GENETIC POLYMORPHISM OF DIHYDROPYRIMIDINE DEHYDROGENASE

二氢嘧啶脱氢酶的基因多态性

• 批准号: 2103214
• 负责人: ROBERT B. DIASIO
• 金额: $ 19.08万
• 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 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2103214
• 关键词: affinity chromatography; breast neoplasms; circadian rhythms; colorectal neoplasms; drug adverse effect; drug metabolism; enzyme activity; enzyme deficiency; family genetics; fluorouracil; gel filtration chromatography; genetic polymorphism; human subject; neoplasm /cancer chemotherapy; pharmacokinetics; purine /pyrimidine metabolism; western blottings

The long term objective of this project is to improve 5-fluorouracil (5- FU) chemotherapy in cancer patients by better understanding the recently reported genetic polymorphism of the pyrimidine catabolic enzyme, dihydropyrimidine dehyrogenase (also known as dihydrouracil dehydrogenase, dihydrothymine dehydrogenase, DPD, EC 1.3.1.2) and its role in determining 5-FU toxicity in patients. Studies in our laboratory have demonstrated the critical role that DPD has in regulating 5-FU catabolism and hence 5-FU available for anabolism. Since 5-FU anabolism determines toxicity, it is hypothesized that decreased DPD activity would increase 5-FU toxicity. In preliminary studies, several patients with severe 5-FU toxicity were identified who were profoundly deficient in DPD activity compared to controls. Family studies demonstrated that DPD activity is inherited as an autosomal recessive. Subsequent studies of patients with moderate toxicity revealed DPD activity in an intermediate range similar to the levels detected in the children or parents (heterozygotes) in the family studies of the profound deficient patients. We propose the following: Spec. Aim 1) Determine population distribution of DPD activity and frequency of genetic deficiency of DPD in the cancer and non-cancer patient population; Spec. Aim 2) Determine in a prospective study the relationship between DPD activity and 5-FU toxicity; Spec Aim 3) Determine biochemical properties of DPD from peripheral blood mononuclear cells of normal and deficient individuals. Comparison of DPD from deficient patients with DPD from normal individuals should provide insight into the mechanism of genetic polymorphism of DPD. Theses studies should be useful in the future in predicting which patients may be susceptible to severe 5-FU toxicity, permitting modification of drug dose before chemotherapy.

本项目的长期目标是提高5-氟尿嘧啶（5-FU）的 FU）化疗在癌症患者中的作用， 报告了嘧啶分解代谢酶的遗传多态性， 二氢嘧啶脱氢酶（也称为二氢尿嘧啶 脱氢酶，二氢胸腺嘧啶脱氢酶，DPD，EC 1.3.1.2）及其 在确定患者5-FU毒性中的作用。 我们实验室的研究 已经证明了DPD在调节5-FU中的关键作用 因此5-FU可用于抗肿瘤。 自5-FU给药后 确定毒性，假设DPD活性降低将 增加5-FU毒性。 在初步研究中，一些患有 严重的5-FU毒性被确定为DPD严重缺乏 与对照组相比。 家庭研究表明，DPD 活动是作为常染色体隐性遗传的。 后续研究 中度毒性的患者显示DPD活性在中间 范围与儿童或父母体内检测到的水平相似 （杂合子）在家庭研究的深刻缺陷的病人。 我们提出以下几点：具体目标1）确定总体分布 癌症中DPD活性和DPD遗传缺陷频率的变化 和非癌症患者人群;规范目标2）在 DPD活性与5-FU关系的前瞻性研究 3）确定DPD的生物化学性质， 正常和缺陷个体的外周血单核细胞。 DPD缺乏症患者与正常人的DPD比较 个体应该提供对遗传机制的深入了解， DPD的多态性 这些研究在今后的工作中应该是有用的， 预测哪些患者可能对重度5-FU毒性敏感， 允许在化疗前改变药物剂量。