Simple gas chromatographic-mass spectrometric procedure for diagnosing pyrimidine degradation defects for prevention of severe anticancer side effects.
Inborn errors of pyrimidine degradation, dihydropyrimidine dehydrogenase deficiency and dihydropyrimidinase deficiency, are less rare than has generally been assumed. Many asymptomatic cases have been reported, and in patients with symptoms, the clinical abnormalities are variable and nonspecific. Withdrawal of pyrimidine analogues such as 5-fluorouracil (5FU), a commonly used anticancer drug, from the cancer chemotherapy regimens of patients with pyrimidine degradation deficiencies, however, is critical because 5FU is degraded in vivo by pyrimidine-degradative enzymes. Patients with these deficiencies suffer from severe neurotoxicity, sometimes leading to death, following administration of 5FU, and even otherwise asymptomatic homozygotes or heterozygotes may develop severe clinical symptoms upon administration of such medication. Therefore, a rapid and specific method for identifying cancer patients with these enzyme deficiencies prior to treatment with 5FU is critical. To address this problem, we established methods for highly sensitive yet specific determinations of thymine, uracil, dihydrothymine, dihydrouracil, orotate and creatinine simultaneously in 0.1-ml liquid urine or filter-paper urine. This method involves stable isotope dilution, a simplified urease treatment previously described and gas chromatography-mass spectrometry without prior fractionation. The high recovery and low C.V. values were obtained and healthy control values were also determined for these metabolites. Using artificially prepared urine specimens simulating these disorders. the chemical diagnosis can be made clearly, and no further analysis appears to be required for differential chemical diagnosis.
Kuhara
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T
Division of Human Genetics, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan. kuhara@kanazawa-med.ac.jp
Ohdoi
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C
Ohse
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D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000652:urine; D011743:Pyrimidines / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D011743:Pyrimidines; C030986:pyrimidine; D005472:Fluorouracil