内科

目的探究二氢嘧啶脱氢酶（DPD）、胸苷酸合成酶（TS）、胸苷磷酸化酶（TP）表达与晚期结直肠癌患者5-氟尿嘧啶（5-FU）稳态血药浓度及临床疗效的关联，为理解5-FU疗效的个体差异提供“生物标志物—药代动力学—临床疗效”联动的线索。方法前瞻性纳入2019年1月至12月就诊于江西省赣州市人民医院的100例接受标准FOLFOX6方案治疗的晚期结直肠癌患者。采用免疫组织化学法检测肿瘤组织中DPD、TS、TP表达（阳性/阴性）。于首个周期5-FU持续输注第24小时检测稳态血药浓度。完成6个周期化学治疗后，依据实体瘤疗效评价标准评估客观缓解率。比较不同蛋白表达患者的客观缓解率，采用点二列相关分析蛋白表达（二分类变量）与血药浓度（连续变量）的关联。结果 DPD、TS、TP蛋白阳性表达患者的客观缓解率分别为32.43%、37.21%、35.56%，均低于相应阴性表达患者（63.49%、61.40%、65.45%，均P<0.05）。点二列相关分析结果显示，DPD、TS、TP表达均与5-FU稳态血药浓度呈负相关（rpb=-0.786，P<0.001；rpb=-0.752，P=0.002；rpb=-0.737，P=0.010）。结论肿瘤组织DPD、TS、TP蛋白阳性表达与更低的5-FU稳态血药浓度及更差的临床疗效相关，提示三者高表达可能通过不同机制共同导致疗效不佳，是潜在的负性预测标志物。

Objective To investigate the respective correlations of dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), and thymidine phosphorylase (TP) expression in tumor tissue with the steady-state plasma concentration of 5-fluorouracil (5-FU) and their associations with clinical efficacy in patients with advanced colorectal cancer, so as to provide clues for the "biomarker-pharmacokinetics-clinical efficacy" axis to understand individual differences in 5-FU efficacy. Methods A total of 100 patients with advanced colorectal cancer treated with the standard FOLFOX6 regimen at Ganzhou People's Hospital of Jiangxi Province from January to December 2019 were prospectively enrolled. Immunohistochemistry was used to detect the expression (positive/negative) of DPD, TS, and TP in tumor tissues. The steady-state plasma concentration was measured at the 24th hour of continuous 5-FU infusion in the first cycle. After 6 cycles of chemotherapy, the objective response rate was evaluated according to the Response Evaluation Criteria in Solid Tumors. The objective response rates were compared between patients with different expression statuses, and point-biserial correlation analysis was used to examine the association between expression (binary variable) and plasma concentration (continuous variable). Results The objective response rates in patients with positive expression of DPD, TS, and TP proteins were 32.43%, 37.21%, and 35.56%, respectively, all lower than those in patients with corresponding negative expression (63.49%, 61.40%, 65.45%, respectively, all P<0.05). Point-biserial correlation analysis showed that expression of DPD, TS, and TP was negatively correlated with steady-state plasma concentration of 5-FU (rpb=-0.786,P<0.001; rpb=-0.752, P=0.002; rpb=-0.737, P=0.010). Conclusion Positive expression of DPD, TS, and TP in tumor tissue is associated with lower steady-state plasma concentration of 5-FU and poorer clinical efficacy.This suggests that high expression of these proteins may collectively contribute to inferior treatment outcomes through distinct mechanisms, indicating their potential as negative predictive biomarkers.