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

癌组织中5-FU代谢酶的表达与氟嘧啶类化疗效果的关系

基本信息

批准号：
17590321
负责人：
KAMOSHIDA Shingo
金额：
$ 2.24万
依托单位：
FUJITA HEALTH UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

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.

在本研究中，我们通过免疫组织化学方法评估了胃肠癌中5-FU代谢酶的表达与氟嘧啶类化疗效果之间的关系，结果总结如下：1）切片拉伸过程中避免高温。热板是在福尔马林固定、石蜡包埋的乳清酸磷酸核糖转移酶 (OPRT) 中进行适当免疫染色的重要因素之一预吸收实验证实了OPRT免疫染色的特异性。OPRT免疫染色评分与酶活性或ELISA水平相关。2)氟嘧啶代谢酶的表达模式，包括OPRT、二氢嘧啶脱氢酶(DPD)、胸苷磷酸化酶。 (TP) 和胸苷酸合酶 (TS)，其表达模式因癌症而异。癌组织中的OPRT免疫染色强度与正常单位基本相似。3）胃癌组织中OPRT免疫染色强度普遍强于正常胃粘膜，肠型癌强于弥漫型癌。4）进展期胃癌，TS 和/或 p53 高表型是对 S-1 加顺铂新辅助化疗耐药的预测因子。 OPRT 和 DPD 的表达与5）大多数产甲胎蛋白的消化器官腺癌（APAD）表现出TP低和金属硫蛋白低的表型，表明APAD对顺铂敏感，但对N^4-戊氧基羰基脱氧氟胞苷耐药（卡培他滨）和 5'-脱氧氟尿苷 (5'-DFUR)。6) OPRT 和 DPD 表达均未表达与尿嘧啶加 ftrafur 或 5'-DFUR 在晚期结直肠癌中的新辅助化疗的效果相关。