Nakayama Yoshifumi, Matsumoto Kentaro, Inoue Yuzuru, Katsuki Takefumi, Kadowaki Koji, Shibao Kazunori, Tsurudome Yosuke, Hirata Keiji, Sako Tatsuhiko, Nagata Naoki, Itoh Hideaki
Department of Surgery 1, University of Occupational and Environmental Health, Kita-kyushu, Japan.
Anticancer Res. 2006 Sep-Oct;26(5B):3983-8.
The determination of dihydropyrimidine dehydrogenase (DPD) deficiency is important in avoiding severe 5-fluorouracil (FU) toxicity. The dihydrouracil (UH2)-uracil (Ura) ratio (UH2/Ura) in plasma might be an important indicator of the risk of 5-FU catabolic deficiency. In order to clarify this possibility, the pyrimidine metabolites and the UH2/Ura were measured in urine and the plasma level of 5-FU was evaluated in patients with gastric and colorectal cancer.
Patients with primary gastric (n=14) and colorectal (n=8) cancer who had undergone surgery were recruited in this study. These patients were divided into the S-1 treatment group, which drug is a novel oral formulation of tegafur, oxonic acid and 5-chloro-2, 4-dihydroxypyridine (CDHP) (n=14) and a group receiving other drugs which include UFT (Uracil/Tegafur) or oral doxifluridine (n=8). The urinary levels of UH2 and Ura were measured by high-performance liquid chromatography (HPLC) using column swiching. The plasma level of 5-FU was assessed by gas chromatography-mass spectrometry (GC-MS).
The UH2/Ura or UH2/Ura (treated/no treated) in the S-1 group significantly decreased in comparison to that in the other-drug group and the plasma 5-FU concentration in the S-1 group significantly increased compared to that in the group treated with other drugs. The plasma 5-FU concentration levels significantly indicated a positive correlation with urinary Ura. Moreover, UH2/Ura treated with 5-FU analogs or UH2/Ura (treated/no treated) significantly showed a negative correlation with the plasma 5-FU concentration levels.
Our findings indicate that either urinary Ura, the UH2/Ura or UH2/Ura (treated/no treated) can predict the plasma 5-FU concentration levels or DPD deficiencies.
确定二氢嘧啶脱氢酶（DPD）缺乏症对于避免严重的5-氟尿嘧啶（FU）毒性至关重要。血浆中二氢尿嘧啶（UH2）-尿嘧啶（Ura）比值（UH2/Ura）可能是5-FU分解代谢缺乏风险的重要指标。为了阐明这种可能性，我们检测了胃癌和结直肠癌患者尿液中的嘧啶代谢产物及UH2/Ura，并评估了其血浆5-FU水平。
本研究纳入了14例原发性胃癌患者和8例原发性结直肠癌患者，这些患者均接受了手术治疗。将这些患者分为S-1治疗组（n=14），该组患者使用的药物是替加氟、奥替拉西钾和5-氯-2,4-二羟基吡啶（CDHP）的新型口服制剂，另一组（n=8）接受包括优福定（尿嘧啶/替加氟）或口服去氧氟尿苷在内的其他药物治疗。采用柱切换高效液相色谱法（HPLC）测定尿液中UH2和Ura的水平。采用气相色谱-质谱联用仪（GC-MS）评估血浆5-FU水平。
与其他药物组相比，S-1组的UH2/Ura或UH2/Ura（治疗组/未治疗组）显著降低，且S-1组的血浆5-FU浓度较其他药物治疗组显著升高。血浆5-FU浓度水平与尿Ura显著呈正相关。此外，接受5-FU类似物治疗后的UH2/Ura或UH2/Ura（治疗组/未治疗组）与血浆5-FU浓度水平显著呈负相关。
我们的研究结果表明，尿Ura、UH2/Ura或UH2/Ura（治疗组/未治疗组）均可预测血浆5-FU浓度水平或DPD缺乏情况。
