Which 5-fluorouracil regimen? — the great debate

Vincent, Mark; Labianca, Roberto; Harper, Peter

doi:10.1097/00001813-199904000-00001

Cited by 19 publications

(6 citation statements)

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“…1 Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. It has been reported that more than 80% of the administered 5-FU is catabolized by DPD, [2][3][4] so the activity of this enzyme may be of paramount importance to predict the efficacy and toxicity of this drug. Deficiency in DPD enzyme activity has been correlated with considerable delay in 5-FU clearance from plasma.…”

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confidence: 99%

Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients

Salgueiro

Veiga

Fragoso

et al. 2004

Genetics in Medicine

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Purpose: Dihydropyrimidine dehydrogenase is a critical enzyme in the catabolism of 5-Fluorouracil, a drug frequently used in cancer therapy. Patients with deficient dihydropyrimidine dehydrogenase activity are at risk of developing severe 5-Fluorouracil-associated toxicity. Genetic analysis of the gene coding for dihydropyrimidine dehydrogenase has shown that mutations in exon 14, especially the splice-site mutation IVS14ϩ1G3 A, were associated with dihydropyrimidine dehydrogenase enzymatic deficiency. Methods: We evaluated the frequency of mutations in exon 14 of dihydropyrimidine dehydrogenase (DPYD) gene in 73 unselected colorectal cancer patients treated with 5-Fluorouracil after surgery at a Portuguese Cancer Institute. Results: Sequencing the entire exon 14 allowed the detection of mutations in two of the 73 patients (2.7%), namely two of the eight (25%) patients who presented grade 3-4 toxicity after 5-Fluorouracil chemotherapy. One patient was heterozygous for the splice-site mutation IVS14ϩ1G3 A, whereas the second patient was heterozygous for a novel missense mutation 1845G3 T (E615D) in exon 14 of DPYD gene. Conclusion: We conclude that mutations in exon 14 of DPYD gene are responsible for a significant proportion of life-threatening toxicity to 5-Fluorouracil, and should therefore be excluded before its administration to cancer patients. Genet Med 2004:6(2):102-107. Key Words: DPYD mutations, dihydropyrimidine dehydrogenase, 5-FU toxicity, 5-FU catabolism, chemotherapy5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic drugs for the treatment of malignant neoplasms, namely colorectal cancer. 5-FU is a pyrimidine analogue, giving rise to cytotoxic metabolites after metabolization by the pyrimidine pathways. One of them, the 5-fluorodUMP, inhibits thymidylate synthase, thus impairing DNA synthesis. Additional cytotoxic effects arise from 5-FU metabolites being incorporated into RNA and DNA. 1 Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. It has been reported that more than 80% of the administered 5-FU is catabolized by DPD, 2-4 so the activity of this enzyme may be of paramount importance to predict the efficacy and toxicity of this drug. Deficiency in DPD enzyme activity has been correlated with considerable delay in 5-FU clearance from plasma. 4,5 The important role of DPD in 5-FU-based chemotherapy has been demonstrated in cancer patients with major deficiency of this enzyme's activity. These patients may present severe toxicity after the administration of 5-FU, including diarrhea, neutropenia, and neurotoxicity, and death may occasionally occur. 6 -9 Population studies suggested that, although total deficiency is rare, as many as 3% to 5% of the population may have low enzyme levels and thus be at increased risk of severe toxicity if treated with 5-FU. 10 Several of these patients are genotypically heterozygous for a mutant DPYD allele. [11][12][13][14][15][16] To date, more than 30 variant DPYD alleles have been identi...

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confidence: 99%

Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients

Salgueiro

Veiga

Fragoso

et al. 2004

Genetics in Medicine

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“…In particular, 5‐fluorouracil remains the first line of therapy for patients with advanced colorectal cancer. However, the optimal infusion regimen for this drug is not known, and it is presently administered with a wide range of treatment schedules 1 , 2 , 3 , 4 . Both the pharmacodynamics and pharmacokinetics of 5‐fluorouracil are schedule dependent.…”

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Dose and time dependencies of 5-fluorouracil pharmacokinetics

Terret

Erdociain

Guimbaud

et al. 2000

Clinical Pharmacology & Therapeutics

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“…5-FU is effective in the treatment of multiple cancers primarily by inhibiting transition through the G1/S phase of the cell cycle . In addition, cell cycle arrest may also trigger apoptosis, thus contributing further to the anti-tumor activity of 5-FU . Using flow cytometry, we investigated the effect of the 5-FU-NCM co-crystal on HCT116 cells.…”

Section: Resultsmentioning

confidence: 99%

“…5-Fluorouracil (5-FU), one of the anti-tumor drugs used in 1960s, is a cell cycle inhibitor that has been widely used clinically against many solid tumors, including advanced colorectal cancer . It has also been administered with other drugs to treat ovarian, gastric, and head and neck cancers. − However, because of rapid metabolism and low oral bioavailability, 5-FU is rarely used in oral dosage forms.…”

Section: Introductionmentioning

confidence: 99%

Potential Anti-Tumor Drug: Co-Crystal 5-Fluorouracil-nicotinamide

Zhang

Xue

et al. 2020

ACS Omega

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5-Fluorouracil-nicotinamide (5-FU-NCM), a co-crystal with a 2D layer structure formed by hydrogen bonds, was synthesized by solvent evaporation and liquid phase-assisted grinding at room temperature. Compared to 5-FU alone, the results of solubility, oil−water partition coefficient, anti-tumor effect in vivo and vitro, acute toxicity, and pharmacokinetic parameters indicate that the co-crystal is a potential anti-tumor drug.

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Which 5-fluorouracil regimen? — the great debate

Cited by 19 publications

References 0 publications

Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients

Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients

Dose and time dependencies of 5-fluorouracil pharmacokinetics

Potential Anti-Tumor Drug: Co-Crystal 5-Fluorouracil-nicotinamide

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