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PubMed2001

Phenytoin and fluorouracil interaction.

OBJECTIVE: To report a probable drug interaction between phenytoin and fluorouracil. CASE REPORT: A 66-year-old white man started adjuvant chemotherapy for colon cancer with weekly bolus injections of fluorouracil and leucovorin calcium. He had been taking phenytoin 300 mg/d for epilepsy for more than four years. Eleven weeks later, the patient was reported to be unsteady on his feet and had fallen several times. The serum phenytoin concentration at that time was 36 microg/mL. The phenytoin dosage was decreased and the symptoms resolved. Phenytoin concentrations were monitored and the dosages were adjusted accordingly throughout the remaining 15 weeks of treatment with fluorouracil. After completion of chemotherapy, the phenytoin dose was gradually increased to the original dose with no signs of toxicity. DISCUSSION: Phenytoin is principally metabolized by CYP2C9. Inhibition of that isoenzyme by fluorouracil, and possible interference with its synthesis, appears to be the most likely cause of this interaction. The reduction in saturating substrate concentration of phenytoin was reduced as a result of this interaction, thus causing decreased clearance and increased serum concentrations. No previous interaction between phenytoin and fluorouracil has been reported. Both phenytoin and warfarin are metabolized by CYP269 and therefore exhibit the same spectrum of interactions when that isoenzyme is inhibited. Interactions have been reported with concurrent administration of warfarin and fluorouracil. CONCLUSIONS: The nature and extent of this phenytoin-fluorouracil interaction should be elucidated by in vitro investigations and a prospective study. Until then, clinicians should be aware of this potentially serious drug interaction and monitor patients closely for phenytoin toxicity.

Aged↗
PubMed2005

Increasing warfarin dosage reductions associated with concurrent warfarin and repeated cycles of 5-Fluorouracil therapy.

Concurrent use of warfarin and 5-fluorouracil has resulted in elevated international normalized ratios (INRs). Although this drug interaction is well established in the literature, we found no documented cases that address its effects on anticoagulation parameters in patients requiring repeated cycles of 5-fluorouracil and continuous warfarin therapy. We describe the effect of multiple cycles of 5-fluorouracil administration in a patient receiving warfarin therapy. The patient's INR increased 11-14 days after each cycle of chemotherapy with 5-fluorouracil and leucovorin. In addition, she required additive reductions of 33-42% in her weekly warfarin dose with each chemotherapy cycle to maintain a therapeutic INR (goal range 2.0-3.0). After three cycles of chemotherapy over a 10-week period, the patient's dosage requirements returned to her baseline level (before treatment with 5-fluorouracil and leucovorin had started). Pertinent literature was reviewed to provide supporting evidence for the mechanism and clinical implications of the drug interaction. Based on this report and previous case reports, caution is advised when concurrent warfarin and 5-fluorouracil are prescribed. In addition, patients should be closely monitored for a possible delayed interaction that may occur with each repeated cycle of 5-fluorouracil chemotherapy.

Adenocarcinoma↗
PubMed1999

Cardiotoxicity of the antiproliferative compound fluorouracil.

The antimetabolite fluorouracil (5-FU) is frequently administered for chemotherapy of various malignant neoplasms. The drug is well known for its adverse effects involving bone marrow, skin, mucous membranes, intestinal tract and central nervous system, whereas its cardiotoxicity is less familiar to clinicians. The pathophysiology of fluorouracil-associated cardiac adverse events is controversial and conclusions are based on clinical studies and case reports more than on solid experimental evidence. While clinical and electrocardiographic features suggest myocardial ischaemia as a main aetiological factor, possibly induced by coronary vasospasm, histomorphological and biochemical studies indicate a more direct drug-mediated cytotoxic action. Estimates of the overall incidence of fluorouracil cardiotoxicity have varied widely from 1.2 to 18% of patients. Patients may present with angina-like chest pain, cardiac arrhythmias or myocardial infarction. There is no unequivocally effective prophylaxis or treatment in this syndrome. Once fluorouracil administration is discontinued symptoms are usually reversible, although fatal events have been described. The overall mortality rate has been estimated to be between 2.2 and 13.3%. There is a high risk of relapse when patients are re-exposed to this drug following previous cardiac incidents. From the present data it is concluded that cardiotoxicity is a relevant but underestimated problem in fluorouracil treatment. Since the mechanisms of fluorouracil-associated cardiotoxicity are not yet fully understood, all patients undergoing this chemotherapy have to be carefully evaluated and monitored for cardiac risk factors and complaints. After cardiotoxic events, fluorouracil should definitely be withdrawn and replaced by an alternative antiproliferative regimen.

Antimetabolites, Antineoplastic↗
PubMed1995

Effects of 5-fluorouracil treatment on rat liver microsomal enzymes.

1. The effects of the administration of the anticancer drug 5-fluorouracil on P450-mediated metabolizing capacity, and the activity of several related enzymes were examined by comparing two different dosage regimes, i.e. a single ip dose of 5-fluorouracil (120 mg/kg) at 1, 4 and 7 days prior to killing, and a repeated dose regimen of 5-fluorouracil (24 mg/kg/day for 5 consecutive days) with animals being killed at 1, 4 and 7 days after the last 5-fluorouracil dose. 2. Rat liver microsomes were assayed for total P450 content, reduced nicotinamide adenine dinucleotide phosphate-P450-reductase, aminopyrine demethylase, cyclophosphamide 4-hydroxylase, aniline hydroxylase, androstenedione 6 beta- and 16 alpha-hydroxylase and delta 4-3-oxo-steroid 5 alpha-oxidoreductase activity. 3. The animals that received 5-fluorouracil as a single, high dose did not show any alterations in any of the measured parameters at any of the times at which they were killed. 4. The animals that received chronic low doses of 5-fluorouracil, however, showed a statistically significant decrease in androstenedione 6 beta- and 16 alpha-hydroxylase and cyclophosphamide 4-hydroxylase activity and a statistically significant increase in delta 4-3-oxo-steroid 5 alpha-oxidoreductase activity 4 and 7 days after completion of dosing. 5. Immunoquantified P4502C11 and 3A content was also decreased at these time points. These alterations occurred concurrently with depleted plasma testosterone levels in the groups that received repeated low doses of 5-fluorouracil.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1976

Antitumor activity of 1-hexylcarbamoyl-5-fluorouracil in a variety of experimental tumors.

Antitumor activity of 1-hexylcarbamoyl-5-fluorouracil against various tumors was examined. Therapeutic ratio (ILSmax/ILS30) in L-1210 system was 4.5 by oral administration, while those of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil were 1.9 and 1.0, respectively. Therapeutic ratio of the compound in C-1498 system was 11, while those of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil were 3.3 and 2.5, respectively. 1-Hexylcarbamoyl-5-fluurouracil was also active against solid and ascites tumors by oral administration. It was markedly active against Nakahara-Fukuoka sarcoma, adenocarcinoma=755, and ascites sarcoma-180, and moderately active against Ehrlich ascites carcinoma. This compound had a wider tumor spectrum than 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil by oral administration.

Adenocarcinoma↗
PubMed2002

The use of topical fluorouracil to treat actinic keratosis.

Actinic keratosis (AK) is a lesion induced by UV radiation, affecting predominantly fair-skinned individuals with a history of excessive sun exposure. Because AKs are potentially cancerous, management of AKs is important for dermatologists. The most frequently performed procedure for AKs is excision or destruction of the lesion, followed by biopsy. Topical fluorouracil creams are an efficient, effective treatment, especially for large quantities of widespread lesions. However, fluorouracil can produce an inflammatory facial reaction that is associated with the destruction of AKs. A new formulation, 0.5% fluorouracil cream, is indicated for once-daily use with a duration of treatment of up to 4 weeks. This regimen may be more cost-effective than the higher concentrations of fluorouracil creams (5% and 1%, respectively), which specify twice-daily application. Less frequent applications also may improve patient compliance with topical fluorouracil treatment. The use of 0.5% fluorouracil cream may provide an effective, safe, and economical option to augment the available treatments of AK, which include liquid nitrogen cryotherapy and 5% and 1% fluorouracil creams.

Administration, Topical↗
PubMed2006

Comparative proteomics of apoptosis initiation induced by 5-fluorouracil in human gastric cancer.

5-Fluorouracil is the first choice chemotherapeutic drug for patients with gastric cancer, but the mechanism that 5-fluorouracil plays the anti-tumor role remains unclear. The aim of this study was to clarify correlated [corrected] proteins induced by 5-fluorouracil in the apoptosis-initiation of human gastric cancer (MGC-803) cells. The time point of apoptosis-initiation induced by 5-fluorouracil in MGC-803 cells was determinated using 5-fluorouracil-withdrawal. Two-dimensional electrophoreses (2-DE) were employed to compare the differentials of protein expressions of the MGC-803 cells at the apoptosis-initiation phase and those of the MGC-803 cells untreated with 5-fluorouracil. The differential proteins included 14 upregulated proteins and 8 downregulated proteins. They indicated a more-than-doubled alteration. These proteins were digested in gels by trypsin and the mass of generated peptides were measured by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The data obtained from peptide mass fingerprinting (PMF) were searched out using the internet available database mascot (http://www.matrixscience.com). The results showed that proteomics analyses have evidenced that many kinds of proteins are involved in the apoptosis initiation of human gastric cancer MGC-803 cells. These proteins are related to metabolism, oxidation, cytoskeleton and signal transduction and other aspects of cells. In conclusion, the experiment model of apoptosis-initiation of human gastric cancer MGC-803 cells induced by 5-fluorouracil based on proteomic analysis has been established, giving an impetus to researches of the mechanism of apoptosis in human gastric cancer, and laying a foundation for the selection of potential drug precursors specific for inducing apoptosis-initiation in human gastric cancer.

Adenocarcinoma↗
PubMed1991

Stability and compatibility of fluorouracil and mannitol during simulated Y-site administration.

The stability and compatibility of fluorouracil admixtures with mannitol during simulated Y-site administration was studied. Fluorouracil injection 50 mg/mL was diluted with 5% dextrose injection, 0.9% sodium chloride injection, and 5% dextrose and 0.45% sodium chloride injection to final concentrations of 1 and 2 mg/mL. Combinations of fluorouracil admixtures with 20% mannitol injection were made using equal volumes in glass test tubes; immediately after mixing and at one, two, and four hours, the samples were examined for visual incompatibilities. Duplicate combinations of fluorouracil admixtures with 20% mannitol injection were made using equal volumes in plastic syringes; immediately after mixing with internal standard in glass test tubes and at 2, 4, 8, and 24 hours, samples were removed for chemical analysis. A high-performance liquid chromatographic assay was used to determine fluorouracil concentrations. No evidence of precipitation, color change, or haze was observed. During the 24-hour study, fluorouracil concentrations remained within 6% of initial concentrations for all combinations with mannitol. Fluorouracil 1 and 2 mg/mL in 5% dextrose injection, 0.9% sodium chloride injection, and 5% dextrose and 0.45% sodium chloride injection was chemically stable and visually compatible when combined with 20% mannitol injection during simulated Y-site administration.

Chemistry, Pharmaceutical↗
PubMed1990

Compatibility of cisplatin and fluorouracil in 0.9% sodium chloride injection.

The effect of drug concentration and light on the compatibility and stability of cisplatin and fluorouracil in i.v. admixtures was studied. Two sets of admixtures were prepared in 0.9% sodium chloride injection in polyvinyl chloride bags--(1) cisplatin 200 micrograms/mL and fluorouracil 1,000 micrograms/mL and (2) cisplatin 500 micrograms/mL and fluorouracil 10,000 micrograms/mL. Half of the admixtures were protected from light. All admixtures were stored at room temperature (24-26 degrees C), and those admixtures not protected from light were stored under room fluorescent light. After visual inspection, the pH of each admixture was determined, and an aliquot was assayed for drug concentration using a stability-indicating high-performance liquid chromatographic assay. Over a four-hour period, no visual changes were observed and the pH changes observed were negligible. In admixtures containing the lower concentrations of cisplatin and fluorouracil, it took approximately 1.5 hours for the concentration of cisplatin to reach 90% of the initial concentration. By four hours (lower concentration range) and three hours (higher concentration range) after the admixtures were prepared, less than 75% of the initial cisplatin concentration remained. There was less than a 5% decrease measured in the fluorouracil concentrations over the observation time. Admixtures of cisplatin and fluorouracil in 0.9% sodium chloride injection at the concentrations evaluated in this study must be used within one hour of preparation, whether or not they are protected from light. Intravenous administration of fluorouracil and cisplatin by continuous infusion will require alternative approaches to mixing the two drugs in the same container.

Chemistry, Pharmaceutical↗
PubMed1985

Fluorouracil paste treatment of thin basal cell carcinomas.

Treatment of thin (superficial) basal cell carcinomas (BCCs) with topical fluorouracil is widely accepted despite the absence of published five-year cure rates. The published short-term data disclose treatment failure rates substantially higher than other modalities. In trials to improve and standardize topical fluorouracil therapy, thin BCCs were treated with 25% fluorouracil in petrolatum under occlusion for three weeks using weekly dressing changes. Of 44 thin BCCs treated only with 25% fluorouracil under occlusion for three weeks, the five-year cumulative recurrence rate was 21%. In a second series of 244 BCCs, light curettage preceded the 25% fluorouracil treatment to yield a five-year cumulative recurrence rate of 6%. Cosmetic results were good to excellent in more than 80% of both series. While fluorouracil by itself is not a satisfactory treatment for thin BCC, when combined with light curettage, topical fluorouracil therapy is capable of cure rates competitive with other modalities.

Adult↗
PubMed1979

Studies on mechanisms of 5-fluorouracil resistance in murine and human tumors.

An in vitro cell free assay system to measure phosphorylated products of 5-Fluorouracil is described. Total phosphorylated products and mono-, di and triphosphates of 5-Fluorouracil are measured along with the rate of fluorodeoxyuridylate generation. This assay has been applied to ten murine tumors and eight biopsy specimens from human breast adenocarcinomas. Phosphorylation patterns have been examined in murine tumors demonstrating in vivo sensitivity or resistance to 5-Fluorouracil. There are distinct differences in the patterns of phosphorylation between sensitive and resistant tumors. In a 5-Fluorouracil sensitive murine tumor, mono-, di and triphosphates are produced. In a resistant tumor only monosphophates are produced. Cell free supernatants from human breast tumors produce less total phosphorylation than murine tumors and some specimens produce only monophosphates whereas others produce mono-, di and triphosphates. Human tumors are in general more efficient producers of fluorodeoxyuridylate than murine tumors. These data suggest that resistance to 5-Fluorouracil may correlate with decreased concentration of di and triphosphates of 5-Fluorouracil in some murine tumors. Further experiences is required to demonstrate the value of this easily performed assay system in predicting clinical response to 5-Fluorouracil in man.

Adenocarcinoma↗
PubMed1979

Enhancement of mammalian cell killing by 5-fluorouracil in combination with X-rays.

The enhanced cytocidal effect of a combination of X-rays and 5-fluorouracil was investigated by means of colony-forming ability in mouse L-cells. Cells were treated with 5-fluorouracil immediately preceding (preirradiation treatment) or following (postirradiation treatment) irradiation. In either pre- or postirradiation treatment with various concentrations of the drug for a fixed time, the enhanced effect was augmented with increasing concentrations of 5-fluorouracil up to 20 microgram/ml. When cells were subjected to postirradiation treatment with a fixed concentration of drug for varying times, the cytocidal effect was further enhanced with increasing duration of drug treatment. In preirradiation treatment, however, drug treatment for longer than 3 hr did not exhibit any further enhancement. Postirradiation treatment with 5-fluorouracil to synchronous cells at various ages demonstrated enhancement at all ages during the cell cycle. The greatest enhancement was observed in the DNA-synthetic phase. Postirradiation treatment with 5-fluorouracil (2.5 microgram/ml) for 24 hr markedly reduced the width of the shoulder of the X-ray survival curve without significantly altering the slope of the exponential portion of the curve. Recovery from sublethal radiation damage was not suppressed by 5-fluorouracil when cells were treated with drug between fractionated X-ray doses. These results indicate that damages caused by 5-fluorouracil and X-rays interact additively to induce cell killing.

Animals↗
PubMed1983

5-fluorouracil modulation of dihydrofolate reductase RNA levels in methotrexate-resistant KB cells.

Cytotoxicity and growth inhibition by 5-fluorouracil in methotrexate-resistant dihydrofolate reductase gene-amplified KB cells in the presence of 30 microM thymidine correlates with incorporation of this fluorinated pyrimidine into RNA. Growth of these cells over several generations in the presence of inhibitory concentrations of 5-fluorouracil does not depress the steady state levels of either 18 or 28 S RNA but actually causes an increase. Similarly the rates of RNA and protein synthesis in 5-fluorouracil-treated cells are not decreased. The level of dihydrofolate reductase RNA from 5-fluorouracil-treated cells increases in a dose-dependent manner correlated with 5-fluorouracil incorporation into RNA. The qualitative size distribution of the dihydrofolate reductase RNA species is unaffected when examined by the Northern blotting technique indicating an RNA processing lesion is not induced by 5-fluorouracil incorporation into RNA. As the dose of dihydrofolate reductase RNA increases, there is no change in the level of dihydrofolate reductase specific activity, but the level of enzyme activity per cell increases. The relevance of these phenomena to the mechanism of 5-fluorouracil effect on RNA and relevance to combination chemotherapy with methotrexate are discussed.

Carcinoma↗
PubMed1985

Fluorouracil (5-FU) and cytarabine (ara-C) inhibition of corneal epithelial cell and conjunctival fibroblast proliferation.

We evaluated the antiproliferative properties of fluorouracil (5-FU) and cytarabine (ara-C) in a tissue culture model of rabbit corneal epithelial cells and conjunctival fibroblasts. Cells were treated with fluorouracil or cytarabine for five days. Corneal epithelial cell proliferation was inhibited to 50% of control proliferation by 0.6 mg/L of fluorouracil or 30 micrograms/L of cytarabine. Proliferation of conjunctival fibroblasts was inhibited to 50% of control by 0.5 mg/L of fluorouracil or 50 micrograms/L of cytarabine. The antiproliferative effect of 10 mg/L of fluorouracil was not blocked by thymidine. The inhibition of proliferation produced by 100 or 1,000 micrograms/L of cytarabine was blocked by 2'-deoxycytidine at concentrations of 10(-5) M and 10(-4) M, respectively. The antiproliferative effects of fluorouracil and cytarabine appear similar for both cell types. Blockage of cytarabine-related ocular toxic effects may be possible with 2'-deoxycytidine.

Animals↗
PubMed1986

Topical fluorouracil. II. Postoperative administration in an animal model of glaucoma filtering surgery.

Unilateral posterior lip sclerectomies were performed in ten owl monkeys. Five milligrams of fluorouracil was injected subconjunctivally in each operated eye immediately after surgery. Three drops (approximately 2.4 mg/drop) of fluorouracil were instilled ten minutes apart in each operated eye twice daily on postoperative days 1 through 7 and once daily on postoperative days 8 through 15, 17, 19, and 21. One monkey died on the seventh postoperative day; its death could not be attributed to systemic fluorouracil toxicity. All of the operated eyes had filtering blebs after the full course of fluorouracil, but seven also had corneal epithelial defects. By the seventh postoperative week, two of the operated eyes manifested moderately severe corneal opacification. Ten weeks postoperatively, the electroretinographic a- and b-wave amplitudes averaged 17% and 12% less, respectively, in the seven operated eyes without clinically significant corneal opacification than in the unoperated fellow eyes. Only two eyes had blebs after the 12th postoperative week. Histopathologic examination was performed on five eyes, of which only two revealed patent sclerostomies. Although topical fluorouracil appears to delay bleb scarring, the corneal findings suggest that it may be more toxic than subconjunctival fluorouracil.

Administration, Topical↗
PubMed1988

The effect of fluorouracil on the corneal endothelium.

The utility of the antiproliferative agent fluorouracil has been demonstrated recently in glaucoma-filtering surgery and in the management of proliferative vitreoretinopathy after vitrectomy. Because of the potential for contact with the corneal endothelium, its toxicity to the endothelium is an important consideration. The effect of fluorouracil on corneal endothelial integrity in an in vitro animal model was studied. Freshly excised sheep corneal buttons were exposed to increasing concentrations of fluorouracil for four hours and were subsequently evaluated microscopically using vital staining with alizarin red and trypan blue. Exposure to normal saline and chlorhexidine gluconate was used to establish negative- and positive-staining controls. Corneal buttons exposed to normal saline or to 1.0 mg/mL or less of fluorouracil had intact endothelial monolayers that completely excluded trypan blue. Corneal buttons exposed to chlorhexidine gluconate or to 10 mg/mL of fluorouracil, however, had severely or totally disrupted endothelial monolayers in which the remaining cells, if any, all had blue-staining nuclei. These results suggest that the threshold concentration for fluorouracil toxicity to corneal endothelium lies between 1 and 10 mg/mL when exposure time is four hours.

Animals↗
PubMed2003

Intraoperative fluorouracil in endonasal laser dacryocystorhinostomy.

BACKGROUND: Although endonasal laser dacryocystorhinostomy (ELDCR) offers many advantages compared with conventional techniques, postoperative scarring leading to occlusion of the rhinostomy is more common with ELDCR. OBJECTIVE: To investigate whether fluorouracil applied to the rhinostomy site intraoperatively has an effect on the outcome. PARTICIPANTS: We randomly allocated 155 consecutive patients (201 procedures) to a control group and a fluorouracil group. Patients and investigators were masked to the choice of treatment. METHODS: All patients underwent ELDCR. A pledget soaked in isotonic sodium chloride solution or 0.5-mg/mL fluorouracil, randomly allocated by the pharmacy, was applied to the rhinostomy site for 5 minutes at the time of surgery. Patients were followed up for 12 months and their symptoms were assessed at each visit. RESULTS: Among patients followed up for 12 months or longer, ELDCR procedures performed with topical application of fluorouracil to the rhinostomy site were successful in 65 (76%), compared with 52 (63%) for the control group. This was not statistically significant when patients who failed to attend follow-up at or after 12 months were not counted as successfully treated (P =.21, chi(2) test). Even if those who failed to attend for follow-up were counted as successes, the effect of fluorouracil did not reach significance at the.05 level (P =.08, chi(2) test). CONCLUSION: The topical application of fluorouracil failed to increase the patency rates in ELDCR.

Administration, Topical↗
PubMed1988

The effect of cisplatin and fluorouracil on xenografted human squamous cell carcinoma of the head and neck.

In combined modality treatment, cisplatin and fluorouracil are considered to act synergistically. The assumption is based on results in murine leukemias and has not hitherto been tested on human squamous cell carcinoma. In the present study, cisplatin and fluorouracil, used singly and in combination, were tested on two human squamous cell carcinomas of the head and neck, xenografted to nude mice. Cisplatin (7.5 mg/kg) was given as a single-dose intraperitoneal injection and fluorouracil as repeated intraperitoneal injections every eight hours for four days to a total dose of 200 mg/kg. The toxicity of the cisplatin and fluorouracil combination was lower (27%) than that of fluorouracil alone (50%). Both drugs gave a dose-dependent inhibition of tumor volume growth. Using gained growth delay as endpoint, cisplatin and fluorouracil therapy exhibited a synergistic effect on both tumor lines.

Animals↗