胃癌患者外周血DPD活性、5-FU血药浓度与毒性反应的相关性分析

背景与目的：以氟尿嘧啶（5-fluorouracil,5-FU）持续静脉滴注为基础的方案治疗胃癌患者。其毒性反应发生率及严重程度有很大的个体差异。二氢嘧啶脱氢酶（dihydropyrimidine dehydrogenase,DPD）是5-FU在人体内代谢的关键性限速酶．与5-Fu化疗时的毒性反应有密切关系。本研究通过检测胃癌患者化疗前体内的DPD活性和化疗后5-FU稳态血药浓度,分析DPD活性、5-FU稳态血药浓度与毒性反应之间的相关性。方法：入组患者均接受相同方案化疗（紫杉醇75mg／m^2静脉滴注3h,醛氢叶酸200mg／m^2静脉滴注2h,5-FU 375mg／m^2静脉推注,5-FU 2．5g／m^2持续静脉滴注46h。每2周重复一次,每2次为一个疗程）,采用高效液相色谱法（HPLC法）检测化疗前DPD活性,并用HPLC法检测化疗后5-FU稳态血药浓度,观察患者化疗后的毒性反应。结果：DPD活性在36例胃癌患者血中呈正态分布,即1．56—6．01不等;并且DPD活性与患者性别、年龄、PS无关。5-FU稳态血药浓度在不同个体中差异较大,即179．2—1589．6μg／L不等．其浓度经对数转换后呈正态分布。DPD活性与5-FU稳态血药浓度呈负相关（r=-0．376,P=0．024）。DPD活性和腹泻、口腔粘膜炎、严重骨髓抑制发生率呈负相关,而5-FU稳态血药浓度与腹泻、Ⅲ／Ⅳ度骨髓抑制呈正相关。结论：化疗前DPD活性和化疗后5-FU稳态血药浓度在胃癌患者血中存在较大差异,对其检测能够预测毒性反应。

Correlative analysis between serum dihydropyrimidine dehydrogenase, activity, concentration of 5-fluorouracil and adverse events in the treatment of advanced gastric cancer patients

BACKGROUND & OBJECTIVE: Toxicities and their severities vary among advanced gastric cancer patients when they receive the same regimen containing continuous infusion of 5-fluorouracil (5-FU). Dihydropyrimidine dehydrogenase (DPD) is the key rate-limiting enzymes which is closely related to toxicities of 5-FU in chemotherapy. This study was to explore the relationship between activity of DPD and concentration of 5-FU, and their correlation to adverse events among advanced gastric cancer patients treated with the same regimen containing 5-FU continuous infusion. METHODS: Patients received the same regimen (intravenous injection of paclitaxel 75 mg/m(2), leucovorin 200 mg/m(2) and 5-FU 375 mg/m(2), continuous infusion of 5-FU 2.5 g/m2 for 46 hours every two weeks). The peripheral blood was collected from 36 patients with advanced gastric cancer before and after chemotherapy to detect the activity of DPD and concentration of 5-FU by high-performance liquid chromatography (HPLC). Adverse events were assessed every cycle. RESULTS: Serum activity of DPD revealed a unimodel distribution, which globally fits to a guassian distribution (range 1.56-6.01). Mean and median DPD activity values were 2.38 and 2.13, respectively. No total DPD deficiency was found in the patients. The concentration of 5-FU varied from 179.2 microg/L to 1 589.2 microg/L, which demonstrated normality distribution after a logarithmic transformation was applied. The DPD activity was inversely correlated with 5-FU concentration (r=-0.376, P=0.024). The patients with low activity of DPD were more frequently suffering from severe diarrhea, mucositis, and myelosuppression. And high level of 5-FU concentration led to the increase of adverse events. CONCLUSION: Pre-chemotherapy DPD activity and 5-FU concentration during chemotherapy vary among gastric cancer patients, which may help to prevent severe toxicities during the treatment.