GENETIC POLYMORPHISM OF DIHYDROPYRIMIDINE DEHYDROGENASE

描述：(申请者摘要)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疗效 更好地了解遗传因素对5-氟尿嘧啶(5-Fu)的影响 控制嘧啶分解代谢中的限速酶， 二氢嘧啶脱氢酶(DPD)。在申请人的学校学习 实验室已经证明了DPD在调节 5-FU分解代谢，因此5-FU可用于合成代谢。因此，虽然 5-FU的合成代谢直接导致肿瘤和肿瘤的毒性 宿主细胞，分解代谢的调节将对这两个宿主产生重大影响 细胞毒性和抗肿瘤作用。显著减少的患者 其宿主细胞中的DPD活性(DPD缺乏)(例如，造血细胞和 粘膜细胞)增加了5-FU毒性的风险。另一方面， 肿瘤组织中DPD活性增加的患者可能会 对5-FU有肿瘤耐药性。DPD基因的最新研究进展 作为DPD基因的初步结构特征，使 现在有可能对控制基因的因素进行更全面的检查 DPD酶活性，包括自然调节元件以及 可以改变DPD活性的突变。申请人在申请期间求婚 下一批授权期将审查以下内容：规格。目标1)人口 DPD缺乏症和已知DPD突变的分析目标2)确定 先前描述的突变产生DPD的机制 不足之处；规格目标3)确定其他特定的分子缺陷 与DPD缺乏症相关；以及规范。目标4)确定和描述 人类DPD基因的转录调控元件。这些研究 应提高对DPD和BE分子调控的理解 对开发特定的分子诊断测试很有用，这些测试可能 在给予5-FU前预测宿主毒性和肿瘤反应。

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.