TY - JOUR
T1 - Thymine as potential biomarker to predict 5-FU systemic exposure in patients with gastro-intestinal cancer
T2 - a prospective pharmacokinetic study (FUUT-trial)
AU - Hanrath, Maarten A.
AU - Banken, Evi
AU - van den Wildenberg, Sebastian A. H.
AU - van de Kerkhof, Daan
AU - Moes, Dirk Jan A. R.
AU - Boisdron-Celle, Michele
AU - van den Bosch, Bianca J. C.
AU - Bax, Ramon
AU - Bet, Pierre M.
AU - Maring, Jan Gerard
AU - Creemers, Geert-Jan M.
AU - van Hellemond, Irene. E. G.
AU - Deenen, Maarten J.
PY - 2025/2/15
Y1 - 2025/2/15
N2 - PurposeIn 20-30% of the patients, fluoropyrimidines (5-FU) based chemotherapy leads to severe toxicity, which is associated with dihydropyridine dehydrogenase (DPD) deficiency. Therefore, DPYD genotyping became standard practice before treatment with fluoropyrimidines. Nevertheless, only 17% of the patients with severe toxicity have a DPYD variant. Therefore, an urgent need persists to investigate other strategies contributing to prediction and prevention of toxicity. Endogenous DPD substrates are considered as potential biomarkers to predict toxicity, yet contradictional data exist on demonstrating uracil as a reliable biomarker. Thymine as biomarker for toxicity has been investigated less. The aim of this study was to determine the association between the concentrations of uracil, thymine dihydrouracil (DHU) and dihydrothymine (DHT), with the systemic drug exposure of 5-FU and DPD enzyme activity in patients treated with 5-FU.MethodsWe included 36 patients with gastrointestinal malignancy who received 5-FU infusion. DPYD genotyping was conducted before start of treatment. Blood samples for determining 5-FU, uracil and thymine concentrations during infusion and DPD enzyme activity were taken.ResultsWe found a significant correlation between the 5-FU systematic exposure and baseline thymine concentrations (R2 = 0.1468; p = 0.0402). DPD enzyme activity was significantly correlated with baseline thymine concentrations but no correlation was found between DPD enzyme activity and 5-FU systemic drug exposure.Conclusion5-FU dose individualization based on thymine concentrations could be a promising addition to DPYD genotyping to predict 5-FU-induced toxicity. Larger prospective trials are needed to examine thymine as predictor for toxicity in daily practice.Trial registrationTrial NL7539 at 'Overview of Medical Research in the Netherlands' (ID NL-OMON21471). Date of registration 19-02-2019.
AB - PurposeIn 20-30% of the patients, fluoropyrimidines (5-FU) based chemotherapy leads to severe toxicity, which is associated with dihydropyridine dehydrogenase (DPD) deficiency. Therefore, DPYD genotyping became standard practice before treatment with fluoropyrimidines. Nevertheless, only 17% of the patients with severe toxicity have a DPYD variant. Therefore, an urgent need persists to investigate other strategies contributing to prediction and prevention of toxicity. Endogenous DPD substrates are considered as potential biomarkers to predict toxicity, yet contradictional data exist on demonstrating uracil as a reliable biomarker. Thymine as biomarker for toxicity has been investigated less. The aim of this study was to determine the association between the concentrations of uracil, thymine dihydrouracil (DHU) and dihydrothymine (DHT), with the systemic drug exposure of 5-FU and DPD enzyme activity in patients treated with 5-FU.MethodsWe included 36 patients with gastrointestinal malignancy who received 5-FU infusion. DPYD genotyping was conducted before start of treatment. Blood samples for determining 5-FU, uracil and thymine concentrations during infusion and DPD enzyme activity were taken.ResultsWe found a significant correlation between the 5-FU systematic exposure and baseline thymine concentrations (R2 = 0.1468; p = 0.0402). DPD enzyme activity was significantly correlated with baseline thymine concentrations but no correlation was found between DPD enzyme activity and 5-FU systemic drug exposure.Conclusion5-FU dose individualization based on thymine concentrations could be a promising addition to DPYD genotyping to predict 5-FU-induced toxicity. Larger prospective trials are needed to examine thymine as predictor for toxicity in daily practice.Trial registrationTrial NL7539 at 'Overview of Medical Research in the Netherlands' (ID NL-OMON21471). Date of registration 19-02-2019.
KW - Gastrointestinal cancer
KW - 5-Flurouracil
KW - Endogenous DPD substrates
KW - Toxicity
KW - Thymine
KW - DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITY
KW - ADVANCED COLORECTAL-CANCER
KW - DEFICIENT PATIENTS
KW - MONONUCLEAR-CELLS
KW - SEVERE TOXICITY
KW - PLASMA RATIO
KW - 5-FLUOROURACIL
KW - URACIL
KW - FLUOROURACIL
KW - DPYD
U2 - 10.1007/s00280-025-04759-8
DO - 10.1007/s00280-025-04759-8
M3 - Article
SN - 0344-5704
VL - 95
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 1
M1 - 34
ER -