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PubMed1991

High-performance liquid chromatographic method for the simultaneous measurement of floxuridine and fluorouracil in human body fluids.

A method for the simultaneous measurement of floxuridine (5-fluorodeoxyuridine) and fluorouracil in human plasma and peritoneal fluid has been developed. This method utilizes high-performance liquid chromatographic analysis with a Zorbax RX column (25 cm x 4.6 mm I.D.) plus a guard cartridge of the same material. The sensitivity limits for this assay are 0.25 mumol/l in a 20-microliters sample. The detection limit at a signal-to-noise ratio of 3 is 2.5 nmol/l. This procedure has been used to quantitatively measure concentration versus time profiles of floxuridine and fluorouracil in plasma and peritoneal fluid of human patients after receiving intraperitoneal administration of floxuridine.

Ascitic Fluid↗
PubMed1992

Determination of 5-fluorouracil and its main metabolites in plasma by high-performance liquid chromatography.

A relatively simple and sensitive ion-pair high-performance liquid chromatographic method has been developed for measuring the anticancer drug fluorouracil and its main metabolites, fluorouridine, fluorodeoxyuridine and fluorodeoxyuridine monophosphate in human plasma. A reversed-phase C18 column (150 mm x 2 mm I.D.) and ultraviolet detection (280 nm) were used. The influence of the tetrabutylammonium phosphate and monopotassium phosphate concentrations and pH of the mobile phase on the various k' values was investigated. The optimal k' values obtained for the four compounds ranged between 0.7 and 5.9. The optimized eluent was (10(-4) M tetrabutylammonium phosphate plus 2.10(-2) M potassium dihydrogen phosphate, pH 5.9)-methanol (95.5:4.5, v/v). The flow-rate was 0.3 ml/min. The procedure for plasma preparation included solvent extraction using ethyl acetate-methanol (80:20) followed by elution on C18 Sep-Pak cartridges to separate the four compounds from constituents normally occurring in plasma. The detection limit of the assay was 2 ng/ml (5-fluorouracil), 10 ng/ml (5-fluorouridine), 10 ng/ml (5-fluoro-2'-deoxyuridine) and 50 ng/ml (5-fluoro-2'-deoxyuridine 5'-monophosphate).

Chromatography, High Pressure Liquid↗
PubMed1992

Gas chromatographic-mass spectrometric method for routine monitoring of 5-fluorouracil in plasma of patients receiving low-level protracted infusions.

A gas chromatographic-mass spectrometric (GC-MS) method is described which quantitates 5-fluorouracil (5-FU) plasma levels ranging from 0.5 to 50 ng/ml. The analysis uses two internal standards, 1,3-[15N2]-5-fluorouracil and 5-chlorouracil. Extraction and derivatization of the pyrimidine bases were accomplished in a single step using acetonitrile. Compounds were analyzed as their 1,3-dipentafluorobenzyl derivatives by electron-impact MS, and the GC-MS analysis was automated with respect to sample injection and data reduction. Stability of the analysis was demonstrated by continuous unattended analysis of 5-FU in human plasma for periods of up to three days with no deterioration of the quantitative results. The method is applicable to quantitating 5-FU plasma levels in patients receiving protracted infusions of the drug for colorectal cancer or other malignancies.

Drug Monitoring↗
PubMed1993

Determination of leucovorin and 5-fluorouracil in plasma by high-performance liquid chromatography.

A method was developed for the determination of (6R)- and (6S)-leucovorin and 5-fluorouracil in plasma. As leucovorin diastereoisomers cannot be separated on a classical reversed-phase column, it was necessary to use a chiral stationary phase. The method presented is based on the same principle as the method described by Wainer and Stiffin [J. Chromatogr., 424 (1988) 158], i.e., coupling of a bovine serum albumin phase to an achiral stationary phase. Before the chromatography, the drug was isolated from the plasma matrix by solid-phase extraction. For 5-fluorouracil, chromatography was performed on a classical RP-18 column after extraction from the plasma by liquid-liquid extraction. Both methods were validated and applied to the analysis of patients' samples.

Buffers↗
PubMed1987

Fluorine-19 NMR spectroscopic studies of the metabolism of 5-fluorouracil in the liver of patients undergoing chemotherapy.

Fluorine-19 nuclear magnetic resonance allows direct observation of fluorinated drugs and their metabolites in the human body without background signal from the tissue. A well-known fluorinated chemotherapeutic drug, 5-fluorouracil, and its metabolites were observed noninvasively in the liver of three patients undergoing cancer chemotherapy. Spectra were obtained at 1.5 T with a surface coil centered over the right lobe of the patient's liver. Administration of 1.5 gm of 5-fluorouracil was done after positioning in the magnet. Serial spectra, collected over a 2-h period, revealed both the nature of the metabolites present in the liver, and the time course of each patient's metabolism. These observations represent the first noninvasive NMR study of drugs in human patients and show the feasibility of using in vivo F-19 NMR spectroscopy for human studies of fluorinated compounds.

Female↗
PubMed1989

Reversed-phase ion-pair analysis of 5-fluorouracil in pig bile, liver homogenate, plasma and urine after administration by isolated liver perfusion.

5-Fluorouracil is at present one of the most administered cytostatic drugs in cancer chemotherapy. However, due to its high toxicity, local administration of the drug, e.g. by isolated liver perfusion, may be advantageous. A bioanalytical procedure, suitable for the routine analysis of 5-fluorouracil in pig bile, liver homogenates, plasma and urine is described using reversed-phase ion-pair chromatography with absorbance detection at 268 nm. Using a protein precipitation procedure with acetonitrile, a determination limit of 3500 ng g-1 was achieved for liver samples, and 5 ng ml-1 for plasma samples using a liquid-liquid extraction step.

Animals↗
PubMedDate not supplied

The role of interferon-alpha as a modulator of fluorouracil and leucovorin.

Several preclinical studies have demonstrated that interferon-alpha (IFN-alpha) may enhance the cytotoxicity of fluoropyrimidines in a greater-than-additive manner in a variety of human cancer cell lines. The underlying mechanism(s) have varied in different cancer cell lines, and include increased fluorouracil anabolism to fluorodeoxyuridine monophosphate, further inhibition of thymidylate synthase, stimulation of thymidine and uridine phosphorylase activities, greater DNA damage, and enhanced natural killer cell-mediated lysis of tumour targets. These preclinical studies stimulated clinical evaluation of IFN-alpha in combination with 5-fluorouracil (5-FU) with and without leucovorin (LV), and the initial clinical results appeared promising. We summarise preclinical research concerning the interaction of 5-FU and IFN-alpha. The rationale for combining 5-FU with IFN-alpha and LV is discussed, and we describe our clinical experience with the combination of 5-FU, LV and IFN-alpha-2a. The insights and unresolved questions concerning the clinical application of this combination are also discussed.

Antidotes↗
PubMed2005

[Reversible cardiogenic shock under 5-fluorouracil treatment].

5-fluorouracil, an antimetabolite agent, has been widely used since 1957 for treatment of varied types of cancer such as gastro-intestinal, pancreas, breast, lung, head and neck malignancies. Cardiotoxicity of 5-fluorouracil is rare and was first described in 1975. It can induce severe complications and involve vital prognosis in the short-term. These complications are less known by cardiologists than medical oncologists. The following clinical case represents a potentially serious and rare case of completely reversible cardiogenic shock in a patient with a colo-rectal cancer. A better knowledge of these complications could reduce cases of death by an earlier diagnosis, and a better evaluation of patients with high cardiotoxicity risk.

Adenocarcinoma↗
PubMed2005

Comparison of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by radiation vs concurrent chemoradiotherapy with TPF in patients with locally advanced squamous cell carcinoma of the head and neck.

AIMS: To compare the effectiveness of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) followed by radiation with that of concurrent chemoradiotherapy with TPF in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: In a group of patients receiving induction chemotherapy followed by radiation, 15 patients received two cycles of chemotherapy with docetaxel 60 mg/m2, cisplatin 70 mg/m2 and 5-day 5-fluorouracil (5-FU) 750 mg/m2/day. Radiotherapy was begun 21 days after completing chemotherapy. In the group receiving concurrent chemoradiotherapy, 19 patients received two cycles of chemotherapy with docetaxel 50 mg/m2, cisplatin 60 mg/m2, and 5-day 5-FU 600 mg/m2/day. Radiation was begun on the first day of chemotherapy. The total radiation dose was between 63 and 74 Gy. RESULTS: Overall response rate (partial and complete response--both 100%) and complete response rate (87% and 84%) were similar, but, in overall survival, concurrent chemoradiotherapy with TPF was better than induction chemotherapy with TPF followed by radiation. Mucositis and anaemia were more frequent in the group receiving concurrent chemoradiotherapy, but the group receiving concurrent chemoradiotherapy with TPF improved overall survival. CONCLUSIONS: This is a small non-randomised comparison. The effectiveness of concurrent chemoradiotherapy with TPF was better than that of induction chemotherapy with TPF followed by radiation.

Aged↗
PubMed2004

Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil.

The identification of genetic factors associated with either responsiveness or resistance to 5-fluorouracil (5-FU) chemotherapy, as well as genetic factors predisposing patients to the development of severe 5-FU-associated toxicity, is increasingly being recognised as an important field of study. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Although the role of tumoral levels as a prognostic factor for clinical responsiviness has not been firmly established, there is ample evidence that a deficiency of DPD is associated with severe toxicity after the administration of 5-FU. Patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia. In addition, the onset of toxicity occurred twice as fast compared with patients with a normal DPD activity. To date, 39 different mutations and polymorphisms have been identified in DPYD. The IVS14+1G>A mutation proved to be the most common one and was detected in 24-28% of all patients suffering from severe 5-FU toxicity. Thus, a deficiency of DPD appears to be an important pharmacogenetic syndrome.

Antimetabolites, Antineoplastic↗
PubMed2005

Combination regimen of epirubicin, vinorelbine and 5-fluorouracil continuous infusion as first-line chemotherapy in anthracycline-naive metastatic breast cancer patients.

We investigated the activity and toxicity of a combination of vinorelbine 25 mg/m2 on days 1 and 15; epirubicin 25 mg/m2 on days 1, 8, 15; and 5-fluorouracil continuous infusion at 200 mg/m2 every day, administered as first-line chemotherapy in anthracycline-naive metastatic breast cancer patients. Fifty-three patients entered the study. Cycles were repeated every 28 days. Objective response was 60% by World Health Organisation (WHO) criteria and 63% by Response Evaluation Criteria in Solid Tumours (RECIST). The median time to progression was 12.7 months (17.6 months in responders) and the median survival duration was 32.9 months. The dose-limiting toxicity was leucopenia (grade 3/4 in 36% of patients). Grade 3/4 non-haematological toxicities included mucositis in 11% of patients, skin and cardiac toxicity in 4% and 2%, respectively. The combination of vinorelbine, epirubicin and 5-fluorouracil continuous infusion was found to be an active and manageable first-line regimen for metastatic breast cancer patients.

Adult↗
PubMed2003

Rosiglitazone-induced protection against myelotoxicity produced by 5-fluorouracil.

Insulin promotes survival of haemopoietic progenitors. We investigated if rosiglitazone, an insulin sensitizer, could confer protection against 5-fluorouracil (5-FU)-induced myelotoxicity in mice. The decrease in bone marrow cellularity, frequency and content of granulocyte-macrophage progenitors (CFU-GM) characterized myelotoxicity in mice, while insulin sensitivity was determined by hyperinsulinaemic euglycaemic glucose clamping. CFU-GM colony numbers increased in groups pre-treated with rosiglitazone (1.5-6 mg/kg, 5 days), compared to that in mice treated with 5-fluorouracil alone. Since rosiglitazone pre-treatment significantly promoted the clonal expansion of CFU-GM when given in the insulin sensitizing dose, we conclude that rosiglitazone had myeloprotective effects possibly by amplifying endogenous insulin action.

Administration, Oral↗
PubMed2006

Evaluation of topical external medicine for 5-fluorouracil-induced oral mucositis in hamsters.

Oral ulcerative mucositis is a common and painful toxicity associated with chemotherapy for cancer. Current treatment for chemotherapy-induced oral mucositis is largely palliative, and no adequate treatment with conclusive evidence exists. The purpose of this study was to evaluate the potential effectiveness of the topical external medicines used in clinical settings, and the authors investigated the effects of 1% azulene ointment, 0.12% dexamethasone ointment, and polaprezinc-sodium alginate suspension on an animal model for oral mucositis induced by chemotherapy. Oral mucositis was induced in hamsters through a combination treatment of 5-fluorouracil and mild abrasion of the cheek pouch. Each drug was administered topically to the oral mucosa of hamsters, and the process of healing of damaged oral mucositis was examined by measuring the size of the mucositis. Azulene ointment did not reduce the size of the mucositis compared with the vaseline-treated control group. Polaprezinc-sodium alginate suspension significantly improved the recovery from 5-fluorouracil-induced damage. In contrast, local treatment with dexamethasone exacerbated the mucositis markedly. These results suggested the healing effect of polaprezinc-sodium alginate suspension and the risk of steroids to severe oral mucositis induced by chemotherapy.

Administration, Topical↗
PubMed2005

Antitumoural properties of benzannelated seven-membered 5-fluorouracil derivatives and related open analogues. Molecular markers for apoptosis and cell cycle dysregulation.

Attention is increasingly being focussed on the cell cycle and apoptosis as potential targets for therapeutic intervention in cancer. We prepared a series of bioisosteric benzannelated seven-membered 5-FU O,N-acetals to test them against the MCF-7 human breast cancer cell line. Benzo-fused seven-membered O,O-acetals or their acyclic analogues led to the expected 5-FU O,N-acetals (or aminals), in addition to six- and 14-membered aminal structures and acyclic compounds. All the cyclic aminals provoked a G0/G1-phase cell cycle arrest, whereas Ftorafur, a known prodrug of 5-FU, and 1-[2-(2-hydroxymethyl-4-nitrophenoxy)-1-methoxyethyl]-5-fluorouracil (11) induced an S-phase cell cycle arrest. Although breast cancer is most often treated with conventional cytotoxic agents it has proved difficult to induce apoptosis in breast cancer cells, but improved clinical responses may be obtained by identifying therapies that are particularly effective in activating apoptosis. 1-(2,3-Dihydrobenzoxepin-2-yl)-5-fluorouracil (5) may be particularly useful in stimulating apoptosis in breast cancer.

Antineoplastic Agents↗
PubMed2004

Colonic drug delivery of 5-fluorouracil: an in vitro evaluation.

Compression coating has been found to be useful for colonic drug delivery. The aim of the present investigation was to design a formulation with a considerably reduced coat weight and gum concentration for colonic delivery of 5-fluorouracil for the treatment of colorectal cancer. Rapidly disintegrating core tablets containing 50 mg of 5-fluorouracil were prepared and compression coating with 175 mg of granules containing a mixture of xanthan gum (XG) and guar gum (GG) in varying proportions was done. With this coat weight, a highly retarded drug release was observed. After 24h of dissolution the mean percent drug release from the compression coated XG:GG 20:20, 20:10 and 10:20 tablets were found to be around 18+/-1.23%, 20+/-1.54% and 30+/-1.77%, respectively. So, the coat weight was further reduced to 150 mg. It was observed that reduction of coat weight did not affect the initial drug release rate in simulated upper gastrointestinal tract (GIT) conditions. At the end of 24h of dissolution the amount of drug released increased to 25+/-1.22%, 36.6+/-1.89% and 42.6+/-2.22%, respectively in XG:GG 20:20, 20:10 and 10:20 tablets. Studies of XG:GG (10:20) tablets in presence of colonic contents showed an increased cumulative percent drug release of 67.2+/-5.23% in presence of 2% cecal content and 80.34+/-3.89% in presence of 4% cecal content after 19 h of incubation.

Administration, Oral↗
PubMed2006

Estimation of 5-fluorouracil-loaded ethylene-vinyl acetate stent coating based on percolation thresholds.

The drug percolation thresholds of 5-fluorouracil-loaded ethylene-vinyl acetate stent coatings were estimated to characterize their drug release behavior and mechanical properties. The stent coatings were prepared using 5-fluorouracil (5-FU) as antitumor drug and ethylene-vinyl acetate (EVA) as matrix forming material in different ratios. In vitro release assays were carried out exposing only one side of coating to pH 6.5 PBS. Based on the release profiles, the drug percolation thresholds were estimated as 0.21 of total porosity (corresponding to ca. 32%, w/w of the drug), which is in approximately agreement with the atomic force microscopy (AFM) result. Based on the coating tensible break strength and tear break strength data, the mechanical percolation thresholds of drug were obtained as 39.7+/-0.3 and 37.5+/-1.4% (w/w) of drug content, respectively.

Antimetabolites, Antineoplastic↗
PubMed2004

5-fluorouracil-based chemoradiation in unresectable pancreatic carcinoma: Phase I-II dose-escalation study.

PURPOSE: A Phase I-II dose-escalation study was performed to evaluate the possible impact of the dose on response, toxicity, pain relief, and outcome in patients with unresectable pancreatic carcinoma. METHODS AND MATERIALS: A total of 50 patients entered the study. The external beam radiotherapy (RT) dose was 39.6 Gy in the first 15 patients, 50.4 Gy in the next 15 patients, and 59.4 Gy in the remaining 20 patients, at five 1.8-Gy fractions weekly. During external beam RT, patients received concurrent continuous infusion of 5-fluorouracil (1000 mg/m(2) on Days 1-4 and 21-24). Patients were evaluated for toxic reactions, local disease control, survival, and pain relief. RESULTS: No treatment-related deaths occurred from acute toxicity. Four patients required a temporary treatment interruption because of acute hematologic (2 patients) or GI (2 patients) toxicity, not correlated with the delivered RT dose. Three patients (6%) developed late toxicity (duodenal ulcer in 2 and duodenal stenosis in 1). All patients who developed late toxicity had received a dose of 59.4 Gy. At univariate analysis, only the RT dose correlated significantly with the incidence of late toxicity (at 2 years, 39.6-50.4 Gy resulted in 0% and 59.4 Gy resulted in 58.2%; p = 0.023). At multivariate analysis, the RT dose also showed a trend with the incidence of late side effects (p = 0.052). Overall, 6 patients had a partial response (12%) and 44 (88%) had no change. The overall response rate was 8.0% (95% confidence interval, 1.5-20.5%). The rate of response was not different in the three groups. In-field locoregional disease progression was seen in 7 patients (14.0%). Distant relapse was documented in 34 patients (68.0%). None of analyzed variables, in particular, the RT dose delivered, showed a statistically significant correlation with objective response, local control, incidence of metastasis, disease-free survival, or overall incidence of pain symptoms after therapy. The whole group median survival was 9 months. The actuarial survival rate at 1, 2, and 3 years was 31.3%, 2.8%, and 0.0%, respectively. None of analyzed parameters correlated significantly with survival at univariate or multivariate analysis. CONCLUSION: In a Phase I-II study, the association of high RT doses with the incidence of severe toxicity in the treatment of unresectable pancreatic carcinoma was confirmed. Furthermore, this dose-escalation study did not document a clearcut correlation, using 5-fluorouracil-based chemoradiation, between the radiation dose and clinical outcome.

Analysis of Variance↗