Relationship between the expression of 5-FU-metabolizing enzymes in cancer tissue and the effect of fluoropyrimidine-based chemotherapy.

在本研究中，我们通过化学方法评价了5-FU代谢酶的表达与以氟尿嘧啶为基础的化疗在胃肠道肿瘤中的作用之间的关系。结果表明：（1）避免热板拉伸过程中的高温是乳清酸磷酸核糖转移酶（OPRT）在福尔马林固定石蜡包埋切片中适宜免疫染色的重要因素之一。通过预吸收实验证实了OPRT免疫染色的特异性。OPRT免疫组化评分与酶活性或ELISA水平相关。2）不同肿瘤组织中OPRT、二氢嘧啶脱氢酶（DPD）、胸苷磷酸化酶（TP）和胸苷酸合成酶（TS）等氟嘧啶代谢酶的表达模式不同。胃癌组织中OPRT的表达强度高于正常胃黏膜组织，肠型胃癌组织中OPRT的表达强度高于弥漫型胃癌组织;进展期胃癌组织中，TS-和/或p53-high表型是S-1联合顺铂新辅助化疗耐药的预测因子。OPRT和DPD的表达与化疗疗效无关。5）消化器官产甲胎蛋白腺癌（APAD）多表现为TP低、金属硫蛋白低的表型，提示APAD对顺铂敏感，但对N^4-戊氧羰基脱氧氟胞苷耐药（卡培他滨）和5 ′-脱氧氟尿苷（5 ′-DFUR）。6）在晚期结直肠癌中，OPRT和DPD表达均与尿嘧啶加氟脲嘧啶或5 ′-DFUR的新辅助化疗的效果无关。

In the present study, we immunohistochemically evaluated the relationship between the expression of 5-FU-metabolizing enzymes and the effect of fluoropyrimidine-based chemotherapy in gastrointestinal cancers. The results were summarized as follows :1) The avoidance of high temperature during section stretching on a hot plate was one of the important factors to suitably immunostain orotate phosphoriboayltransferase (OPRT) in formalin-fixed, paraffin-embedded sections. The specificity of OPRT immunostaining was confirmed by the preabsorption experiment. The OPRT immunostaining scores were correlated with the enzyme activities or the ELISA levels.2) Expression pattern of fluoropyrimidine-metabolizing enzymes, including OPRT, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and thymidylate synthase (TS), differed from cancer to cancer. Their expression patterns in cancer tissue were generally similar to those of the normal counterparts.3) The intensity of OPRT immunostaining was generally stronger in gastric cancer tissues than in normal gastric mucosa, and in intestinal type cancers than in diffuse type cancers.4) In advanced gastric cancer, the TS-and/or p53-high phenotype was a predictor of the resistance to neoadjuvant chemotherapy with S-1 plus cisplatin. There was no relationship between the expression of OPRT and DPD, and the chemotherapeutic effects.5) Most of α-fetoprotein-producing adenocarcinoma of the digestive organs (APAD) showed the TP-low and metallothionein-low phenotype, suggesting that APAD should be sensitive to cisplatin, but resistant to N^4-pentyloxycarbonyl deoxyfluorocytidine (capecitabine) and 5'-deoxyfluorouridine (5'-DFUR).6) Neither OPRT nor DPD expression was correlated to the effects of neoadjuvant chemotherapy with uracil plus ftorafur or 5'-DFUR in advanced colorectal cancers.