-actin as an internal standard and expressed as a TS:beta-actin mRNA ratio. A close linear relationship was noted between TS protein expression and TS gene expression (r2 = 0.60) for the 21 tumor samples analyzed. TS immunohistochemical staining on 15 of the 21 samples revealed that the TS staining intensity correlated closely with TS protein and mRNA expression. In two biopsy samples, TS protein levels and TS gene expression did not correlate; however, one of these exhibited a focal TS staining pattern. Both the TS protein level and TS gene expression were significantly associated with response to 5-FU-based therapy. Patients with responsive disease had a mean TS protein level of 0.17 +/- 0.03 arbitrary units (range, 0.05 to 0.38), whereas in patients whose tumors did not respond, the mean TS protein level was significantly higher 0.60 +/- 0.09 (range, 0.06 to 1.01; P < 0.01). A similar pattern was noted with TS gene expression. In patients with responsive disease, the mean TS:beta-actin gene ratio was 1.36 +/- 0.3 (range, 0.5-3.3 x 10(-3). In contrast, biopsies from patients with unresponsive disease had a mean TS:beta-actin gene ratio of 15.4 +/- 2.6 x 10(-3) (range, 2.7-35.9; P < 0.01). TS protein and TS mRNA expression are highly correlated, and each predict for response to 5-FU/LV-based chemotherapy in patients with colorectal and gastric cancer.