A ROLE FOR DIHYDROPYRIMIDINE DEHYDROGENASE AND THYMIDYLATE SYNTHASE IN TUMOR SENSITIVITY TO FLUOROURACIL
A ROLE FOR DIHYDROPYRIMIDINE DEHYDROGENASE AND THYMIDYLATE SYNTHASE IN TUMOR SENSITIVITY TO FLUOROURACIL
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DOI：
10.1016/0959-8049(94)00216-r
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发表时间：
1994-01-01
影响因子：
8.4
通讯作者：
MILANO, G
中科院分区：
文献类型：
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作者：
BECK, A;ETIENNE, MC;MILANO, G
尽管氟尿嘧啶(FU)是最古老的抗癌药物之一，但它仍越来越多地被用于癌症化疗。患者对FU敏感性的变异来源可能是复杂的，尽管胸苷合成酶(TS)的过度产生是从FU耐药患者的肿瘤中发现的唯一耐药机制。二氢嘧啶脱氢酶(DPD)是FU分解代谢的第一个限速酶。因此，DPD活性可能是控制FU反应性的一个潜在因素。对19个人类肿瘤细胞系进行了研究，包括消化道、乳腺和头颈部癌细胞。TS和DPD活性与FU反应性平行测量。没有一种细胞系以前接触过FU，因此对FU表现出自发的敏感性。不同细胞系之间的敏感性有显著差异，IC50值从45 ng/ml(结肠细胞系)到5063 ng/ml(头颈部细胞系)不等。TS活性在所有细胞系中都可测到，变化范围在46倍以内，DPD活性在除4个细胞系外的所有细胞系中都检测到，显示出100倍的变化范围。对FU最敏感的细胞株的DPD和TS活性最低，反之亦然。简单线性回归分析显示，TS(r2=0.22，P=0.042)和DPD(r2=0.27，P=0.022)活性均与FU疗效(Log10IC50)显著相关：酶活性越大，FU IC50越高。TS和DPD被证明是自变量。多元回归分析显示，TS和DPD活性联合作用可解释FU IC50变异的36%(r(2)=0.36，P=0.01)。可鉴定出两组细胞系，一组同时具有低TS和低DPD活性(G1)，另一组具有高TS和/或高DPD活性(G2)。G1组和G2组的FU IC50值分别为193和930 ng/ml，两组间的FU敏感性差异有高度显著性(P=0.009)。本研究首次表明，肿瘤细胞中的DPD活性是与FU敏感性显著相关的一个独立因素。这些结果应该鼓励在FU治疗前对患者肿瘤进行DPD和TS联合测量，以建立它们与预后的相关性。在治疗过程中，DPD和TS的测量也可以用来确定这些酶在肿瘤对FU的耐药性发展中的意义。
Despite being one of the oldest anti-cancer drugs, fluorouracil (FU) is still being increasingly used in cancer chemotherapy. The source of variability for FU sensitivity in patients may be complex, although an overproduction of thymidylate synthase (TS) was the only mechanism of resistance identified in tumours from FU-resistant patients. Dihydropyrimidine dehydrogenase (DPD) is the first and rate-limiting enzyme of FU catabolism. Thus, DPD activity may be a potential factor for controlling FU responsiveness. A panel of 19 human tumour cell lines, including digestive tract, breast and head and neck cancer cells, were investigated. Both TS and DPD activities were measured in parallel to FU responsiveness. None of the cell lines had been previously exposed to FU, and thus expressed a spontaneous sensitivity to FU. Sensitivity between cell lines showed marked differences, with IC50 values ranging from 45 ng/ml (colon cell line) to 5063 ng/ml (head and neck cell line). TS activity was measurable in all cell lines and varied within a 46-fold range, DPD activity was detected in all but four cell lines, showing a 100-fold range of variation. Cell lines most sensitive to FU exhibited the lowest DPD and TS activities and vice versa. Simple linear regression analysis showed that both TS (r(2) = 0.22, P = 0.042) and DPD (r(2) = 0.27, P = 0.022) activities were significantly correlated to FU effectiveness (log 10 IC50): the greater the enzyme activities, the higher the FU IC50. TS and DPD were demonstrated to be independent variables. A multiple regression analysis showed that the combination of TS and DPD activities explained 36% of the variability in FU IC50 (r(2) = 0.36, P = 0.01). Two groups of cell lines could be identified, one group with both low TS and low DPD activities (G1), and the other with either high TS and/or high DPD activities (G2). Mean FU IC50 values were 193 and 930 ng/ml in G1 and G2, respectively, and this difference in FU sensitivity was highly significant (P = 0.009). The present study shows, for the first time, that DPD activity in tumour cells is an independent factor significantly related to FU sensitivity. These results should encourage DPD and TS coupled measurements in tumours of patients before FU treatment in order to establish their prognostic relevance. DPD and TS measurements could also be used during the treatment course to determine the implication of these enzymes in the development of tumour resistance to FU.