Screening for Decreased 5-Fluorouracil Catabolism

描述（由申请人提供）：该项目的长期目标是通过在治疗前快速识别癌症患者尿嘧啶分解代谢的改变，将可能危及生命的5-氟尿嘧啶（例如5-FU或卡培他滨（希罗达））的毒性降到最低。我们小组早期进行的临床药代动力学（PK）研究表明，80%给药的5-FU被尿嘧啶分解代谢途径的三种酶所消除：二氢嘧啶脱氢酶（DPD）（初始酶和限速酶）、二氢嘧啶酶（DHP）和β -尿嘧啶丙酸酶（BUP1）。我们的实验室随后描述并继续描述了一种药物遗传综合征，DPD缺乏症，在给予标准剂量的5-FU后，与危及生命和有时致命的毒性有关。这种药物遗传综合征最初估计发生在3-5%的普通人群中。令人感兴趣的是，DHP或BUP1的缺乏也可能与5-FU毒性有关，尽管明显不如DPD缺乏常见。不幸的是，在给予5-FU化疗之前，由于无法获得诊断测试来评估该途径的效率和完整性，很难在每个酶解步骤中检测尿嘧啶（Ura）分解代谢的改变。在过去的几年里，我们开发了一种新的诊断测试，[2-13C]- Ura呼气测试（13C-UraBT），它有可能成为一种无创的临床有用的检测Ura分解代谢改变的测试（允许检测DPD， DHP或BUP1的缺乏）。去年，我们在更大的志愿者人群中进一步验证了13C-UraBT: 1)与DPD放射检测相比，在检测DPD缺乏方面具有高水平的敏感性和特异性；2)呼吸中的13CO2与血浆[2- 13c]-二氢尿嘧啶（分解代谢物）形成之间存在相关性；3)非洲裔美国人DPD缺乏症明显增加；4) DPD基因启动子甲基化（DPYD）是DPD缺乏症的未被认识的基础；5) UraBT在检测Ura分解代谢途径中其他缺陷方面的潜力。Specific Aims将检验：1)13C-UraBT呼吸13CO2和血浆13c -尿嘧啶PK是否与13C-5-FU呼吸13CO2和血浆13C-5-FU PK相关。2)在大型癌症患者研究中，13C-UraBT通过有限的采样方法，可以快速检测出5-FU分解代谢减少的癌症患者。3)Specific Aim 2中研究的癌症患者13C-UraBT减少的分子（遗传/表观遗传学）基础。

DESCRIPTION (provided by applicant): The long term objective of this project is to minimize potentially life-threatening 5-fluorouracil [e.g., 5-FU or Capecitabine (Xeloda)] toxicity through the rapid identification of altered uracil catabolism in cancer patients prior to therapy. Clinical pharmacokinetic (PK) studies performed earlier by our group demonstrated that >80% of administered 5-FU is eliminated by the three enzymes of the uracil catabolic pathway: dihydro- pyrimidine dehydrogenase (DPD) (the initial and rate limiting enzyme), dihydropyrimidinase (DHP), and beta- ureidopropionase (BUP1). Our laboratory subsequently described and has continued to characterize a pharmacogenetic syndrome, DPD deficiency, associated with life-threatening and at times fatal toxicity following the administration of standard doses of 5-FU. This pharmacogenetic syndrome was initially estimated to occur in 3-5% of the general population. Of interest is the fact that deficiency of DHP or BUP1 may also be associated with 5-FU toxicity, although clearly less common than DPD deficiency. Unfortunately, detection of altered uracil (Ura) catabolism at each of these enzymatic steps prior to the administration of 5-FU chemotherapy has been difficult due to the unavailability of diagnostic test(s) to assess the efficiency and integrity of this pathway. Over the past few years, we have developed a new diagnostic test, the [2-13C]- Ura breath test (13C-UraBT) that has potential as a non-invasive and clinically useful test for the detection of altered Ura catabolism (permitting detection of deficiency of DPD, DHP or BUP1). In the last year, we have further validated the 13C-UraBT in a larger volunteer population demonstrating: 1) a high level of sensitivity and specificity in detecting DPD deficiency compared to the DPD radioassay 2) correlation between 13CO2 in breath with plasma [2-13C]-dihydrouracil (catabolite) formation; 3) an apparent increase of DPD deficiency in African Americans; 4) methylation of the promoter of the gene for DPD (DPYD) as an unrecognized basis for DPD deficiency; and 5) potential of the UraBT in detection of other defects in the Ura catabolic pathway. Specific Aims will examine whether: 1) 13C-UraBT breath 13CO2 and plasma 13C-Uracil PK correlate with 13C-5-FU breath 13CO2 and plasma 13C-5-FU PK. 2) the 13C-UraBT, with a limited sampling approach, can rapidly detect cancer patients with decreased 5-FU catabolism in a large cancer patient study 3) Molecular (genetic/epigenetic) basis of decreased 13C-UraBT in cancer patients studied in Specific Aim 2.