John A Duley1,2, Ming Ni1, Catherine Shannon2, Ross L Norris3, Leslie Sheffield4, David Cowley2, Marion Harris5, André B P van Kuilenburg6, Nuala Helsby7, Rani George8, Bruce G Charles1. 1. School of Pharmacy, Pharmacy Australia Center of Excellence, The University of Queensland. 2. Mater Research Institute, The University of Queensland, Woolloongabba, Queensland. 3. Discipline of Clinical Pharmacology, School of Medicine & Public Health, University of Newcastle, Newcastle, New South Wales. 4. MyDNA Life Australia Pty Limited, South Yarra, Victoria, Australia. 5. Monash Health, East Bentleigh, Victoria, Australia. 6. Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands. 7. Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand. 8. Mater Health Services, Raymond Terrace, South Brisbane, Australia.
Abstract
BACKGROUND: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil 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 most fluorouracil toxicity cases remains unexplained. METHODS: For this small cohort study, thymine (THY) 250 mg was administered orally to 6 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 6 patients, 2 had decreased THY elimination and raised urinary THY recovery consistent with inherited partial dihydropyrimidine dehydrogenase deficiency, confirmed by DPYD sequencing. Unexpectedly, 3 patients displayed grossly raised plasma THY concentrations but normal elimination profiles (compared with a normal range for healthy volunteers previously published by the authors). DPYD and DPYS sequencing of these 3 patients did not reveal any significant loss-of-activity allelic variants. The authors labeled the phenotype in these 3 patients as "enhanced thymine absorption". Only 1 of the 6 cases of toxicity had a normal postdose plasma profile for THY and its catabolites. Postdose urine collections from all 6 patients had THY/DHT urinary ratios above 4.0, clearly separated from the ratios in healthy subjects that were all below 3.0. CONCLUSIONS: This small cohort provided evidence for a hypothesis that fluorouracil toxicity cases may include a previously undescribed pyrimidine absorption variant, "enhanced thymine absorption," and elevated THY/DHT ratios in urine may predict fluorouracil toxicity. A prospective study is currently being conducted.
BACKGROUND: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil 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 most fluorouraciltoxicity cases remains unexplained. METHODS: For this small cohort study, thymine (THY) 250 mg was administered orally to 6 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 6 patients, 2 had decreased THY elimination and raised urinary THY recovery consistent with inherited partial dihydropyrimidine dehydrogenase deficiency, confirmed by DPYD sequencing. Unexpectedly, 3 patients displayed grossly raised plasma THY concentrations but normal elimination profiles (compared with a normal range for healthy volunteers previously published by the authors). DPYD and DPYS sequencing of these 3 patients did not reveal any significant loss-of-activity allelic variants. The authors labeled the phenotype in these 3 patients as "enhanced thymine absorption". Only 1 of the 6 cases of toxicity had a normal postdose plasma profile for THY and its catabolites. Postdose urine collections from all 6 patients had THY/DHT urinary ratios above 4.0, clearly separated from the ratios in healthy subjects that were all below 3.0. CONCLUSIONS: This small cohort provided evidence for a hypothesis that fluorouraciltoxicity cases may include a previously undescribed pyrimidine absorption variant, "enhanced thymine absorption," and elevated THY/DHT ratios in urine may predict fluorouraciltoxicity. A prospective study is currently being conducted.
Authors: Nuala A Helsby; John Duley; Kathryn E Burns; Claire Bonnet; Soo Hee Jeong; Elliott Brenman; Paula Barlow; Katrina Sharples; David Porter; Michael Findlay Journal: Br J Clin Pharmacol Date: 2019-12-12 Impact factor: 4.335
Authors: Kathryn E Burns; Ottiniel Chavani; Soo Hee Jeong; John A Duley; David Porter; Michael Findlay; R Matthew Strother; Nuala A Helsby Journal: Cancer Chemother Pharmacol Date: 2021-03-09 Impact factor: 3.333