Preliminary evidence for enhanced thymine absorption: a putative new phenotype associated with fluoropyrimidine toxicity in cancer patients

BACKGROUND: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily upon 5-fluorouracil (5FU) and its oral prodrug capecitabine. Associations of serious fluoropyrimidine adverse effects have focused on inherited deficiency of the catabolic enzyme, dihydropyrimidine dehydrogenase. However, abnormal dihydropyrimidine dehydrogenase activity accounts for only about one-third of observed toxicity cases. Thus, the cause of the majority of fluorouracil toxicity cases remains unexplained. METHODS: For this small cohort study, thymine (THY) 250 mg was administered orally to six patients who had experienced severe toxicity during treatment with 5FU or capecitabine. Plasma and urine were analyzed for THY and its catabolites dihydrothymine (DHT) and β-ureidoisobutyrate. RESULTS: Of the six patients, two had decreased THY elimination and raised urinary THY recovery consistent with inherited partial dihydropyrimidine dehydrogenase deficiency, confirmed by DPYD sequencing. Unexpectedly, three patients displayed grossly raised plasma THY concentrations but normal elimination profiles (compared to a normal range for healthy volunteers previously published by the authors). DPYD and DPYS sequencing of these three patients did not reveal any significant loss-of-activity allelic variants. The authors labeled the phenotype in these three patients as "enhanced thymine absorption" (ETA). Only one of the six cases of toxicity had a normal post-dose plasma profile for THY and its catabolites. Post-dose urine collections from all six patients had THY/DHT urinary ratios above 4.0, clearly separated from the ratios in healthy subjects that were all below 3.0. CONCLUSION: This small cohort provided evidence for a hypothesis that fluorouracil toxicity cases may include a previously undescribed pyrimidine absorption variant, ETA, and that elevated THY/DHT ratios in urine may predict fluorouracil toxicity. A prospective study is currently being conducted