5-fluorouridine-5--triphosphate and Neoplasms

Topics: Animals; Enzyme Activation; Fluorouracil; Humans; Neoplasms; Pyrimidines; RNA; Thymidylate Synthase; Transcription, Genetic; Uracil Nucleotides; Uridine Triphosphate

Capecitabine is an oral pro-drug of 5-fluorouracil. Patients with solid tumours who are treated with capecitabine may develop hand-and-foot syndrome (HFS) as side effect. This might be a result of accumulation of intracellular metabolites. We characterised the pharmacokinetics (PK) of 5-fluorouridine 5'-triphosphate (FUTP) in peripheral blood mononuclear cells (PBMCs) and assessed the relationship between exposure to capecitabine or its metabolites and the development of HFS. Plasma and intracellular capecitabine PK data and ordered categorical HFS data was available. A previously developed model describing the PK of capecitabine and metabolites was extended to describe the intracellular FUTP concentrations. Subsequently, a continuous-time Markov model was developed to describe the development of HFS during treatment with capecitabine. The influences of capecitabine and metabolite concentrations on the development of HFS were evaluated. The PK of intracellular FUTP was described by an one-compartment model with first-order elimination (k

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Biological Variation, Population; Capecitabine; Computer Simulation; Datasets as Topic; Dose-Response Relationship, Drug; Drug Dosage Calculations; Hand-Foot Syndrome; Humans; Leukocytes, Mononuclear; Markov Chains; Models, Biological; Neoplasms; Primary Cell Culture; Prodrugs; Uridine Triphosphate

Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy).. Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8.. The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m

Topics: Adult; Aged; Antineoplastic Agents; Capecitabine; Circadian Rhythm; Dihydrouracil Dehydrogenase (NADP); Drug Chronotherapy; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Thymidylate Synthase; Uridine Triphosphate

The major molecular mode of action of the cytotoxic drug 5-fluorouracil (5-FU) is generally considered to result from thymidylate synthase inhibition. Recent findings relating to the function of the human uracil-5 methyltransferase (U5MT), TRMT2A, and its interaction with 5-FU metabolites incorporated within tRNAs, lead to an additional hypothesis that is proposed here.

Topics: Cell Cycle; Cell Survival; DNA Damage; Fluorouracil; Humans; Methylation; Neoplasms; Recombinational DNA Repair; RNA, Transfer; tRNA Methyltransferases; Uridine Triphosphate

Three intracellularly formed metabolites are responsible for the antineoplastic effect of capecitabine: 5-fluorouridine 5'-triphosphate (FUTP), 5-fluoro-2'-deoxyuridine 5'-triphosphate (FdUTP), and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). The objective of this study was to explore the pharmacokinetics of these intracellular metabolites during capecitabine treatment.. Serial plasma and peripheral blood mononuclear cell (PBMC) samples were collected from 13 patients treated with capecitabine 1000 mg QD (group A) and eight patients receiving capecitabine 850 mg m(-2) BID for fourteen days, every three weeks (group B). Samples were collected on day 1 and, for four patients of group B, also on day 14. The capecitabine and 5-fluorouracil (5-FU) plasma concentrations and intracellular metabolite concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using non-compartmental analysis.. Only FUTP could be measured in the PBMC samples. The FdUTP and FdUMP concentrations were below the detection limits (LOD). No significant correlation was found between the plasma 5-FU and intracellular FUTP exposure. The FUTP concentration-time profiles demonstrated considerable inter-individual variation and accumulation of the metabolite in PBMCs. FUTP levels ranged between

Topics: Antimetabolites, Antineoplastic; Area Under Curve; Capecitabine; Chromatography, Liquid; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Deoxyuracil Nucleotides; Deoxyuridine; Fluorouracil; Humans; Leukocytes, Mononuclear; Neoplasms; Tandem Mass Spectrometry; Uridine Triphosphate