Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours.
Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours.
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DOI：
10.1038/bjc.1998.73
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发表时间：
1998
影响因子：
8.8
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中科院分区：
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二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5-FU）降解的限速酶。DPD活性在肝脏和外周单核细胞（pmnc）中变化很大，在人类肿瘤中尚未得到很好的研究。DPD在结肠直肠癌中的作用与5-FU的调节有关，而5-FU是结肠直肠癌中使用的主要化疗药物。因此，我们分析了63例结直肠肿瘤和邻近正常组织中的DPD活性，其中包括3例肝转移。DPD活性在所有研究组织中变化很大（变异系数为43-61%），正常组织中的DPD活性高于肿瘤组织。肿瘤与正常活性比为0.19 ~ 3.32（中位0.76）。57例患者可获得PMNC DPD活性，并与肿瘤活性相关（r(s) = 0.29, P < 0.001）。在上午获得的pmnc和肿瘤样本之间观察到更高的相关性（r(s) = 0.49），与DPD活性的昼夜变化一致。正常组织DPD活性与肿瘤（r(s) = 0.11）或PMNC活性（r(s) = -0.06）均无相关性。这项研究首次分析了DPD在结直肠癌中的活性，并说明了肿瘤活性的很大程度上的变化。肿瘤-正常活性比结果表明，肿瘤DPD升高可以通过增加肿瘤细胞的失活而在5-FU耐药中发挥作用，但在结直肠肿瘤中并不常见。研究结果支持使用pmnc来监测肿瘤DPD活性，特别是当考虑到昼夜变化时。由于肿瘤DPD活性的很大程度上的变化不能用PMNC活性来解释，因此在DPD活性用于靶向5-FU治疗之前，需要更准确的替代方法。
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for degradation of 5-fluorouracil (5-FU). DPD activity is highly variable in liver and peripheral mononuclear cells (PMNCs) and it has not been well studied in human tumours. Characterization of DPD in colorectal cancer is of clinical interest through its role in the regulation of 5-FU, the main chemotherapeutic agent used in this disease. Therefore, DPD activity was analysed in colorectal tumour and adjacent normal tissue from 63 patients, including three liver metastasis. DPD activity was highly variable in all tissues studied (coefficient of variation 43-61%) and was higher in normal tissue than in tumour. The tumour-normal activity ratio ranged from 0.19 to 3.32 (median 0.76). PMNC DPD activity was available for 57 patients and was correlated with tumour activity (r(s) = 0.29, P < 0.001). A higher correlation was observed between PMNCs and tumour samples that were both obtained in the morning (r(s) = 0.49), consistent with circadian variation in DPD activity. Normal tissue DPD activity was not correlated with either tumour (r(s) = 0.11) or PMNC activity (r(s) = -0.06). This study provides the first analysis of DPD activity in colorectal cancer and illustrates the large degree of variation in tumour activity. The tumour-normal activity ratio results suggest that elevated tumour DPD can play a role in 5-FU resistance through increased inactivation in tumour cells, but is an uncommon event in colorectal tumours. The results support the use of PMNCs for monitoring tumour DPD activity, particularly when circadian variation is taken into account. As a large degree of the variation in tumour DPD activity is not explained by PMNC activity, more accurate alternatives are needed before DPD activity can be used for targeting 5-FU therapy.