Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients

Casale, Federico; Canaparo, Roberto; Serpe, Loredana; Muntoni, Elisabetta; Pepa, Carlo Della; Costa, M.; Mairone, Lorenza; Zara, Gian Paolo; Fornari, Gianni; Eandi, Mario

doi:10.1016/j.phrs.2004.01.006

Cited by 88 publications

(48 citation statements)

References 18 publications

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“…While high doses of 5-FU exposure result in drastic and rapid cytotoxic effects, low doses, which correspond to doses used in the clinic [34, 35], promote delay in cytotoxicity. In particular, cells exposed to 10 μM of 5-FU for 24 hrs remain viable and metabolically active, and keep their capacity to synthesize proteins.…”

Section: Discussionmentioning

confidence: 99%

Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism

et al. 2017

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5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the translational machinery and that 5-FU affects the amount of some mRNAs associated with ribosomes. However, the impact of 5-FU on translational regulation remains unclear. Using translatome profiling, we report that a clinically relevant dose of 5-FU induces a translational reprogramming in colorectal cancer cell lines. Comparison of mRNA distribution between polysomal and non-polysomal fractions in response to 5-FU treatment using microarray quantification identified 313 genes whose translation was selectively regulated. These regulations were mostly stimulatory (91%). Among these genes, we showed that 5-FU increases the mRNA translation of HIVEP2, which encodes a transcription factor whose translation in normal condition is known to be inhibited by mir-155. In response to 5-FU, the expression of mir-155 decreases thus stimulating the translation of HIVEP2 mRNA. Interestingly, the 5-FU-induced increase in specific mRNA translation was associated with reduction of global protein synthesis. Altogether, these findings indicate that 5-FU promotes a translational reprogramming leading to the increased translation of a subset of mRNAs that involves at least for some of them, miRNA-dependent mechanisms. This study supports a still poorly evaluated role of translational control in drug response.

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Section: Discussionmentioning

confidence: 99%

Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism

et al. 2017

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“…Although 5-FU was shown to have substantial antibacterial effects, the tested concentrations in these studies were much higher than what is usually present in vivo. Notwithstanding the fact that after an intravenous bolus injection with 5-FU, plasma concentrations in cancer patients can reach some hundred micromolars, the plasma levels eventually drop to 15-30 µM after 30 min and to 0 µM after 2 h (Casale et al, 2004;Kosovec et al, 2008), owing to the short half-life time (6-22 min) of 5-FU (Bocci et al, 2000). In the case of continuous infusion with 5-FU, the plasma concentrations are much lower, ranging from 3 to 10 µM and kept for a longer time period (24 h) (Joulia et al, 1999;Takimoto et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

5-Fluorouracil sensitivity varies among oral micro-organisms

Vanlancker

Vanhoecke

Smet

et al. 2016

Journal of Medical Microbiology

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5-Fluorouracil (5-FU), a commonly used chemotherapeutic agent, often causes oral mucositis, an inflammation and ulceration of the oral mucosa. Micro-organisms in the oral cavity are thought to play an important role in the aggravation and severity of mucositis, but the mechanisms behind this remain unclear. Although 5-FU has been shown to elicit antibacterial effects at high concentrations (>100 µM), its antibacterial effect at physiologically relevant concentrations in the oral cavity is unknown. This study reports the effect of different concentrations of 5-FU (range 0.1-50 µM) on the growth and viability of bacterial monocultures that are present in the oral cavity and the possible role in the activity of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU resistance. Our data showed a differential sensitivity among the tested oral species towards physiological concentrations of 5-FU. Klebsiella oxytoca, Streptococcus salivarius, Streptococcus mitis, Streptococcus oralis, Pseudomonas aeruginosa and Lactobacillus salivarius appeared to be highly resistant to all tested concentrations. In contrast, Lactobacillus oris, Lactobacillus plantarum, Streptococcus pyogenes, Fusobacterium nucleatum and Neisseria mucosa showed a significant reduction in growth and viability starting from very low concentrations (0.2-3.1 µM). We can also provide evidence that DPD is not involved in the 5-FU resistance of the selected species. The observed variability in response to physiological 5-FU concentrations may explain why certain microbiota lead to a community dysbiosis and/or an overgrowth of certain resistant micro-organisms in the oral cavity following cancer treatment.

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“…For these reasons, some inter-patient differences in terms of toxicity and efficacy can be expected based on individual pharmacokinetic parameters, especially in the area under the time vs. concentration curve (AUC) Casale et al, 2004). Another problem with 5-FU therapy is its toxicity to the bone marrow and the gastrointestinal tract (Tanaka et al, 2000;Lai, Guo, 2011).…”

Section: Introductionmentioning

confidence: 99%

Development and validation of an HPLC method for the determination of fluorouracil in polymeric nanoparticles

Mattos

Khalil

Mainardes

2013

Braz. J. Pharm. Sci.

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The objective of this work was to develop and validate a rapid high performance liquid chromatography (HPLC) method for the quantitative analysis of fluorouracil (5-FU) in polymeric nanoparticles. Chromatographic analyses were performed on an RP C18 column with a mobile phase consisting of acetonitrile and water (10:90, v/v) at a flow rate of 1 mL/min. The 5-FU was detected and quantitated using a photodiode array detector at a wavelength of 265 nm. The method was shown to be specific and linear in the range of 0.1-10 μg/mL (r = 0.9997). The precision (intra-and inter-day) was demonstrated because the maximum relative standard deviation was 3.51%. The method is robust relative to changes in flow rate, column and temperature. The limits of detection and quantitation were 10.86 and 32.78 ng/mL, respectively. The method fulfilled the requirements for reliability and feasibility for application to the quantitative analysis of 5-FU in polymeric nanoparticles.Uniterms: Fluorouracil/determination. Nanoparticles. High performance liquid chromatography/ quantitative analysis/method validation.O objetivo deste trabalho foi desenvolver e validar um método rápido de cromatografia líquida de alta eficiência (CLAE) para análise quantitativa de fluorouracila (5-FU) em nanopartículas poliméricas. Corridas cromatográficas foram realizadas sob uma coluna RP C18 com uma fase móvel consistindo de acetonitrila e água (10:90, v/v) a um fluxo de 1 mL/min. O 5-FU foi detectado e quantificado através de um detector de fotodiodos em um comprimento de onda de 265 nm. O método demonstrou ser específico e linear na faixa de 0,1-10 μg/mL (r =0.9997). As precisões (intra e inter dia) revelaram um desvio padrão relativo máximo de 3,51%. O método é robusto considerando mudanças realizadas no fluxo da fase móvel, temperatura e marca da coluna. Os limites de detecção e quantificação foram de 10,86 e 32,78 ng/mL, respectivamente. O método cumpriu os requisitos para ser considerado confiável e viável para aplicação na análise quantitativa de 5-FU em nanopartículas poliméricas.Unitermos: Fluorouracila/determinação. Nanopartículas. Cromatografia líquida de alta eficiências/ análise quantitativa/validação de método.

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Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients

Cited by 88 publications

References 18 publications

Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism

Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism

5-Fluorouracil sensitivity varies among oral micro-organisms

Development and validation of an HPLC method for the determination of fluorouracil in polymeric nanoparticles

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