Screening for Decreased 5-Fluorouracil Catabolism

描述（由申请方提供）：本项目的长期目标是尽量减少可能危及生命的5-氟尿嘧啶[例如，5-FU或卡培他滨（希罗达）]毒性，通过在治疗前快速鉴定癌症患者中改变的尿嘧啶催化剂。我们小组早期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）（初始和限速酶）、二氢嘧啶酶（DHP）和β-脲基丙酸酶（BUP 1）。我们的实验室随后描述并继续描述药物遗传学综合征，DPD缺乏症，与标准剂量5-FU给药后危及生命，有时致命的毒性相关。这种药物遗传学综合征最初估计发生在3-5%的一般人群中。令人感兴趣的是，DHP或BUP 1的缺乏也可能与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，在这些酶促步骤中的每一个中检测改变的尿嘧啶（Ura）催化剂是困难的，这是由于无法获得诊断测试来评估该途径的效率和完整性。在过去的几年里，我们开发了一种新的诊断测试，[2- 13 C]- Ura呼吸测试（13 C-UraBT），它有可能作为一种非侵入性和临床上有用的测试，用于检测改变的Ura catalysts（允许检测DPD，DHP或BUP 1的缺乏）。去年，我们在更大的志愿者人群中进一步验证了13 C-UraBT，证明：1）与DPD放射性测定相比，13 C-UraBT在检测DPD缺乏方面具有高水平的灵敏度和特异性2）呼气中的13 CO2与血浆[2- 13 C]-二氢尿嘧啶之间的相关性（分解代谢物）形成; 3）非裔美国人中DPD缺乏症的明显增加; 4）DPD（DPYD）基因启动子的甲基化作为DPD缺乏症的未被认识的基础;和5）UraBT在检测Ura分解代谢途径中的其它缺陷中的潜力。特定目的将检查：1）13 C-UraBT呼气13 CO2和血浆13 C-尿嘧啶PK是否与13 C-5-FU呼气13 CO2和血浆13 C-5-FU PK相关。2)在一项大型癌症患者研究中，13 C-UraBT采用有限的采样方法，可以快速检测出5-FU催化剂减少的癌症患者。3）在特定目标2中研究的癌症患者中13 C-UraBT减少的分子（遗传/表观遗传）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.