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PubMed1976

Differential recovery of intestine, bone marrow, and thymus of rats with solid tumors following 5-fluorouracil administration.

Time relationships for recovery of several host organs from toxic effects of 5-fluorouracil were determined in ACI rats bearing Morris hepatoma 3924A. A single injection of 150 mg/kg body weight 5-fluorouracil (the LD10) resulted in loss of 90% of the tibial bone marrow, 60% of the intestinal mucosa, and 90% of the thymus as measured by total DNA content of the organs. Organ DNA contents following 150 mg/kg of the drug were minimal on day 3 for intestine and on day 5 for marrow and thymus. A return to pretreatment or higher levels of DNA was observed by day 4 for intestine, day 11 for tibial marrow, and day 19 for thymus. Incorporation of 3H-deoxyuridine into host organ DNA after 150 mg/kg 5-fluorouracil was inhibited 36 hrs for intestine, 3 days for thymus, and 5 days for tibial bone marrow. Inhibition of 3H-deoxyuridine incorporation into DNA was similar for 50, 100, and 150 mg/kg doses both in tumor and in host organs, but recovery of 3H-deoxyuridine incorporation and DNA content of host organs began later with the higher doses of 5-fluorouracil. Maximal incorporation of 3H-deoxyuridine into DNA was observed on day 4 for intestine, day 8 for marrow, and day 9 for thymus after treatment with 150 mg/kg 5-fluorouracil. Animal lethality following the second of two 150 mg/kg injections of 5-fluorouracil was related to the extent of recovery of intestinal mucosa and bone marrow at the time of the second injection. Survival decreased to 0% for normal rats when the interval between injections was 3-4 days, improved at 5 days and was 100% when the interval was 10-11 days.

Animals↗
PubMed1989

Stability of fluorouracil administered through four portable infusion pumps.

The stability of fluorouracil in four portable infusion pumps under simulated infusion conditions was studied. Three commercially available fluorouracil aqueous solutions (50 mg/mL) were used. Samples adjusted to six pH levels were examined for precipitate. Drug reservoirs of four different portable infusion pumps were filled with 70 mL of each fluorouracil injection. Under conditions simulating actual use, the reservoirs were attached to the pumps and the solutions were pumped at a rate of 10 mL/24 hours over a seven-day period at 25 degrees C and 37 degrees C. Samples at the distal end of the extension tubing were collected hourly for the first 10 hours and at 12-hour intervals thereafter. Visual observations and pH determinations were made immediately. Drug concentrations were determined by reverse-phase high-performance liquid chromatography. Diethylhexylphthalate (DEHP) concentrations (the result of leaching from the plastic tubing and container) were determined by gas chromatography. In the pH study, precipitate appeared immediately in all fluorouracil injections below pH 8.52; precipitate was observed after two to four hours at pH 8.60-8.68. Under simulated infusion conditions, no apparent changes in concentration or pH were detected with any of the brands of drugs or portable infusion devices. At 25 degrees C, a fine white precipitate was observed in the extension tubing of all devices with the Roche brand of fluorouracil 48 to 96 hours after the pumping cycle began. The amount of DEHP leached from the drug reservoirs over the seven-day period was less than 1 ppm at both temperatures. All tested brands of fluorouracil injection were found to be stable under simulated infusion conditions over a seven-day period at 37 degrees C.

Chemistry, Pharmaceutical↗
PubMed1984

Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity.

The clinical effects and pharmacokinetics of high-dose uridine were determined in seven patients with advanced-stage cancer and in one healthy volunteer. Uridine was also examined for its effect on 5-fluorouracil toxicity in two patients. Uridine was administered as a 1-hr i.v. infusion at doses of 1 to 12 g/sq m. Plasma and urine samples were analyzed for uridine and uracil using high-pressure liquid chromatography. In 23 courses of uridine alone, the only toxicity observed was transient shivering after one of two courses at 12 g/sq m. This side effect was also seen after administration of uridine (10 g/sq m) during combination with 5-fluorouracil. The pretreatment plasma uridine concentration was elevated from low micromolar to millimolar levels with uridine administration at doses up to 12 g/sq m. Maximal areas under the concentration-time curve were about 5 mmol/liter/hr. Both peak plasma level and area under the curve for uridine increased linearly with dose. Uridine plasma decay curves were biphasic with a terminal half-life of 118 min. Half-life, volume of distribution (634 ml/kg), and total clearance (4.98 ml/kg/min) appeared to be independent of dose. Plasma uracil concentration increased gradually after administration of uridine to plateau levels. Maximal plasma uracil concentrations were about one-tenth that of peak uridine concentrations. The plasma uracil level declined with a half-life of about 40 min after uridine levels decreased to 300 microM. Total urinary excretion of uridine was 24% of the dose, while the amount of uracil recovered in urine was 3.4%. In two patients, uridine rescue was attempted during 5-fluorouracil dose escalation. Uridine at 5 to 6 g/sq m given on 1 or on 2 days after 5-fluorouracil did not prevent myelosuppression and gastrointestinal toxicity associated with increasing plasma concentrations of 5-fluorouracil. These data show that uridine administered as a 1-hr infusion at doses which provide peak plasma uridine concentrations in the millimolar range is well tolerated. Rapid elimination of uridine primarily due to catabolism results in modest exposure to substantially elevated plasma uridine concentrations. Preliminary findings suggest that prolonged treatment with uridine may be required to test its potential to rescue patients from 5-fluorouracil toxicity.

Adult↗
PubMed1982

Combined actions of 5-fluorouracil and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea on human colonic carcinoma cells in vitro.

Two lines of human colonic carcinoma cells have different sensitivities to 5-fluorouracil and 1-(2-chlorethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU). The growth of the BE line is 50% inhibited by 330 microM 5-fluorouracil and 15 microM methyl-CCNU, and the HT-29 line is 50% inhibited by 85 and 140 microM, respectively. On cloning, 50% of BE cells are killed by 500 microM 5-fluorouracil and 6 microM methyl-CCNU, and the HT-29 cells are killed by 250 and 120 microM respectively. When the drugs were combined, there were additive effects which occurred in cell growth of both lines and killing of BE cells. Synergism occurred in killing HT-29 cells when a low concentration of 5-fluorouracil was combined with methyl-CCNU. The synergism did not increase with increasing concentrations of 5-fluorouracil. Both drugs caused growth delay of spheroids (HT-29 cells), an effect that was additive when the drugs were combined. Growth inhibition of both lines in monolayer culture by 5-fluorouracil was more sensitive than was cell killing or inhibition of spheroid growth but, with methyl-CCNU, killing of BE cells was more sensitive than was growth inhibition. HT-29 cells showed similar sensitivity to methyl-CCNU in all three systems. The type and sensitivity of drug effect seen in vitro depends on the particular drug used, the cell line tested, and the parameter measured.

Cell Division↗
PubMed1977

Allergic contact dermatitis to topical fluorouracil.

We designed a prospective and retrospective study to determine the incidence of allergic contact dermatitis to topical application of fluorouracil. Intracutaneous and epicutaneous skin tests of various fluorouracil concentrations were given to patients who were to be treated with the drug for actinic keratoses (group A) and to patients who had previously been treated with fluorouracil for actinic keratoses (group B). Six patients in group B had allergic contact dermatitis to topical fluorouracil. The common clinical characteristic of the six patients was a severe pruritic eruption at the site of fluorouracil application. Allergic contact dermatitis should be suspected in the presence of severe pruritus or a severe eczematous response in patients treated with topical fluorouracil.

California↗
PubMed1996

[Feasability of the dose adjustment of continuous infusion administration over 120 hours of 5-fluorouracil associated with cisplatin].

Therapeutic monitoring of 120 hours continuous 5-fluorouracil associated with cisplatin. For 31 patients treated by continuous 5-fluorouracil with cisplatin, a therapeutic monitoring of 5-fluorouracil is performed, based on the 48 first hours area under the curve (AUC) and the total AUC. The 5-fluorouracile taylorization allows to reduce some toxicity's while preserving an efficiency (objective responses 42%). Many patients are considered with potentially low 5-fluorouracile clearance. Dose reductions of 5-fluorouracile are frequent, reach 50% during the third cure and allow the achievement of targeted AUC. The role of cisplatin in this necessary reduction of dose is unknown.

Adult↗
PubMed1976

Noninflammatory destruction of actinic keratoses by fluorouracil.

Sequential topical application of fluorouracil and 0.5% triamcinolone acetonide cream is as effective in the treatment of actinic keratoses as fluorouracil alone, but the combination obviates the unpleasent irritation caused by fluorouracil. Diluted (0.1%) triamcinolone acetonide cream preparations are ineffective in the suppression of the associated inflammation. There is no detectable difference in the number of new actinic keratoses between the combination therapy and fluorouracil alone. These findings demonstrate that the degree of success with fluorouracil therapy in actinic keratosis is not related to the degree of inflammation associated with the treatment and are consistent with a chemotherapeutic explanation of fluorouracil's effect on actinic keratosis.

Aged↗
PubMed2005

Oxo-hydroxy tautomerism of 5-fluorouracil: water-assisted proton transfer.

Post-Hartree-Fock ab initio quantum chemical calculations were performed for 5-fluorouracil in the gas phase and in a three-water cluster. Full geometry optimizations of the 5-fluorouracil-water complexes were carried out at the MP2/6-31+G(d,p) level of theory. MP4/6-31+G(d,p)//MP2/6-31+G(d,p) and MP4/6-31++G(d,p)//MP2/6-31+G(d,p) single-point calculations were performed to obtain more accurate energies. In water solution, 5-fluorouracil exists mainly in the 2,4-dioxo form (A). We propose that the populations of the 2-hydroxy-4-oxo (B) and 4-hydroxy-2-oxo (D) tautomers are 1 x 10(-4)% and 3.9 x 10(-8)%, respectively, on the basis of the relative stabilities of the tautomers calculated at the MP4/6-31++G(d,p)//MP2/6-31+G(d,p) level of theory. A profound difference between isolated and hydrated 5-fluorouracil is noted for the height of the tautomerization barrier. In the absence of water, the process of proton transfer is very slow. The addition of water molecules decreases the barrier by 2.3 times, making the process much faster. The minimum energy path (MP2/6-31+G(d,p)) for water-assisted proton transfer in trihydrated 5-fluorouracil was followed. CNDO/S-CI calculations predict singlet pi-pi(*) electron transitions at 312 nm for B and at 318 nm for D. The fluorescence spectrum of 5-fluorouracil in water confirms the presence of the hydroxy tautomer.

Journal Article↗
PubMed2006

Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial.

OBJECTIVE: To compare the efficacy, tolerability, and cosmetic outcome of photodynamic therapy (PDT) using topical methyl aminolevulinate with cryotherapy or topical fluorouracil for treatment of squamous cell carcinoma in situ. DESIGN: Randomized, placebo-controlled study, with follow-up at 3 and 12 months after last treatment. SETTING: Forty outpatient dermatology centers in 11 European countries. PATIENTS: Random sample of 225 patients with histologically confirmed squamous cell carcinoma in situ (lesion size, 6-40 mm) and no evidence of progression. INTERVENTIONS: Treatment with PDT with methyl aminolevulinate (160 mg/g; n = 96) or matching placebo cream (n = 17), cryotherapy (n = 82), or topical fluorouracil (5% cream; n = 30). Methyl aminolevulinate or placebo cream was applied for 3 hours before illumination with broadband red light (75 J/cm2, 570-670 nm). Treatment was repeated 1 week later. Cryotherapy was performed with liquid nitrogen spray. Fluorouracil was applied for 4 weeks. Lesions with a partial response at 3 months were re-treated. MAIN OUTCOME MEASURES: Clinically verified complete response of lesions; blinded and on-site assessment of cosmetic outcome (4-point rating scale). RESULTS: At 12 months, the estimated sustained lesion complete response rate with methyl aminolevulinate PDT was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P = .047), and better than that with fluorouracil (80% vs 69%; odds ratio, 1.64; 95% confidence interval, 0.78-3.45; P = .19). Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with methyl aminolevulinate PDT vs 66% with cryotherapy and 76% with fluorouracil, and was maintained at 12 months. CONCLUSION: Methyl aminolevulinate PDT is an effective treatment option for squamous cell carcinoma in situ, with excellent cosmesis.

Administration, Cutaneous↗
PubMed1988

Concentration change of fluorouracil in the external segment of the eye after subconjunctival injection.

Five milligrams of fluorouracil was injected subconjunctivally in the rabbit eye, and its concentration changes in the cornea, aqueous humor, and conjunctiva and sclera (both at the injection site and 180 degrees away from it) were determined by microbiological assay. The fluorouracil concentrations in the cornea and the aqueous humor averaged about 20 micrograms/g at one hour. The former decreased to 0.5 micrograms/g at 24 hours, while the latter was 0.03 micrograms/g at ten hours or later. At five hours, the fluorouracil concentrations in the conjunctiva and sclera at the injection site were similar to those 180 degrees away from it, both averaging about 2 micrograms/g. They decreased to 0.3 through 0.9 micrograms/g at 24 hours. The fluorouracil concentrations in the cornea, conjunctiva, and sclera at 24 hours were still above the reported 50% inhibition levels for the cultured conjunctival fibroblast. These findings have potential clinical implications for the safe use of fluorouracil.

Animals↗
PubMed1991

Trabeculectomy with mitomycin. A comparative study with fluorouracil.

We conducted a prospective, randomized study to compare mitomycin with fluorouracil for efficacy and safety as an adjunct to trabeculectomy in eyes with glaucoma with poor surgical prognosis. Thirty-two eyes of 32 patients were randomly allocated to either mitomycin (17 eyes) or fluorouracil therapy (15 eyes). Mitomycin (0.2 mg) was applied only once during trabeculectomy, and fluorouracil (5 mg) was subconjunctivally injected 10 times in the 2 weeks after surgery. Fifteen eyes (88%) in the mitomycin group and seven (47%) in the fluorouracil group achieved an intraocular pressure of less than or equal to 20 mm Hg without antiglaucoma medication. The follow-up period was 7 to 12 months. Corneal complications were less common in the group given mitomycin than in that given fluorouracil (12% vs 53%). The incidence of other complications was similar between the two groups.

Adult↗
PubMed1992

A randomized study of trabeculectomy and subconjunctival administration of fluorouracil in primary glaucomas.

Forty-one adult patients with primary open angle glaucoma and nine adult patients with chronic angle closure glaucoma underwent trabeculectomy in one eye each. Twenty-one eyes with primary open angle glaucoma and four with chronic angle closure glaucoma were randomly assigned to receive four to six subconjunctival injections of fluorouracil for 10 days after surgery. Twenty-five control eyes did not receive fluorouracil. Intraocular pressure was 20 mm Hg or lower in 24 eyes (96%) in the treatment group after mean follow-up of 17.8 months and in 19 control eyes (76%) after mean follow-up of 17.5 months (P less than .05). Encapsulated bleb developed in three (12%) of the fluorouracil-treated eyes vs two (8%) of the control eyes. A few injections of fluorouracil adequately inhibited scarring. This might be explained by its toxic effect on existing fibroblasts. Overall, trabeculectomy with injection of fluorouracil was found to be efficacious and relatively safe. Further studies regarding late complications are required.

Aged↗
PubMed1988

Effects of cisplatin plus fluorouracil vs cisplatin plus cytarabine on head and neck squamous multicellular tumor spheroids.

We compared the efficacy of cisplatin plus fluorouracil vs cisplatin plus cytarabine against HEp-2 head and neck carcinoma cells in monolayer and multicellular tumor spheroid (MTS) systems. Increases in exposure time to cisplatin and fluorouracil from one to 24 hours resulted in approximately tenfold and 1000-fold increases, respectively, in cell lethality for both monolayer and MTS cells. Dose-response curves for cisplatin or fluorouracil on MTS cells closely followed those from monolayer cells, indicating good drug penetration into the MTS core. In contrast, dose-response curves on MTS cells after 24-hour exposure to cisplatin and cytarabine showed progressively lesser efficacy at higher drug concentrations. For monolayer cells, cisplatin plus fluorouracil and cisplatin plus cytarabine were both synergistic, the latter combination more synergistic than the former. For MTS cells, both combinations again showed synergistic interaction at moderate to high effect levels. Heightened synergistic interaction was demonstrated especially with the cisplatin plus cytarabine combination. Thus, the cisplatin plus cytarabine combination was always more synergistic than cisplatin plus fluorouracil. These data may serve as a basis for additional clinical trials of cisplatin plus cytarabine in the treatment of patients with head and neck carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Ultrastructural and cytochemical observations on 5-fluorouracil-induced cleft-palate development in hamster.

Sequential alterations in 5-fluorouracil-treated hamster fetal palate were studied by light and electron microscopy and by acid phosphatase cytochemistry. At an early stage in 5-fluorouracil-treated fetuses, when the palatal shelves were vertical, lysosomes first appeared in cells of the prospective fusion epithelium and then in the cells of subjacent mesenchyme. In contrast to controls, increasing numbers of both the epithelial and mesenchymal cells of the vertical palate showed lysosomal injury in 5-fluorouracil-treated fetuses as development progressed. Subsequently, the basal lamina in the vertical palate showed alterations, characterized initially by disturbances in lamina lucida, by fingerlike extensions of lamina densa, and ultimately by its complete breakdown. At a later stage, when shelves became horizontal, the lysosomes were absent in both the epithelial and mesenchymal cells, and the basal lamina continuity was restored. Unlike controls, however, 5-fluorouracil-treated horizontal shelves never contacted one another. Instead, the epithelia of the horizontal shelves underwent stratification. It appears that premature formation of lysosomes in palatal epithelial and mesenchymal cells following 5-fluorouracil treatment disrupts normal cytodifferentiation and affects the integrity of the basal lamina; both effects are associated with cleft-palate development.

Acid Phosphatase↗
PubMed1980

Analysis of fluorouracil in human plasma by combined gas-liquid chromatography mass spectrometry.

Fluorouracil in human plasma of a concentration as low as 2 ng ml-1 can be assayed with the use of gas-liquid chromatography and a multiple ion detector. Fluorouracil is isolated from plasma by anion exchange extraction. The extract is butylated and the derivative obtained extracted into a mixture of cyclohexane + dichloromethane (95:5). An aliquot is submitted to combined gas-liquid chromatography mass spectrometry. The use of chlorouracil or oxygen-18 labelled fluorouracil as internal standard is discussed. Linearity is proven from 100 microgram to 5 ng of fluorouracil per ml plasma. The coefficients of variation are 7.2 and 8.4% for within-run and between-run precision, respectively, at the 50 ng ml-1 level. The biological applicability of our procedure is demonstrated by analysing plasma samples obtained at different time intervals from three patients given 1 g of fluorouracil once intravenously and once orally.

Fluorouracil↗
PubMed2004

Simultaneous determination of capecitabine and its metabolite 5-fluorouracil by column switching and liquid chromatographic/tandem mass spectrometry.

A liquid chromatographic/tandem mass spectrometric method was developed and validated for the quantitation of capecitabine and its metabolite 5-fluorouracil in human plasma. The simultaneous determination of both analytes was achieved by a column switching method using a trapping column and two analytical columns with different stationary phases. Isocratic elution was used for the separation of capecitabine on a C18 column whereas 5-fluorouracil was separated using gradient elution on an non-polar carbon phase. The calibration curves were linear for both compounds with a correlation factor (R2) > 0.9993 for 5-fluorouracil and >0.9942 for capecitabine. The assay was validated in the concentration range 5.00-1000 ng ml(-1) for both compounds. The intra-day precision was better than 10% for 5-fluorouracil and better than 11% for capecitabine whereas the inter-day precision was better than 8% for 5-fluorouracil and better than 14% for capecitabine.

Antimetabolites, Antineoplastic↗
PubMed1983

5-Fluorouracil concentrations in rat plasma, parotid saliva, and bile and protein binding in rat plasma.

The pharmacokinetics of 5-fluorouracil were studied over a 60-min period in rats that received 12.5, 25.0, and 50.0 mg/kg iv. The plasma concentration-time relationship and the detectability in bile and parotid saliva (a route of elimination heretofore given little or no attention) were examined. Protein binding of 5-fluorouracil at concentrations chosen to approximate those found in plasma was determined by equilibrium dialysis. Bile-plasma and parotid saliva-plasma concentration ratios were calculated. 5-Fluorouracil concentrations were quantitated by high-performance liquid chromatography. Plasma concentrations at all doses studied appeared to rapidly decline. The half-life, however, at the 50.0-mg/kg dose (27 min) was significantly longer (p less than 0.025) than the corresponding half-life at the 25.0-mg/kg dose (22 min). This may be attributed to an easily saturable hepatic degradation. Although an observed decline in bile-plasma and parotid saliva-plasma concentration ratios at higher doses may represent saturation of these excretary routes, the small amounts of 5-fluorouracil detected in bile and parotid saliva probably contribute negligibly to the elimination of the total drug equivalents administered. Parotid saliva-plasma concentration ratios were not useful in predicting plasma protein binding as determined by equilibrium dialysis. Excretion of intravenously administered 5-fluorouracil in saliva, however, exposes the upper GI tract to this agent and may play a part in causing stomatitis in patients receiving the drug by this route.

Animals↗
PubMed1994

Combination of the chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism results in increased micronucleus induction.

The rate limiting step in 5-fluorouracil catabolism is catalyzed by the enzyme dihydropyrimidine dehydrogenase. Since degradation of 5-fluorouracil decreases its efficacy in chemotherapy, the inhibition of its catabolism is a promising tool. We investigated the formation of micronuclei in vitro in mouse L5178Y cells. 5-fluorouracil induced an increase in micronucleus frequency, which could significantly be enhanced by the concurrent application of 2,6-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase. The 5-fluorouracil concentration necessary to reach maximal genotoxic effects could be reduced to half in the presence of inhibitor 2,6-Dihydroxypyridine alone and the naturally occurring enzyme substrate uracil did not induce micronucleus formation. Combined application of the chemotherapeutic agent 5-fluorouracil and an inhibitor of its could reduce side-effects by lowering the effective dose of the active drug. With this study we provide further support for the usefulness of this concept.

Animals↗