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PubMed2002

Fluorouracil as a treatment for corneal papilloma in a Malayan tapir.

A 26-year-old, wild caught, male Malayan tapir at the Miami Metrozoo with bilateral corneal papillomas was serially immobilized and given subconjunctival injections of fluorouracil. Over the course of 17 weeks five bilateral injections of 25 mg fluorouracil were given. This treatment caused regression of the corneal lesions as evidenced by decreased lesion diameter, decreased corneal vascularity, increased corneal clarity, and improved visual function. No adverse drug effects were observed.

Animals↗
PubMed2001

Squamous cell carcinoma in situ (Bowen's disease) in renal transplant patients treated with 5% imiquimod and 5% 5-fluorouracil therapy.

BACKGROUND: Depending upon the patient's age at transplant, skin type, sun exposure, and the need for immunosuppressive therapy to prevent rejection, there is escalation in the development of cutaneous malignancies in organ transplant patients a number of years after transplantation. Thus, with the expansion in these procedures over the past decades, and the ever-lengthening survival of these patients, we are seeing an increase in cutaneous malignancies in this patient population. OBJECTIVE: To determine if combined therapy with 5% 5-fluorouracil and 5% imiquimod may be useful in the treatment of squamous cell carcinoma in situ. METHODS: We present five renal transplant patients, all more than 10 years posttransplantation, three with insulin-dependent diabetes, who developed multiple areas of squamous cell carcinoma (SCC) in situ. All these patients were on chronic immunosuppressive chemotherapy to prevent rejection, but were otherwise doing well. All the patients had biopsy-proven SCC in situ on their lower extremities that even in normal patients may be a challenge to treat. RESULTS: We treated these five patients with a combination of a local immune therapy, imiquimod cream, and a topical chemotherapeutic agent, 5% 5-fluorouracil (5-FU), with clearing of the areas of SCC in situ. CONCLUSION: Although immunotherapy must be used with caution in organ transplant patients to avoid graft rejection, topical imiquimod is a local immune modulator that potentiates local innate and possible adaptive immunity without measurable effects on systemic immunity. In addition, there is evidence that cytokines induced by imiquimod may improve the therapeutic efficacy of topical 5% 5-FU in the treatment of SCC in situ.

Administration, Cutaneous↗
PubMed1990

[Cardiac side effects of 5-fluorouracil].

In four patients (a 54-year-old man and three women aged 57, 60 and 65 years, respectively) with colorectal carcinoma and no obvious cardiac abnormality anginal symptoms and ECG changes occurred during chemotherapy with 5-fluorouracil at a dose of 400 and 600 mg/m2. The ECG changes consisted of descending ST depressions with preterminally negative T waves, terminally negative T waves, ventricular extrasystoles and sinus tachycardia with intermittent atrial fibrillation. The signs first appeared between the second and fourth day of treatment; in two patients they improved with glyceryl trinitrate. A few days after 5-fluorouracil had last been administered all ECG changes had disappeared. The causes of cardiotoxicity of the drug remain unknown.

Aged↗
PubMed1982

[Sequential methotrexate and fluorouracil in metastasizing colorectal carcinomas. Results of a phase II pilot study (author's transl)].

A sequential combination of methotrexate and 5-fluorouracil was used for treatment of 20 patients with metastasizing colorectal carcinomas. Pretreatment with 5-fluorouracil had been given to five patients. While the chemotherapeutically pretreated patients showed two partial remissions, two minimal remissions and one progression, the remaining patients showed one full remission, six partial remissions, five minimal remissions and three progressions. The average partial remission time of these patients was 7,9 months. The average survival time will probably be more than one year. The toxicity of treatment was slight.

Adult↗
PubMed1980

Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.

To evaluate the treatment of advanced islet-cell carcinoma, we randomly assigned 84 patients to streptozocin alone or streptozocin plus fluorouracil. Each regimen was given in five-day courses. The most frequent toxic effects were nausea and vomiting, mild and reversible renal toxicity, and bone-marrow depression with the combination regimen. The combination had advantages over streptozocin alone in overall rate of response (63 vs. 36 per cent) and in rates of complete response (33 vs. 12 per cent). There was no evidence of a preferential response among types of functional tumors. Objective responses were generally of long duration (median, 17 months) and of substantive clinical benefit. Treatment with the combination also yielded a survival advantage over treatment with streptozocin alone (medians, 26 and 16 1/2 months), but this difference is not statistically significant. In spite of gastrointestinal side effects, streptozocin combined with fluorouracil appears to be a valuable treatment for advanced islet-cell carcinoma.

Adenoma, Islet Cell↗
PubMed1989

A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors.

We evaluated the postoperative use of sequential methotrexate and fluorouracil followed by leucovorin in 679 patients with primary breast cancer, histologically negative axillary nodes, and estrogen-receptor-negative (less than 10 fmol) tumors. No survival advantage was observed with this therapy as compared with no postoperative therapy during four years of follow-up (87 percent vs. 86 percent; P = 0.8). However, there was a significant prolongation of disease-free survival among women who received this therapy as compared with those who did not (80 percent vs. 71 percent; P = 0.003). An advantage was observed in both the patients less than or equal to 49 years old and those greater than or equal to 50. At four years, treatment failure was reduced by 24 percent in the younger group and by 50 percent in the older group. The rates of both local and regional and distant metastases were decreased. These benefits, achieved without the use of an alkylating agent, were associated with tolerable side effects. Multivariate analysis testing for potential interactions failed to identify subgroups of patients who did not benefit from the therapy. These results, although promising, do not obviate the need for additional trials to evaluate potentially better regimens of therapy, but they do suggest that sequential methotrexate-fluorouracil should be used in the control arm in such studies. Their use is also justified for the treatment of patients who refuse to participate in clinical trials, provided the patients meet the eligibility criteria of the present study. Since women with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not included in this study, we do not recommend systemic treatment for them outside of a clinical trial.

Aged↗
PubMed1993

Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate, and fluorouracil.

BACKGROUND: Although ondansetron was found to be effective as an antiemetic in numerous clinical trials of highly emetogenic combination-chemotherapy regimens that included cisplatin, its role in milder emetogenic regimens has not been fully defined. To address its use with a widely used but less emetogenic regimen, we performed a double-blind, randomized clinical trial comparing ondansetron with dexamethasone and metoclopramide in patients with breast cancer receiving chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. METHODS: A total of 165 women with breast cancer from 14 Canadian centers who were about to receive this chemotherapy for the first time were randomly assigned to receive either ondansetron (n = 85) or dexamethasone plus metoclopramide (n = 80), a widely used, standard antiemetic regimen. The patients recorded the incidence of nausea, emesis, and other side effects in diaries, and these data were compared in the two groups. RESULTS: The patients who received dexamethasone and metoclopramide had significantly less nausea during the first 24 hours after chemotherapy was begun. Otherwise, there were no statistically significant differences in efficacy between the regimens. The incidence of drowsiness and increased appetite was higher in the group given dexamethasone and metoclopramide. CONCLUSIONS: For women with breast cancer who are being treated with cyclophosphamide, methotrexate, and fluorouracil, the efficacy of dexamethasone and metoclopramide in controlling nausea and vomiting equaled or exceeded that of ondansetron.

Analysis of Variance↗
PubMed2004

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. METHODS: Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. RESULTS: The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. CONCLUSIONS: The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

Antibodies, Monoclonal↗
PubMed2004

Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.

BACKGROUND: The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. METHODS: We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. RESULTS: A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). CONCLUSIONS: Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.

Adult↗
PubMed2000

Topical tretinoin and 5-fluorouracil in the treatment of linear verrucous epidermal nevus.

Treatment of a linear verrucous epidermal nevus using topical 0.1% tretinoin cream and 5% 5-fluorouracil in a young patient is described. In 1994, successful topical therapy using this combination was described in the management of an inflammatory linear verrucous epidermal nevus. We report another case in which treatment of a noninflamed epidermal verrucous nevus with 0.1% tretinoin and 5% 5-fluorouracil resulted in significant improvement. An updated summary of the literature discussing management of epidermal nevi is presented.

Antimetabolites↗
PubMed2004

UPS1 and UPS2 from Arabidopsis mediate high affinity transport of uracil and 5-fluorouracil.

Salvage pathways play an important role in providing nucleobases to cells, which are unable to synthesize sufficient amounts for their needs. Cellular uptake systems for pyrimidines have been described, but in higher eukaryotes, transporters for thymine and uracil have not been identified. Two plant transporters, AtUPS1 and PvUPS1, were recently identified as transporters for allantoin in Arabidopsis and French bean, respectively. However, Arabidopsis, in contrast to tropical legumes, uses mainly amino acids for long distance transport. Allantoin transport has not been described in the Brassicaceae. Thus, the physiological substrates of ureide permease (UPS) transporters in Arabidopsis may be compounds structurally related to allantoin. A detailed analysis of the substrate specificities of two members of the AtUPS family shows that AtUPS1 and AtUPS2 mediate high affinity uracil and 5-fluorouracil (a toxic uracil analogue) transport when expressed in yeast and Xenopus oocytes. Consistent with a function during germination and early seedling development, AtUPS1 expression is transiently induced during the early stages of seedling development followed by up-regulation of AtUPS2 expression. Arabidopsis ups2 insertion mutants and ups1 lines, in which transcript levels were reduced by post-transcriptional gene silencing, are more tolerant to 5-fluorouracil as compared with wild type plants. The results suggest that in Arabidopsis UPS transporters are the main transporters for uracil and potentially other nucleobases, whereas during evolution legumes may have taken advantage of the low selectivity of UPS proteins for long distance transport of allantoin.

Allantoin↗
PubMed2005

Efficacy and toxicity of fluorouracil, doxorubicin, and cisplatin/nedaplatin treatment as neoadjuvant chemotherapy for advanced esophageal carcinoma.

OBJECTIVE: Patients with advanced esophageal carcinoma including clinical T4 tumor, extensive lymph node metastasis, or intramural metastasis have a dismal prognosis, despite recent multimodality treatments. The aim of this study was to evaluate the efficacy and toxicity of neoadjuvant chemotherapy using fluorouracil, doxorubicin, and cisplatin or nedaplatin (FAP/N) in these patients. MATERIAL AND METHODS: Twenty-six patients were enrolled in this study. The first 9 patients received 600 mg/m2 fluorouracil on days 1-7 and days 29-35, and 30 mg/m2 doxorubicin and 60 mg/m2 cisplatin on days 1 and 29 (FAP). The next 17 patients received modified FAP, in which 50 mg/m2 nedaplatin was given instead of cisplatin (FAN). RESULTS: Grade 3 or 4 toxicities developed in 6 patients (23.1%) during chemotherapy, but there was no discontinuation of treatment. The clinical response rate was 46.2%. Twenty-one patients (80.8%) underwent esophagectomy, and R0 resection was achieved in 16 patients (61.5%). The 1-year survival rates of 26 patients, 21 patients with resectable tumor, 16 with R0 resection, and 12 clinical responders, were 31.3%, 32.1%, 33.3%, and 45.5%, respectively, each with a median survival time of 9 months. The median progression-free survival time of 26 patients was 6 months; in 16 patients with R0 resection progression-free survival was 6.5 months. There was no correlation between the recurrence pattern and tumor spread before treatment. CONCLUSIONS: FAP/N was found to have acceptable toxicities and the ability to control locoregional tumors, but made little contribution to patient survival. The efficacy of this treatment for patients with advanced esophageal carcinoma, however, may not yet be apparent.

Adult↗
PubMed2001

Lack of interaction between bropirimine and 5-fluorouracil on human dihydropyrimidine dehydrogenase.

1. Bropirimine (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a member of a class of antineoplastic agents that are administered concomitantly or sequentially with anticancer 5-fluorouracil (5-FU) prodrugs in clinical patients. Interactions between bropirimine and 5-fluorouracil (5-FU) were investigated on dihydropyrimidine dehydrogenase (DPD) activity, the rate-limiting enzyme of 5-FU metabolism, in human liver cytosol. Apparent DPD activity was determined by measuring the recovery of [14C]5-FU by HPLC. 2. The apparent activity of 5-FU metabolism (2.1-100 microM) showed a linear relationship in the Eadie-Hofstee plot in the pooled cytosol, suggesting that a single enzyme is responsible for apparent 5-FU metabolism. Km and Vmax were estimated to be 23 microM and 0.32 nmol min(-1) mg(-1) protein, respectively. Apparent DPD activity for 5-FU (25 microM) in the cytosol from 12 individual donors ranged from 0.017 to 0.39 (0.16 +/- 0.12) nmol min(-1) mg(-1) protein, indicating a large intersubject variance. 3. The suicidal inactivators of the DPD enzyme, (E)-5-(2-bromovinyl)uracil and 5-bromouracil (6.3-50 microM), illustrated concentration-dependent inhibition on DPD activity. Isocytosine (6.3-100 microM), used as a negative control, did not affect DPD activity. Bropirimine (6.3-100 microM) also did not show any inhibition of DPD activity. Therefore, bropirimine is unlikely to cause increases in 5-FU levels in clinical patients after co-administration of bropirimine with 5-FU prodrugs.

Adolescent↗
PubMed1983

Dietary wheat bran inhibits DNA synthesis and enhances 5-fluorouracil toxicity in rat pancreas.

The effect of a 20% wheat bran dietary supplement on pancreatic growth and on the content and synthesis of pancreatic RNA and DNA was examined in male Sprague-Dawley rats fed defined diets for 4-5 weeks. Nutrient intake and body weight gain were similar in the control group (fed a fiber-free diet) and the groups fed the wheat bran supplement. The wheat bran diet produced no significant change in pancreatic weight, protein, RNA content, or DNA content, but was associated with a 28.8% fall in pancreatic DNA synthesis, measured by [3H]thymidine incorporation into DNA, when compared with the controls (p less than 0.05). When rats were injected with 50 mg/kg of 5-fluorouracil (two injections, one week apart), those fed wheat bran exhibited a 40.1% increase in pancreatic wet weight (p less than 0.005) and a 24.5% decrease in RNA content (p less than 0.001), when compared to controls fed a fiber-free diet. RNA synthesis, measured by the incorporation of 32P into RNA, increased 3.6-fold in rats fed wheat bran, when compared with controls (p less than 0.01). These results suggest that wheat bran should be tested further for any inhibitory action on pancreatic carcinogenesis and for its modifying effect on 5-fluorouracil toxicity.

Animals↗
PubMedDate not supplied

Studies on microencapsulation of 5-fluorouracil with poly(ortho ester) polymers.

Microencapsulation of 5-fluorouracil was successfully accomplished with poly(ortho ester) polymers by the emulsification-solvent evaporation method. While actual drug loading increased with increasing drug load (5-15% w/w), the entrapment efficiency remained essentially unaffected, under a given set of experimental conditions. Incorporation of sorbitan sesquioleate enhanced entrapment efficiency, decreased the volume-surface mean diameter of the poly(ortho ester) microspheres and provided controlled release of 5-fluorouracil. The volume of the aqueous phase was more important than the concentration of polyvinyl alcohol in it. The entrapment efficiency improved from 13 to 33% when the volume of the aqueous phase was increased from 20 to 80 ml. The volume of organic phase (methylene chloride) and the concentration of polymer in it played an important role. The use of smaller volumes of more concentrated polymer solution enhanced actual drug loading, entrapment efficiency and produced larger microspheres. The release studies conducted in 0.01 M phosphate buffer at 37+/-1.0 degrees C demonstrated that the release of 5-FU from the microspheres prepared with sorbitan sequioleate was nearly independent of the initial drug load with a mean zero-order rate constant of 0.0063% per hour. The data suggested that drug release was largely a diffusional process with contributions from dissolution and polymer degradation.

Antimetabolites, Antineoplastic↗
PubMedDate not supplied

Niosomal delivery of 5-fluorouracil.

Non-ionic surfactant vesicles (niosomes) have shown promise as cheap, chemically stable alternatives to liposomes. Niosomes of spans (Sorbitan monoesters) have shown promise of commercial exploitation. Hence, niosomes were prepared of 5-fluorouracil (FU) using different spans. Niomsomes were prepared by the hand shaking method (HSM), reverse phase evaporation (REV) and ether injection method (EIM) using a series of Spans, i.e. Span 20, 40, 60 and 80. HSM giving least permeable vesicles were used to study the effect of variables like type of Span, composition of lipid and total lipid concentration on entrapment efficiency (EE) and release rate. Span 40 and 60 released 40.9 and 37.1% drug in 6 h while Span 20 and 80 displayed 52.2 and 57.1% release, respectively in the same time. Niosomes of Span 40 showed a mean vesicle size of 8.1 microns, EE of 15.3 +/- 1.3% and released 78.6% drug in 6 h; inclusion of cholesterol reduced the vesicle size to 4.8 microns, EE to 12.3 +/- 0.9% and the release to 50.5% (in 6 h), while incorporation of dicetyphosphate further reduced the vesicle size to 3.87 microns, EE to 10.9 +/- 1.1% and reduced release to 40.9% (in 6 h). Increase in the amount of lipid used translated into an almost linear increase in EE. Biodistribution of drug in rats was modified on encapsulation. The concentration of niosomal drug in liver, lung and kidney was increased while it decreased in intestine compared to free drug solution following intravenous administration. The niosomal formulation displayed higher and sustained plasma drug level profile compared to free drug solution. Pharmacokinetic calculations revealed an increase in half-life, area under the curve and decrease in volume of distribution of the drug on encapsulation. Thus, the study suggests that niosomes can act as promising carriers for 5-Fluorouracil.

Animals↗
PubMed2003

Vinorelbine, epirubicin and fluorouracil as first-line therapy in metastatic breast cancer--a phase II trial.

A phase II study was conducted to assess the toxicity and response rate of vinorelbine (NavelbineR) combined with epirubicin and fluorouracil (NEF) in metastatic breast cancer. Vinorelbine was delivered at a dose of 25 mg/m2 on days 1 and 8, epirubicin at 60 mg/m2 on day 1 and fluorouracil at 600 mg/m2 on day 1, at 3-week intervals. Forty consecutive ambulant patients with breast cancer with measurable metastases were treated with a total of 310 cycles (median 8) as first-line therapy. The objective response rate was 83% (95% CI 71-95) (6/40 CR 15%, 27140 PR 68%). In 3 patients, CNS metastases were detected during NEF therapy those who had a partial response in their visceral metastases. Median time to progression was 13 months (95% CI 7-19) and estimated median survival time was 32 months. The main dose-limiting adverse effect, grade III-IV haematological toxicity, was reported in 92% of patients. One patient died of neutropenic sepsis. Grade III infections requiring hospitalization were observed in 8 patients (20%). Half of the patients complained of mild constipation, nausea or stomatitis, which were easily managed. Almost all patients had grade III alopecia. One patient with previous adjuvant anthracycline therapy (CEF x 9 two years earlier) developed fatal grade IV cardiac failure associated with pulmonary emboli 2 months after completion of NEF therapy (PR with 6 cycles). In line with the observations of others conducting phase II first-line trials combining vinorelbine and epirubicin, it is concluded that the NEF regimen is effective in metastatic breast cancer. Haematological toxicity, however, requires dose reductions in many patients. Furthermore, careful monitoring of cardiac function is necessary, particularly in patients who received prior adjuvant anthracycline therapy.

Adult↗
PubMed2004

Upper extremity deep venous thrombosis in patients with 5-fluorouracil-containing adjuvant chemotherapy--three case reports and a review.

Catheter-related deep venous thrombosis is a complication that can occur in patients receiving chemotherapy. Three such cases are described and a review of the literature is made, focusing on recent results regarding possible thrombogenic mechanisms and the high prevalence of non-symptomatic thrombosis as well as the high morbidity and mortality associated with upper extremity deep venous thrombosis. Special emphasis is given to the cytotoxic effects of 5-fluorouracil on vascular endothelium and the likely link to thrombotic complications. The possible differences between two different methods of administering chemotherapy, continuous infusion and bolus dose administration, in this regard are briefly discussed. It is concluded that the first steps towards an understanding of the mechanisms behind the vascular effects of 5-fluorouracil have been taken. Much remains to be done before active interaction with the pathogenic processes leading to vascular and cardiac complications can be realized, yet various forms of anticoagulant therapy could well be an efficient form of prophylaxis.

Adult↗