A Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of 5-Fluorouracil Degradation Rate by Intact Peripheral Blood Mononuclear Cells

Lostia, Alfonso; Lionetto, Luana; Ialongo, Cristiano; Gentile, Giovanna; Viterbo, Antonella; Malaguti, Paola; Paris, Ida; Marchetti, Luca; Marchetti, Paolo; Blasi, Antonio De; Simmaco, Maurizio

doi:10.1097/ftd.0b013e3181ae4516

Cited by 32 publications

(24 citation statements)

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“…16,17 Then, we studied the association of the detected SNPs with a parameter that evaluates the individual ability to metabolize fluorouracil, the 5-FUDR, that has been previously reported to be associated with 5-FU-related severe toxicity even in the absence of the *2A DPYD allele. 12 The 5-FUDR value, assessed before As the individual pretreatment 5-FUDR value is independent of cancer type and therapeutic regimens, the study of correlations between the DPYD genotype and the 5-FUDR phenotype allows the rapid identification of genetic markers, which are likely to affect even toxicity, to be validated in larger clinical studies.…”

Section: Discussionmentioning

confidence: 99%

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Genotype–phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction

et al. 2015

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5-Fluorouracil is among the most widely used anticancer drug, but a fraction of treated patients develop severe toxicity, with potentially lethal injuries. The predictive power of the available pretreatment assays, used to identify patients at risk of severe toxicity, needs improvements. This study aimed to correlate a phenotypic marker of 5-fluorouracil metabolism (the individual degradation rate of 5-fluorouracil-5-FUDR) with 15 functional polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD). Single SNP (single-nucleotide polymorphism) analysis revealed that the SNPs rs1801160, rs1801265, rs2297595 and rs3918290 (splice site variant IVS14+1G>A) were significantly associated with a decreased value of 5-FUDR, and the rs3918290 causing the larger decrease. Multi-SNP analysis showed that a three-SNP haplotype (Hap7) involving rs1801160, rs1801265 and rs2297595 causes a marked decrease in 5-FUDR, comparable to that caused by the splice site variant rs3918290, which is the main pharmacogenetic marker associated with severe fluorouracil toxicity. The similar effect played by Hap7 and by the splice site variant rs3918290 upon individual 5-FUDR suggests that Hap7 could also represent a similar determinant of fluorouracil toxicity. Haplotype assessment could improve the predictive value of DPYD genetic markers aimed at the pre-emptive identification of patients at risk of severe 5-fluorouracil toxicity.The Pharmacogenomics Journal advance online publication, 28 July 2015; doi:10.1038/tpj.2015.56.

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Section: Discussionmentioning

confidence: 99%

“…12 This study was aimed to investigate genotype-phenotype correlation in 5-FU metabolism by an association analysis of 15 DPYD polymorphisms (Table 1) with the individual 5-FUDR value.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction

et al. 2015

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“…PBMCs were isolated from whole blood by means of Ficoll-Paque Plus (GE Healthcare Piscataway, NY, USA) density gradient centrifugation [17]; 10-mL heparinized whole blood diluted 1:1 with phosphate-buffered saline (PBS), were layered on top of 5-mL Ficoll and centrifuged without a brake at 500× g (20°C) for 30 min and the PBMC ring was collected, and diluted with GIBCO RPMI 1640 (Invitrogen, Carlsbab, CA, USA) to a final volume of 50 mL, and centrifuged at 500× g for 15 min at room temperature. The pellet was washed again with RPMI 1640 for the measurement.…”

Section: Methodsmentioning

confidence: 99%

Alteration of Interferon-α/β Receptors in Chronic Hepatitis B Patients

Meng

Wang

et al. 2011

J Clin Immunol

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Background The present study determined type I interferon (IFN) receptor (interferon-α/β receptor (IFNAR)) and its predicable role in interferon-α2b treatment in chronic hepatitis B (CHB) patients. Methods Expression of IFN-α/βR-1 and IFN-α/βR-2 in peripheral blood mononuclear cells and in liver tissue was measured by flow cytometry, immunofluorescence, immunohistochemistry and RT-PCR. Results IFN-α/βR-1 and IFN-α/βR-2 in monocytes and lymphocytes increased in CHB patients. Expression of IFNAR-1 and IFNAR-2 in liver had positive correlation with HBV-DNA in liver tissue. Expression of IFN-α/βR in lymphocytes and monocytes increased in the first month, but then decreased during the subsequent interferon-α2b treatment, patients who had higher levels of IFN-α/βR-2 in monocytes prior to therapy showed better viral response than those with lower levels. Conclusions Expression of IFN-α/βR-2 in monocytes can be used as a predictable parameter to evaluate the effect of IFN-α treatment in CHB patients.

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“…[7, 27, 28] To overcome this limit, we have previously developed a pre-treatment ex-vivo assay to determine the velocity at which the peripheral blood mononuclear cells (PBMC) metabolize 5-FU. [29] This parameter, named individual 5-FU degradation rate (5-FUDR, expressed as nmol of drug consumed by cells in a time unit), is performed in intact and viable cells, thus it the final result of all the enzymatic transformation of 5-FU, not just the DPD activity. The individual, pre-treatment 5-FUDR value, was found to be significantly lower in patients who develop grade 3-4 toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…The individual, pre-treatment 5-FUDR value, was found to be significantly lower in patients who develop grade 3-4 toxicity. [29]…”

Section: Introductionmentioning

confidence: 99%

Pre-treatment assay of 5-fluorouracil degradation rate (5-FUDR) to improve prediction of 5-fluorouracil toxicity in gastro-esophageal cancer

et al. 2016

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Background5-fluorouracil (5-FU) based chemotherapy is the most common first line regimen used in gastric and gastroesophageal junction cancer, but development of severe toxicity is a main concern in the treatment. The present study is aimed to evaluate a novel pre-treatment assay, known as the 5-FU degradation rate (5-FUDR), as a predictive factor for 5-FU toxicity.MethodsPre-treatment 5-FUDR and gene polymorphisms related to 5-FU metabolism (DPYDIVS14+1G>A, MTHFRA1298T or C677T, TMYS TSER) were characterized in gastro-esophageal cancer patients. Association with toxicities was retrospectively evaluated, using multivariate logistic regression analysis.Results107 gastro-esophageal cancer patients were retrospectively analyzed. No relation between gene polymorphisms and toxicity were detected, while low (< 5th centile) and high (> 95th centile) 5-FUDRs were associated with development of grade 3-4 toxicity (OR 11.14, 95% CI 1.09-113.77 and OR 9.63, 95% CI 1.70-54.55, p = 0.002).ConclusionsCompared to currently used genetic tests, the pre-treatment 5-FUDR seems useful in identifying patients at risk of developing toxicity.

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A Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of 5-Fluorouracil Degradation Rate by Intact Peripheral Blood Mononuclear Cells

Cited by 32 publications

References 23 publications

Genotype–phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction

Genotype–phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction

Alteration of Interferon-α/β Receptors in Chronic Hepatitis B Patients

Pre-treatment assay of 5-fluorouracil degradation rate (5-FUDR) to improve prediction of 5-fluorouracil toxicity in gastro-esophageal cancer

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