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PubMed1994

Prevention of experimental proliferative vitreoretinopathy with a biodegradable intravitreal implant for the sustained release of fluorouracil.

OBJECTIVE: To test the efficacy of a biodegradable device for the intravitreal sustained release of fluorouracil in the treatment of tractional retinal detachment due to proliferative vitreoretinopathy. METHODS: A 6 x 0.9-mm (20-gauge) cylindrical solid implant molded from copolymers of lactide and glycolide admixed with 1 mg of fluorouracil was placed in the vitreous cavity of rabbits in which retinal detachment with proliferative vitreoretinopathy had been initiated. Comparisons of the control (drug-free polymer) and experimental (fluorouracil polymer) groups were made with weekly indirect ophthalmoscopic examinations. In another experiment, the intravitreal concentration of fluorouracil was tested at each time point. RESULTS: Retinas of eight (89%) of nine rabbits that received the polymer with fluorouracil remained attached compared with only one animal (11%) that received the control polymer without the drug. The therapeutic effect of the drug-containing implant was associated with sustained intravitreal concentrations of fluorouracil between 1 and 13 mg/L for at least 14 days, and fluorouracil concentrations remained above 0.3 microgram/mL for almost 21 days. No evidence of the toxic effects of the drug or polymer implant was observed with electroretinographic and histopathologic study. CONCLUSION: Intravitreal implantation of biodegradable polymers containing fluorouracil can prevent proliferation of epiretinal membranes resulting in complicated retinal detachment in an animal model of proliferative vitreoretinopathy and indicate their possible usefulness for intravitreal delivery of therapeutic agents.

Animals↗
PubMed1986

The effects of perioperative fluorouracil administration on convalescence and wound healing.

Administration of chemotherapy is delayed by most clinicians until complete recovery from surgery because it is generally feared that cytotoxic drugs impair wound healing, reduce resistance against infection, and may hinder the recovery process. However, clinical experience is lacking. This clinical study examines the effect of perioperative administration of fluorouracil on the healing of wounds and intestinal anastomoses and the recovery process in general. Forty patients with advanced gastrointestinal tract cancers entered the study. Intravenous bolus administration of 0.5 g of fluorouracil was started during surgery. The patients underwent a variety of abdominal operations for palliation or cure. A total of 22 gastric and enteric anastomoses were performed. One half gram of fluorouracil diluted in 150 mL of 5% glucose solution was given intravenously over one hour daily for ten days postoperatively. The patients were carefully evaluated for any alteration in the postoperative recovery. Thirty-eight of the 40 patients received the full course of fluorouracil. Twenty-one patients had an uneventful postoperative course. Eighteen had mild to moderate respiratory and cardiovascular complications unrelated to fluorouracil administration. One patient died of pulmonary emboli 16 days after abdominoperineal resection. Surgical wounds healed without complications in 37 patients. One case of wound disruption occurred after sigmoidectomy. Two patients developed wound infections that healed secondarily. All 22 patients with anastomoses recovered without any evidence of leakage. Colostomies and gastrostomies functioned as anticipated. Side effects attributed to fluorouracil appeared in seven of the patients; in only two of the patients were complications life-threatening, involving bone marrow depression. All patients recovered after discontinuation of fluorouracil therapy and with supportive treatment. On the whole, the course of recovery of this group was no different than expected from patients with advanced malignant neoplasms who were undergoing extensive surgery. Based on this study, it seems that fluorouracil administration during and immediately after surgery has no deleterious effect on wound healing and recovery.

Abdominal Neoplasms↗
PubMed1982

Quantitative analysis of 5-fluorouracil and 5,6-dihydrofluorouracil in plasma by gas chromatography mass spectrometry.

5-Fluorouracil and 5,6-dihydro-5-fluorouracil were analysed in the plasma of patients by combined gas chromatography mass spectrometry. 5-Bromouracil was the internal standard. After extraction from plasma with an isopropanol-diethyl ether mixture (20/80) the components were pentylated and the derivatives produced extracted into diethyl ether. Electron impact mass spectrometry was used for the simultaneous quantitative determinations of 5-fluorouracil and 5,6-dihydro-5-fluorouracil (detection limit 10 ng ml-1 5-fluorouracil, 80 ng ml-1 5,6-dihydro-5-fluorouracil). Chemical ionization was utilized to measure 5,6-dihydro-5-fluorouracil concentrations less than 80 ng ml-1 (sensitivity 10 ng ml-1). The biological applicability of these two techniques was demonstrated by analysing plasma samples from patients after administration of 5-fluorouracil or 5'-deoxyfluorouridine by intravenous injections and infusions.

Chromatography, High Pressure Liquid↗
PubMed1996

Enhancement of 5-fluorouracil cytotoxicity by cisplatin in brain tumour cell lines.

Cisplatin reportedly plays an important role as a chemical modulator in enhancing the chemotherapeutic effects of 5-fluorouracil on tumour cells. The aim of the present study was to test the synergistic cytotoxicity of cisplatin and 5-fluorouracil in 5-fluorouracil-resistant (C6) and -sensitive (9L) rat brain tumour cell lines. Survival fractions, determined using colony-formation assays, were compared following 5-fluorouracil treatment, with and without cisplatin. The presence of cisplatin (1-10 microM) enhanced cytotoxicity by more than three times compared with 5-fluorouracil alone in 5-fluorouracil-resistant C6 cells, whereas no enhancement effects were noted in 9L cells. These results suggest that a cisplatin-fluorouracil-based regimen may be promising in the treatment of 5-fluorouracil-resistant brain tumours.

Animals↗
PubMed2006

Total body topical 5-fluorouracil for extensive non-melanoma skin cancer.

BACKGROUND: Topical 5-fluorouracil 5% cream is one of the treatment modalities for non-melanoma skin cancer (NMSC). There is a lack of suitable therapies to treat patients with extensive NMSC. In this paper we report two patients with extensive NMSC treated by total body application of topical 5-fluorouracil 5% cream. OBSERVATIONS: Topical 5-fluorouracil 5% cream was applied twice daily to the total body, including normal appearing skin. During the treatment, weekly blood samples were taken for measurement of 5-fluorouracil levels. All samples showed a 5-fluorouracil level less than the detection level of 10 microg/l. Total body 5- fluorouracil 5% cream was shown to be an effective treatment in our patients; the majority of lesions cleared in both patients. CONCLUSIONS: In conclusion, total body topical 5- fluorouracil 5% cream application was successful in two patients with extensive NMSC. No detectable serum level of 5-fluorouracil could be determined. Pain and secondary infections were important side effects in our patients. However, in patients with extensive NMSC this treatment may be considered.

Administration, Topical↗
PubMed1991

Highly sensitive method for the determination of 5-fluorouracil in biological samples in the presence of 2'-deoxy-5-fluorouridine by gas chromatography-mass spectrometry.

A highly sensitive and convenient gas chromatographic-mass spectrometric (GC-MS) method is described for the determination of 5-fluorouracil in the presence of 2'-deoxy-5-fluorouridine (which breaks down into 5-fluorouracil during ordinary GC derivatization) in biological samples such as plasma and urine. After extraction with ethyl acetate, 5-fluorouracil and 5-chlorouracil, the latter being used as an internal standard, were converted into their tert.-butyldimethylsilyl derivatives by allowing the mixture to stand for 30 min at room temperature and were assayed by electron-impact ionization GC-MS. Under these conditions, 2'-deoxy-5-fluorouridine did not decompose or interfere with the determination of 5-fluorouracil. The assay method, including the extraction and tert.-butyldimethylsilyl derivatization of 5-fluorouracil, showed good linearity in the range 0-100 ng/ml for 5-fluorouracil in plasma (detection limit 0.5 ng/ml) and urine (detection limit 1 ng/ml). The usefulness of this method was demonstrated by determining plasma concentrations of 5-fluorouracil in rats treated intravenously with 5-fluorouracil and 2'-deoxy-5-fluorouridine.

Acetamides↗
PubMed1993

Trabeculectomy, phacoemulsification, and posterior chamber lens implantation with and without 5-fluorouracil.

Subconjunctival 5-fluorouracil has been an effective adjunct in glaucoma filtering surgery. We investigated the effectiveness of 5-fluorouracil in primary trabeculectomy combined with phacoemulsification and posterior chamber intraocular lens implantation (glaucoma triple procedure). Seventy-four patients were enrolled and randomly assigned into two groups to receive either no 5-fluorouracil (control patients) or low-dose 5-fluorouracil (mean total dose, 24.8 mg; mean number of injections, 5.0 +/- 1.3). The mean preoperative intraocular pressure was 20.1 +/- 5.4 mm Hg for the 5-fluorouracil group and 21.0 +/- 5.2 mm Hg for the control group (P = .48, Student's unpaired t-test). The mean number of medications was 2.2 +/- 1.0 and 2.0 +/- 1.0 (P = .49, Mann Whitney U test), respectively. At all postoperative visits, there were no statistically significant differences in mean intraocular pressures between the two groups. Mean follow-up was 13.2 months for 5-fluorouracil-treated patients and 15.0 months for control patients. At the last postoperative visit, mean intraocular pressures were 15.4 +/- 3.7 mm Hg and 15.0 +/- 5.0 mm Hg, respectively (P = .45, Student's unpaired t-test). Both groups showed comparable visual outcome (20/40 or better in 31 of 38 5-fluorouracil-treated patients [82%] vs 32 of 36 control patients [89%]) and a decrease in number of medications needed, 0.7 +/- 1.0 and 0.7 +/- 0.9, respectively (P = .96, Mann Whitney U test). Thus, 5-fluorouracil administered as in our study did not seem to have any effect in primary trabeculectomy combined with phacoemulsification and posterior chamber intraocular lens implantation.

Aged↗
PubMed2001

A comparison of the skin permeation of three topical 0.5% fluorouracil formulations with that of a 5% formulation.

BACKGROUND: Topical fluorouracil has proven efficacy in the treatment of actinic keratosis. The systemic absorption of various topical formulations of fluorouracil varies, however, and may be affected by the concentration and delivery system used. OBJECTIVE: This study compared the flux and percutaneous absorption of 3H-labeled fluorouracil from three 0.5% fluorouracil formulations incorporated into a porous microsphere delivery system with those from a commercially available 5% fluorouracil formulation. METHODS: Penetration of all formulations through the skin was sampled every 3 hours for 24 hours using full-thickness human cadaver skin samples mounted in a Bronaugh flow-through diffusion cell apparatus. Total absorption was defined as the sum of the amount of cumulative flux through the skin over 24 hours and the amount retained in the skin at 24 hours. RESULTS: The flux through the skin of the 5% fluorouracil formulation was 20 to 40 times greater (normalized, 2-4 times greater) than that of the 0.5% fluorouracil formulations. A higher percentage of absorbed fluorouracil was retained in the skin after 24 hours with the 0.5% formulations (86%-92%) than with the 5% formulation (54%). CONCLUSION: These findings suggest that the 0.5% formulations are associated with less flux through the skin than the 5% formulation and, therefore, potentially less systemic exposure.

Administration, Topical↗
PubMed2002

In vitro drug release studies on guar gum-based colon targeted oral drug delivery systems of 5-fluorouracil.

Intravenous administration of 5-fluorouracil for colon cancer therapy produces severe systemic side-effects due to its cytotoxic effect on normal cells. The broad objective of the present study was to develop novel tablet formulations for site-specific delivery of 5-fluorouracil to the colon without the drug being released in the stomach or small intestine using guar gum as a carrier. Fast-disintegrating 5-fluorouracil core tablets were compression coated with 60% (FHV-60), 70% (FHV-70) and 80% (FHV-80) of guar gum, and were subjected to in vitro drug release studies. The amount of 5-fluorouracil released from the compression-coated tablets in the dissolution medium at different time intervals was estimated by a HPLC method. Guar gum compression-coated tablets released only 2.5-4% of the 5-fluorouracil in simulated GI fluids. When the dissolution study was continued in simulated colonic fluids (4% w/v rat caecal content medium) the compression-coated FHV-60, FHV-70 and FHV-80 tablets released another 70, 55 and 41% of the 5-fluorouracil respectively. The results of the study show that compression-coated tablets containing 80% (FHV-80) of guar gum are most likely to provide targeting of 5-fluorouracil for local action in the colon, since they released only 2.38% of the drug in the physiological environment of the stomach and small intestine. The FHV-80 formulation showed no change either in physical appearance, drug content or dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. The differential scanning calorimetric study showed that 5-fluorouracil did not interact with the formulation excipients used in the study.

Administration, Oral↗
PubMed1994

Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer.

Pharmacokinetics of total platinum, 5-fluorouracil, l-folinic and d-folinic acid, and 5-methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m2/day), 5-fluorouracil (600 mg/m2/day), and folinic acid (300 mg/m2/day). Drugs were administered with a programmable-in-time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 pm and peak of 5-fluorouracil and folinic acid at 4 am. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 pm, and maximum 5-fluorouracil and folate concentrations near 4 am. When drugs were administered at a constant rate, mean plasma concentration of 5-fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 am (approximately 800 ng/ml) and a trough at 1 pm (approximately 100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive d-folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 am, trough near 6 pm, and amplitude approximately 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5-fluorouracil concentrations were least sensitive to 5-fluorouracil-related toxicity. Thus amplification or induction of such rhythm in 5-fluorouracil exposure may permit dose escalation.

Adult↗
PubMed2002

A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer.

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified 'Modified de Gramont' (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m(-2)), then ambulatory 46-h fluorouracil infusion (2000-3600 mg m(-2), cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m(-2). Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m(-2) bolus + 2800 mg m(-2) 46-h infusion. A lower dose of 400 mg m(-2) bolus + 2400 mg m(-2) infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC(0-48 h)) at this lower dose is equivalent to dG. With OxMdG, grade 3-4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea <1% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. MdG and OxMdG are convenient and well-tolerated. OxMdG was particularly active as 1st-line treatment of advanced colorectal cancer. Both regimens are being further evaluated in the current UK MRC phase III trial.

Adenocarcinoma↗
PubMed1993

[5-fluorouracil injection treatment after fistulating glaucoma operations].

BACKGROUND: Since 1984 subconjunctival 5-Fluorouracil injections have been applied with success after filtering surgery. It was the purpose of this retrospective study to find out whether the results justify this treatment in view of all side effects. MATERIALS AND METHODS: Between 2/1991 and 1/1993 twenty-nine eyes of 11 female and 16 male patients with high-risk glaucoma (unsuccessful previous filtering surgery and a high risk of scarring) were treated with subconjunctival injections of 5-Fluorouracil after filtering surgery in the University Eye Hospital Düsseldorf. The mean age of the patients was 58 (11-84) years and the mean follow-up period was 16 (4-24) months. The mean amount of injected 5-Fluorouracil was 43 (5-85) mg. Glaucoma was regarded as controlled when intraocular pressure levels were reduced by more than 20% of the preoperative level and stayed consistently below 21 mm Hg. RESULTS: 26 (89.6%) of the eyes had controlled intraocular pressure during the follow-up period. Two eyes were controlled only after additional cyclocrycoagulation, and 1 glaucoma has remained uncontrolled. Postoperatively we observed fistulas of the conjunctiva in 24% of the eyes and 69% of the eyes had corneal epithelial breakdown problems. It is unlikely that subconjunctival injections of 5-Fluorouracil work only by inhibiting scarring of the filtration bleb. Long-lasting e-vacuo-symptoms in single cases with no functioning bleb at all as well as scarred blebs in 9 of 26 eyes with controlled glaucoma must be interpreted as a probable sign of 5-Fluorouracil toxicity on the ciliary epithelium. CONCLUSIONS: Subconjunctival injections of 5-Fluorouracil after filtering surgery are helpful to control high-risk glaucoma, but there are several disadvantages of this treatment as fistulas of the conjunctiva, corneal surface problems, discomfort for the patient, difficult follow-up and a potential toxicity on the ciliary epithelium that may be pronounced in some cases. Therefore, subconjunctival injections of 5-Fluorouracil after filtering surgery are a useful means for eyes with a high risk of scarring. However, 5-Fluorouracil should not be applied for primary normal glaucoma surgery.

Adolescent↗
PubMed2002

Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer.

BACKGROUND: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). METHODS: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m(2) per day as an intravenous bolus, plus leucovorin, 100 mg/m(2) per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). RESULTS: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% +/- 1.41%; percentage RMSE = 12.70% +/- 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h x microg/mL) = 0.119 x C(5) + 1.436 x C(45) + 2.066, in which C(5) and C(45) are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% +/- 1.37%; percentage RMSE = 12.17% +/- 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% +/- 0.86% and a percentage RMSE of 7.64% +/- 0.81%, and the optimal sampling time points were 45 and 180 minutes. CONCLUSION: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.

Adenocarcinoma↗
PubMed2006

Inhibitory effect of 5-fluorouracil on cytochrome P450 2C9 activity in cancer patients.

Drug interactions have been reported between 5-fluorouracil and cytochrome P450 2C9 (CYP2C9) substrates, S-warfarin and phenytoin. This study was performed to determine the influence of 5-fluorouracil on cytochrome P450 2C9 (CYP2C9) activity in colorectal cancer patients (n=17) receiving 5-fluorouracil. Losartan was used as a marker to assess CYP2C9 activity. Losartan and its CYP2C9 dependent metabolite, E-3174, were determined in urine. The ratios of urinary losartan/E-3174 before and after the 5-fluorouracil treatment were compared for each patient. Genotyping was performed to detect the CYP2C9*2 and CYP2C9*3. At the end of the first cycle of 5-fluorouracil, losartan/E-3174 ratio was increased by 28.0% compared to the pre-treatment values (P=0.15). In five patients recruited for phenotyping after three 5-fluorouracil cycles, the metabolic ratio was increased significantly by 5.3 times (P=0.03). The results suggest that in most patients 5-fluorouracil inhibited CYP2C9 activity. This inhibition was more pronounced when the total administered dose increased. This finding may help explain the mechanism of interaction between 5-fluorouracil and CYP2C9 substrates.

Adult↗
PubMed2002

Fluorouracil for allergic reactions to capecitabine.

OBJECTIVE: To report the safe use of fluorouracil in a patient with breast cancer who had allergic reactions to capecitabine. CASE SUMMARY: A 42-year-old African American woman with metastatic breast cancer developed progressive disease. Capecitabine 1500 mg taken by mouth twice daily was prescribed as the salvage chemotherapy. She developed a generalized rash and itching, sore throat, and dizziness approximately 4 hours after the first dose of capecitabine. These reactions recurred immediately after the second dose. Capecitabine was discontinued and the allergic reactions resolved after the woman took diphenhydramine for 1 week. In view of limited therapeutic options for her progressive disease, a trial of fluorouracil 300 mg/m(2)/d continuous intravenous infusion over 5 days was initiated without any premedications. She did not experience any reactions. The dose of fluorouracil in the second cycle was increased to 400 mg/m(2)/d continuous infusion over 5 days. DISCUSSION: Capecitabine is not intrinsically cytotoxic, but is converted to fluorouracil in tumor tissues via a 3-step enzymatic pathway. Capecitabine reaches peak blood concentrations in about 1.5 hours, with peak fluorouracil concentrations occurring at 2 hours. The elimination half-life of both drugs is 0.5-0.7 hours. The patient tolerated the rechallenge with fluorouracil without complications. Objective causality assessment revealed that the adverse event was probably drug induced. It was postulated that the allergic reaction was most likely caused by capecitabine or the intermediate metabolites based on the immediate reappearance of symptoms from the rechallenge, pharmacokinetic data, and well-tolerance of fluorouracil. CONCLUSIONS: The use of fluorouracil treatment with careful monitoring can be considered in a patient with mild allergic reactions to capecitabine.

Adult↗
PubMed1989

Clinical pharmacology of 5-fluorouracil.

5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.

Female↗
PubMedDate not supplied

Interleukin-2 as a modulator of 5-fluorouracil in hepatic arterial immunochemotherapy for liver metastases.

BACKGROUND/AIMS: Hepatic arterial infusion of interleukin-2-based immunochemotherapy has yielded a high response rate (> 75%) in patients with unresectable liver metastases. In order to clarify the mechanisms that underlie the apparent benefit of combination treatment, the role of IL-2 as a modulator of 5-fluorouracil metabolism was investigated. METHODOLOGY: A single dose of 5-fluorouracil (50 mg/kg) with or without IL-2 (3500 Japan Reference Units/kg) was given via the hepatic artery to rats bearing liver metastases. Thirty minutes later samples of liver metastatic foci or surrounding normal liver tissue were removed for the measurement of thymidylate synthase, thymidine kinase and dihydropyrimidine dehydrogenase activity, and 5-fluorouracil content. RESULTS: 5-fluorouracil levels in tumor were significantly higher than in normal liver. Although the addition of IL-2 reduced 5-fluorouracil levels in both tumor and normal liver tissues by the activation of dihydropyrimidine dehydrogenase, the ratio of tumor/normal liver 5-fluorouracil levels was unchanged. Both thymidylate synthase and thymidine kinase activities were significantly inhibited in tumor tissue when the combination of 5-fluorouracil and IL-2 was administered. CONCLUSIONS: IL-2 increases 5-fluorouracil cytotoxicity through the inhibition of thymidylate synthase/thymidine kinase activities in the hepatic arterial infusion.

Adenocarcinoma↗
PubMed1997

[Determination of dihydropyrimidine dehydrogenase in the prediction of toxic side effects of 5-fluorouracil].

In the chemotherapy of colorectal cancers the most frequently given drug is 5-fluorouracil, which in certain cases reduces or delays the appearance of the local recurrence or metastasis. It is well known that the patient's response to 5-fluorouracil is very different concerning both, effects and side effects. More than 80% of the infused drug is catabolised in the first 20 minutes after the treatment. The first and rate limiting enzyme of the catabolism is dihydropyrimidine dehydrogenase, which has the highest activity in the liver and lymphocytes. The activity of this enzyme shows correlation with the blood level of 5-fluorouracil. The deficiency of this enzyme caused severe, in some cases lethal toxicity, its congenital deficiency is responsible for familial pyrimidinaemia. Authors intended to collect data about the dihydropyrimidine dehydrogenase activity of colorectal cancer patients, in order to screen enzyme deficiency or very low enzyme activity, which might be in connection with the appearance of severe side effects, moreover to determine the optimal dose of 5-fluorouracil before the treatment. Dihydropyrimidine dehydrogenase activity was determined in the lymphocytes of 48 colorectal cancer patients, treated by 5-fluorouracil, at the beginning of each cytostatic cycle. The enzyme activity of the patients was between 1.2 and 24.4 pmol/min/10(6) lymphocyte. The value of the enzyme activity fluctuated in a range, characteristic for the individual patients and this value was not modified by the 5-fluorouracil treatment. Dividing the patients in two groups, low (lower than 5 pmol/min 10(6) lymphocyte) and high (higher than 15 pmol/min 10(6) lymphocyte) dihydropirimidine dehydrogenase activity, we found that decrease in the white blood cell number and appearance of the side effects occurred with much higher frequency in the low activity group which resulted in the reduction of the dose or in more serious cases interruption of the treatment. Authors conclude that the determination of the dihydropyrimidine dehydrogenase activity in the lymphocytes is a valuable method in the prediction of the toxic side effects of 5-fluorouracil, in the screening of the congenital enzyme deficiency and in the individualization of the 5-fluorouracil dosage.

Adjuvants, Pharmaceutic↗