GENETIC POLYMORPHISM OF DIHYDROPYRIMIDINE DEHYDROGENASE

该项目的长期目标是改进5-氟尿嘧啶(5-氟尿嘧啶) 更好地了解近年来癌症患者的FU)化疗 已报道的嘧啶分解代谢酶的遗传多态， 二氢嘧啶脱氢酶(又称二氢尿嘧啶 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。我们实验室里的研究 已经证明了DPD在调节5-FU中的关键作用 分解代谢，因此5-FU可用于合成代谢。自5-FU合成代谢以来 决定了毒性，假设DPD活性降低将 增加5-FU的毒性。在初步研究中，几名患有 严重的5-FU毒性被确定为DPD严重缺乏的人 活动量与对照组的比较。家庭研究表明，DPD 活性遗传为常染色体隐性遗传。的后续研究 中度毒性的患者在一种中间体中显示出DPD活性 与在儿童或父母体内检测到的水平相似的范围 (杂合子)在严重缺乏患者的家系研究中。 我们建议如下：规范。目标1)确定人口分布 肿瘤中DPD活性和DPD基因缺陷频率的研究 和非癌症患者群体；规范。目标2)确定在 DPD活性与5-FU关系的前瞻性研究 毒性；SPEC目标3)测定DPD的生化性质 正常人和缺陷者外周血单个核细胞。 DPD虚弱患者与正常患者DPD的比较 个人应该提供对遗传机制的洞察力 DPD基因的多态性。这些研究在未来应该会对 预测哪些患者可能对严重的5-FU毒性敏感， 允许在化疗前修改药物剂量。

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.