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变化，将潜在危及生命的5-FU或卡培他滨(希罗达)毒性降至最低。本课题组早些时候进行的临床药代动力学(PK)研究表明，80%的5-FU被尿嘧啶分解代谢途径的三种酶消除：二氢嘧啶脱氢酶(DPD)(起始酶和限速酶)、二氢嘧啶酶(DHP)和β-尿素丙酸酶(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，与标准剂量的5-FU管理后危及生命，有时甚至致命的毒性有关。这种药物遗传综合征最初估计发生在3%-5%的普通人群中。有趣的是，DHP或BUP1缺乏也可能与5-FU毒性相关，尽管明显不如DPD缺乏常见。不幸的是，在给予5-FU化疗之前，由于无法使用诊断试验(S)来评估这一途径的有效性和完整性，因此很难在这些酶步骤的每一个步骤中检测到改变的尿嘧啶(Ura)分解代谢。在过去的几年里，我们开发了一种新的诊断试验，[2-13C]-Ura呼气试验(13C-UraBT)，它有可能成为一种无创的、临床上有用的检测Ura分解代谢异常的方法(允许检测DPD、DHP或BUP1的缺陷)。在过去的一年里，我们在更大的志愿者人群中进一步验证了13C-UraBT，证明了：1)与DPD放射分析方法相比，13C-UraBT在检测DPD缺乏方面具有高水平的敏感性和特异性；2)呼气中的13CO2与血浆[2-13C]-二氢尿嘧啶(分解代谢)形成之间的相关性；3)非裔美国人中DPD缺乏的明显增加；4)DPD基因启动子(DPYD)的甲基化是DPD缺乏的未知基础；以及5)UraBT在检测Ura分解代谢途径中的其他缺陷方面的潜力。具体指标将检查：1)13C-UraBT呼气13CO2和血浆13C-Uracil PK与13C-5-FU呼气13CO2和13C-5-FU PK是否相关。2)~(13)C-UraBT以有限的采样方法，可以在大型癌症患者中快速检测5-FU分解代谢降低的癌症患者。3)在特定目的研究的癌症患者中，~(13)C-UraBT降低的分子(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.