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. ? ? ? ?
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