Genetic Polymorphism of Dihydropyrimidine Dehydrogenase

二氢嘧啶脱氢酶基因多态性

• 批准号: 6989733
• 负责人: ROBERT B. DIASIO
• 金额: $ 28.06万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989733
• 关键词: clinical research; drug adverse effect; enzyme activity; enzyme deficiency; enzyme linked immunosorbent assay; fluorouracil; genetic polymorphism; genetic promoter element; human subject; laboratory mouse; neoplasm /cancer; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; orotate phosphoribosyltransferase; oxidoreductase; pentosyltransferase; proteasome; pyrimidine analog; thymidine kinase; thymidylate synthase; transcription factor; ubiquitin; uridine phosphorylase; western blottings

DESCRIPTION (provided by applicant): The long-term objective of this research project is to better understand the genetic basis for severe, potentially life-threatening toxicity secondary to treatment with 5-Fluorouracil (5-FU) and in particular further characterize the pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency. During the next grant period we will further clarify the molecular mechanisms of regulation of the gene responsible for expression of DPD (DPYD), the role of the ubiquitin-proteasome system in DPD protein turnover, develop phenotypic and genotypic diagnostic tests for DPD deficiency, and lastly examine the role of other enzymatic steps in 5-FU metabolism in the cause of severe 5-FU toxicity. In approaching each of the specific aims listed below, we will continue to obtain and utilize biochemical and molecular data (e.g., DPD enzyme activity, DPD mRNA level, and analysis for mutations in DPYD gene) from patients presenting with grade IV toxicity after 5-FU therapy. The specific aims will include: Spec. Aim 1) - Identify and clarify the role of additional transcriptional regulatory elements affecting DPYD gene expression including identification of a.) transcription factor(s) that bind to regulatory elements I and II in the previously identified promoter, and b) additional potential regulatory regions in intron 1 and the 3'-untranslated region; Spec. Aim 2) - Determine the role of the ubiquitin (Ub) proteasome system in the regulation of DPD protein - a) determine DPD protein half-life for wild type and mutant DPD protein, and b) identify putative destabilizing element(s) of DPD protein; Spec. Aim 3) - Develop user-friendly diagnostic tests for DPD deficiency including a) phenotypic tests of DPD deficiency suitable for routine screening, and b) genotypic tests for specific causes of DPD deficiency; and Spec. Aim 4) - Determine the role of other factors that may contribute to severe 5-FU toxicity including a) altered gene expression of the 5-FU site of action - thymidylate synthase, b) altered gene expression of anabolic enzymes, e.g. uridine and thymidine phosphorylases and kinases and orotate phosphoribosyltransferase, and c) altered gene expression of other catabolic enzymes, e.g. dihydropyrimidinase. Successful progress on this research project should translate into improved care for patients receiving fluoropyrimidine drugs in the future.

描述（由申请人提供）：本研究的长期目标

项目成果

microRNAs miR-27a and miR-27b directly regulate liver dihydropyrimidine dehydrogenase expression through two conserved binding sites.

• DOI: 10.1158/1535-7163.mct-13-0878
• 发表时间: 2014-03
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Offer SM;Butterfield GL;Jerde CR;Fossum CC;Wegner NJ;Diasio RB
• 通讯作者: Diasio RB

Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years.

• DOI: 10.1200/jco.2006.24.18_suppl.2056
• 发表时间: 2006-06
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: R. Mehra;L. Mattison;L. Ledbetter;H. Ezzeldin;R. Diasio;M. Saif

Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil.

• 发表时间: 1999-08
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Martin R. Johnson;Alexander Hageboutros;Kangsheng Wang;Lisa High;Jeffrey B. Smith;R. Diasio

Peripheral neuropathy exacerbation associated with topical 5-fluorouracil.

与局部 5-氟尿嘧啶相关的周围神经病变恶化。

• DOI: 10.1097/01.cad.0000231479.30524.0e
• 发表时间: 2006
• 期刊: Anti-cancer drugs
• 影响因子: 2.3
• 作者: Saif,MuhammadWasif;Hashmi,Shahrukh;Mattison,Lori;Donovan,WilliamB;Diasio,RobertB
• 通讯作者: Diasio,RobertB

Molecular cloning and characterization of the human dihydropyrimidine dehydrogenase promoter.

人二氢嘧啶脱氢酶启动子的分子克隆和表征。

• DOI: 10.1016/s0167-4781(00)00213-x
• 发表时间: 2000
• 期刊: Biochimica et biophysica acta
• 作者: Shestopal,SA;Johnson,MR;Diasio,RB
• 通讯作者: Diasio,RB