Surgical-Oncology Laboratory, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, the Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
Cancer. 2012 Jun 1;118(11):2935-43. doi: 10.1002/cncr.26595. Epub 2011 Oct 21.
In Nordic countries, the standard treatment of colorectal cancer (CRC) in the adjuvant setting is bolus 5-fluorouracil (5-FU) plus leucovorin alone or in combination with oxaliplatin. 5-FU competes with the natural occurring pyrimidine uracil (Ura) as a substrate for dihydropyrimidine dehydrogenase (DPD; enzyme commission number 1.3.1.2). Low DPD activity is associated with toxicity during treatment. Pretherapeutic detection of DPD deficiency could prevent severe toxicity otherwise limiting drug administration. Assays showing that DPD deficiency impairs breakdown of Ura to dihydrouracil (UH(2)) seem promising for clinical use.
Urine was collected from 56 untreated volunteers and 143 patients with CRC before adjuvant treatment. Ura and UH(2) were analyzed using a column-switching high-performance liquid chromatography method that incorporates reversed-phase and cation-exchange columns. Ura, UH(2), and UH(2)/Ura levels were related to toxicity.
Ura and UH(2) in patients were not different from controls. UH(2) was significantly higher in women compared with men. The UH(2)/Ura ratio, however, did not differ according to sex. Low UH(2) and UH(2)/Ura levels were associated with diarrhea in men. Women experiencing thrombocytopenia had significantly higher Ura compared with women with no thrombocytopenia. The UH(2)/Ura ratio correlated negatively with total toxicity score in men (r = -0.39, P = .020).
Pretherapeutic Ura and UH(2) levels per se may be related to risk of side effects during adjuvant 5-FU-based treatment, whereas the UH(2)/Ura ratio may not always reveal such a risk. Sex is a strong risk factor for toxicity, showing the importance of evaluating male and female patients separately.
在北欧国家，结直肠癌（CRC）辅助治疗的标准方案是氟尿嘧啶（5-FU）推注治疗，联合或不联合奥沙利铂，同时给予亚叶酸。5-FU 可作为二氢嘧啶脱氢酶（DPD；酶委员会编号 1.3.1.2）的天然底物与嘧啶尿嘧啶（Ura）竞争。低 DPD 活性与治疗期间的毒性有关。在治疗前检测 DPD 缺乏可预防严重毒性，否则会限制药物的使用。显示 DPD 缺乏会损害 Ura 分解为二氢尿嘧啶（UH(2))的测定似乎有临床应用的前景。
收集 56 例未治疗的志愿者和 143 例结直肠癌患者辅助治疗前的尿液。使用柱切换高效液相色谱法分析 Ura 和 UH(2)，该方法包含反相和阳离子交换柱。将 Ura、UH(2)和 UH(2)/Ura 水平与毒性相关联。
患者的 Ura 和 UH(2)与对照组无差异。与男性相比，女性的 UH(2)显著升高。然而，男女之间 UH(2)/Ura 比值没有差异。男性腹泻者 UH(2)和 UH(2)/Ura 水平较低。血小板减少症女性的 Ura 水平明显高于无血小板减少症女性。男性 UH(2)/Ura 比值与总毒性评分呈负相关（r = -0.39，P =.020）。
辅助 5-FU 治疗前 Ura 和 UH(2)水平本身可能与不良反应风险相关，而 UH(2)/Ura 比值并不总是能揭示这种风险。性别是毒性的一个强烈危险因素，表明分别评估男性和女性患者的重要性。
