GENETIC POLYMORPHISM OF DIHYDROPYRIMIDINE DEHYDROGENASE

二氢嘧啶脱氢酶的基因多态性

• 批准号: 2467958
• 负责人: ROBERT B. DIASIO
• 金额: $ 28.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-09 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2467958
• 关键词: blood chemistry; breast neoplasms; clinical research; colon neoplasms; cytotoxicity; drug hypersensitivity; drug metabolism; drug screening /evaluation; enzyme activity; enzyme deficiency; fluorouracil; gene mutation; genetic polymorphism; genetic promoter element; genetic transcription; genetic translation; human population study; human subject; luciferin monooxygenase; neoplasm /cancer chemotherapy; oxidoreductase; pharmacokinetics; purine /pyrimidine metabolism

DESCRIPTION: (Applicant's Abstract) The long term objective of this project is to improve the effectiveness of the widely used cancer chemotherapy drug 5-fluorouracil (5-FU) by better understanding the genetic factors controlling the rate-limiting enzyme in pyrimidine catabolism, dihydropyrimidine dehydrogenase (DPD). Studies in the applicant's laboratory have demonstrated the critical role that DPD has in regulating 5-FU catabolism and hence 5-FU available for anabolism. Thus, while anabolism of 5-FU is directly responsible for toxicity in both tumor and host cells, regulation of catabolism will have major effects on both host cell toxicity and antitumor effects. Patients with significantly decreased DPD activity (DPD deficiency) in their host cells (e.g., hematopoietic and mucosal cells) are at increased risk of 5-FU toxicity. On the other hand, patients with increased DPD activity in their tumor tissue are likely to have tumor resistance to 5-FU. The recent availability of the DPD cDNA as well as a preliminary structural characterization of the DPD gene makes possible now a more complete examination of the genetic factors controlling DPD enzyme activity, including both natural regulatory elements as well as mutations that can alter DPD activity. The applicant proposes during the next grant period to examine the following: Spec. Aim 1) Population Analysis of DPD Deficiency and Known DPD Mutations; Spec. Aim 2) Determine the mechanism by which Previously Characterized Mutations Produce DPD Deficiency; Spec. Aim 3) Identify Other Specific Molecular Defects Associated with DPD Deficiency; and Spec. Aim 4) Identify and Characterize Transcriptional Regulatory Elements of the Human DPD Gene. These studies should improve understanding of the molecular regulation of DPD and be useful in the development of specific molecular diagnostic tests that may predict both host toxicity and tumor response before administration of 5-FU.

描述：（申请人摘要）本项目的长期目标 是为了提高广泛使用的癌症化疗药物的有效性 5-氟尿嘧啶（5-FU）通过更好地了解遗传因素 控制嘧啶催化剂中的限速酶， 二氢嘧啶脱氢酶（DPD）。 在申请人的研究 实验室已经证明了DPD在调节 5-FU卡他霉素，因此5-FU可用于抗肿瘤。 因此，虽然 5-FU的抑制直接导致肿瘤和 在宿主细胞中，催化剂的调节将对两种宿主都有重要影响 细胞毒性和抗肿瘤作用。 显著降低的患者 在它们的宿主细胞中的DPD活性（DPD缺乏）（例如，造血和 粘膜细胞）的5-FU毒性风险增加。 另一方面，在一项研究中， 肿瘤组织中DPD活性增加的患者可能 肿瘤对5-FU耐药。 DPD cDNA的最近可用性， 以及DPD基因的初步结构特征， 现在有可能更全面地检查控制基因的遗传因素， DPD酶活性，包括天然调节元件以及 可以改变DPD活性的突变。 申请人在 下一个资助期审查以下问题：具体目标1）人口 DPD缺陷和已知DPD突变的分析;规范目的2）确定 先前表征的突变产生DPD的机制 缺陷;规范目标3）识别其他特定分子缺陷 与DPD缺乏相关;以及规范目标4）识别和表征 人类DPD基因的转录调控元件。 这些研究 应该提高对DPD分子调控的理解， 可用于开发特异性分子诊断试验， 在5-FU给药前预测宿主毒性和肿瘤反应。