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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，我们用免疫组织化学方法研究了5-FU代谢酶在胃肠道肿瘤中的表达与以氟嘧啶为基础的化疗效果之间的关系。结果如下：1)在福尔马林固定石蜡包埋切片中，避免高温是福尔马林固定石蜡包埋切片中OPRT免疫组织化学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EL ISA水平有关。2)不同癌变组织中OPRT、二氢嘧啶脱氢酶(DPD)、胸苷磷酸化酶(TP)和胸苷合成酶(TS)的表达模式不同。3)Oprt在胃癌组织中的表达强于正常胃粘膜，肠型癌高于弥漫型癌。4)在进展期胃癌中，TS-和/或P53的高表达预示着对S-1联合顺铂新辅助化疗的耐药。5)α-胎儿蛋白产生型消化器官腺癌多表现为低TP和低金属硫蛋白表型，提示APAD对顺铂敏感，但对5‘-脱氧氟尿苷和卡培他滨耐药。6)OPRT和DPD的表达与新辅助化疗方案的疗效无关。