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PubMed1980

Metabolic fate of 1-hexylcarbamoyl-5-fluorouracil after oral administration in mice.

1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro[6-14C]uracil (14C-HCFU) was compared with that of 5-fluoro[6-14C]uracil (14C-FU) after oral administration to mice. 2. 1-(5-Hydroxyhexylcarbamoyl)-5-fluorouracil (5-hydroxy-HCFU) and 1-(5-oxohexylcarbamoyl)-5-fluorouracil (5-keto-HCFU) were found as major intermediate metabolites of 14C-HCFU and were produced by omega-1 oxidation. 3. FU was detected in plasma 180 min after oral administration of 14C-HCFU, whereas unchanged FU disappeared within 60 min after 14C-FU. 4. 14C-HCFU and resulting FU were retained in tissues for a long period after oral administration, while administered 14C-FU was rapidly degraded.

Administration, Oral↗
PubMed1987

Metabolism of 1-phthalidyl 5-fluorouracil in rat liver and enzyme induction by phenobarbital.

1. When 1-phthalidyl 5-fluorouracil (PH-FU) was incubated with isolated rat hepatocytes, 5-fluorouracil, 2-carboxybenzaldehyde (CBA) and alpha-hydroxymethylbenzoic acid (HMB) were detected as the major metabolites. 2. The enzymes involved in the metabolism of PH-FU, PH-FU hydrolase and CBA reductase are cytosolic and were induced by treating the rats with phenobarbital (PB). Treatment of rats with 3-methylcholanthrene (3-MC) did not affect either enzyme activity. 3. The PB-induced PH-FU hydrolase was inhibited by NADH and several aldehydes, while NAD stimulated the hydrolase and protected it from inactivation by SH reagents. 4. Study in vivo revealed that treatment of rats with PB accelerated the metabolism of PH-FU in the liver and markedly decreased the blood PH-FU after its oral administration to rats, which resulted in reduction of the anti-tumour activity of PH-FU. This activity was not affected by treatment of the rats with 3-MC.

Aldehyde Oxidoreductases↗
PubMedDate not supplied

Preparation of controlled release anticancer agents. I: 5-Fluorouracil-ethyl cellulose microspheres.

Microspheres of 5-fluorouracil have been prepared, using three grades of ethyl cellulose as wall forming materials, and utilizing a solvent evaporation technique under ambient conditions. An alcoholic solution of 5-fluorouracil and polymer was dispersed in liquid paraffin containing 33.3 per cent n-heptane. The effect of stirring rate, time of stirring, drug loading, and polymer grade on drug release in two different media were evaluated. The drug loaded particles were spherical in shape and had a diameter range of 25-200 mm and were suitable for incorporating into a gel base. Drug release studies in aqueous media, showed that acidic media provide a faster release rate than neutral media. The drug release study from an aqueous gel base preparation at pH 7.0 through a synthetic membrane was found to be promising for formulation of a gel-microsphere product for the treatment of skin lesions.

Administration, Topical↗
PubMed1979

Treatment of carcinoma of base of tongue with radiation therapy and 5-fluorouracil. Potential for optimization with 18F-FU.

The treatment of advanced base of tongue carcinoma with concurrent radiation therapy and 5-fluorouracil versus radiation therapy alone is compared. Although the results are inconclusive, it is noteworthy that all the 5-year survivors were patients given combined treatment. Important questions regarding optimization of time-dose relationships with combined therapy were generated. Accordingly, 18F-5 fluorouracil was synthesized in an attempt to answer some of these questions.

Carcinoma, Squamous Cell↗
PubMed1988

Treatment of probable subclinical liver metastases and gross pancreatic carcinoma with hepatic artery 5-fluorouracil infusion and radiation therapy.

Since subclinical hepatic metastases are frequently present at time of diagnosis of pancreatic carcinoma, any meaningful effort to improve survival must include 'prophylactic' liver therapy in addition to treatment of the pancreatic primary. We report the results of a prospective, unrandomized clinical trial of a 2-week liver and pancreas infusion (by hepatic artery) of 5-fluorouracil (5-FU) and pancreatic irradiation to 50-60 Gy, combined with prophylactic irradiation of the liver with approximately 20 Gy. Of 21 evaluable patients, 17 completed therapy without excessive toxicity and had a median survival of 50 weeks. Contrary to historical controls, the liver in our series was rarely the first site of failure (6%), suggesting that the combination of hepatic artery 5-fluorouracil and 20 Gy liver radiation may suppress subclinical (microscopic) liver metastases without significant hepato-toxicity. When radiation doses to the pancreas were increased above 50 Gy there was improvement in primary tumor control, although failure in the pancreatic bed remained the most common site of failure. Future clinical investigation of this form of combined therapy for eradication of micro-metastasis in the liver, combined with more aggressive local pancreatic therapy, would seem appropriate.

Adenocarcinoma↗
PubMed1989

The effect of sequential methotrexate and 5-fluorouracil in patients with recurrent head and neck cancer.

Sequential methotrexate and 5-fluorouracil was given to 105 patients with recurrent head and neck cancer. All 105 patients had previously received radiotherapy in curative doses; 41 patients had also been surgically treated and 21 had received previous chemotherapy for recurrence. The treatment consisted of methotrexate 125 mg/m2, followed by 5-fluorouracil 600 mg/m2 after 1 h. Leucovorin rescue was administered after 24 h. A response was observed in 24 patients (23%), including 9 (9%) with complete response. The majority of the responders were patients with a good performance status and with primary tumour in the oropharynx. The toxicity was not negligible, as 5 patients (5%) died of treatment-related causes, mainly due to leukopenia, which was the most frequent and important complication. This sequential methotrexate/5-fluorouracil treatment-schedule cannot be recommended for recurrent head and neck cancer patients.

Adult↗
PubMed1990

Dose-dependent leucovorin efficacy with an intermittent high-dose 5-fluorouracil schedule.

Sixteen patients with metastatic carcinoma of the colon were treated with a regimen of leucovorin 200 mg/m2, given as a 10-min infusion followed by a median dose of 833 mg/m2 (range 500-1000 mg/m2) 5-fluorouracil every two weeks. For the 16 patients with proven metastatic disease, two-year survival exceeds 50%. Responses were: 2 complete; 4 partial; 4 minor; 3 progression; and 3 not evaluable but without progression to date. Toxicities include: 8 (50%) leukopenia; 9 (56%), 1 severe thrombocytopenia; 9 (56%), 2 severe, diarrhea; 9 (56%), 3 severe, nausea/vomiting; 8 (50%), 1 severe, stomatitis; 7 (44%) conjunctivitis; 6 (38%) alopecia; and 13 (81%), 3 severe, neurotoxicity. Leucovorin appears to exert a dose-dependent beneficial effect on both the response and survival produced by the intermittent high-dose 5-fluorouracil schedule. This benefit first appears to increase substantially when the leucovorin dose is increased from 120 to 200 mg/m2. Findings identify a testable candidate regimen for selected good risk patients. Full selection criteria remain to be identified.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Platinol (CDDP) and continuous intravenous infusion 5-fluorouracil in refractory stage IV breast cancer: a phase II study.

Twenty-four patients with refractory Stage IV breast cancer were treated with platinol (100 mg/m2 i.v. Day 1) and 5-fluorouracil (1000 mg/m2 as a continuous infusion over 24 h daily for 5 days). Objective responses occurred in 12 of 24 patients (50%). The median duration of response was 4.9 months. Platinol and 5-fluorouracil in combination are active agents in patients with refractory breast cancer, and clinical trials are warranted in previously untreated patients.

Adult↗
PubMed1991

5-Fluorouracil by protracted venous infusion: a review of recent clinical studies.

The pharmacokinetics of continuous infusion 5-fluorouracil make it an ideal drug to administer as a protracted infusion (continuous infusion more than 30 days). During the last decade numerous clinical studies have been conducted to evaluate the efficacy of 5-fluorouracil (5FU) administered as a protracted venous infusion. Phase II studies in metastatic colorectal cancer in 345 patients have demonstrated an average response rate of 36% (range 15-59%) and a prospective randomized study performed by the Mid-Atlantic Oncology Program (MAOP) has confirmed a higher response rate with 5FU infusion compared with a bolus schedule. Phase II studies in refractory carcinoma of the breast in 177 patients have demonstrated a 30% response rate (range 17-50%); studies in pancreatic, gastric, and refractory prostate cancer have also demonstrated clinical utility. The major toxicities of 5FU infusion are mucositis and hand-foot syndrome; life-threatening myelosuppression is rare and treatment-related deaths have not been reported. 5FU infusion is a useful palliative treatment for many adult patients with advanced malignancies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Cisplatinum in combination with 5-fluorouracil and citrovorum factor in the treatment of advanced colorectal carcinoma.

A phase II trial of citrovorum factor, 500 mg/m2/week, plus 5-fluorouracil, 400 mg/m2/week on day 1, and cisplatin, 20 mg/m2/week on day 2, was carried out in a group of 40 patients with metastatic colorectal carcinoma. A partial response with a mean duration of 8.4+ months was achieved in 24% of patients, a minimal response with a mean duration of 5.4 months was obtained in 6% of patients, and a stabilization of 6.2 months was achieved in 41%. Ten patients (29%) progressed. A 38% partial response rate was seen in patients with advanced rectal carcinoma, whereas no response was obtained in patients with colon cancer. Interestingly, 5 partial responses were seen in 12 patients pretreated with 5-fluorouracil. The overall survival was 9.8+ months. The mean survival of patients who achieved a partial response was 12.0+ months, whereas patients who progressed survived a mean of 6.6+ months. Patients with colon cancer had a mean survival of 8.1+ months, and those with rectal cancer survived a mean of 11.1+ months. This difference was not statistically significant. The treatment was generally very well tolerated, with patients showing mostly grade 1-2 gastrointestinal and/or hematological toxicity.

Adult↗
PubMed1992

Treatment of advanced colorectal cancer with recombinant interferon alpha and fluorouracil: activity in liver metastasis.

A cohort of 35 patients with advanced colorectal cancer, not previously exposed to chemotherapy, were included in a phase II study exploring the combination of interferon-alpha, 9 MU subcutaneously three times weekly, and 5-fluorouracil 750 mg/m2/day during 5 consecutive days in continuous intravenous infusion followed with weekly bolus injection of fluorouracil 750 mg/m2. Of 33 cases evaluable for activity; 5 patients achieved partial response and 3 complete response for an overall response rate of 24% (95%; confidence limit 11-42%). Most of the responses were observed in liver metastases, response rate = 30% (95%; CL 13-53%), with little activity observed in other sites; response rate 3% (95%; CL 8-16%), p = .0006. The median time to progression and median overall survival were 16+ (range 1+ to 48+) and 21+ weeks (range 1+ to 52+). All patients were evaluable for analysis of toxicity. Severe mucositis and diarrhea, present in 14 patients were the limiting side effects. Two patients developed progressive renal toxicity and died. Weakness, myalgia, and nonneutropenic fever were observed frequently, one patient developed dementia. This combination is able to induce major responses in patients with advanced colorectal cancer, particularly in liver metastasis. Additional trials evaluating this approach are indicated.

Aged↗
PubMed1994

Cerebral demyelination with 5-fluorouracil and levamisole.

We report a patient who developed multifocal cerebral demyelination with the use of 5-fluorouracil, levamisole, and leucovorin as adjuvant treatment for intestinal adenocarcinoma. The clinical features were acute confusion, restlessness, ataxia, and slurred speech. Magnetic resonance imaging revealed multifocal enhancing white matter lesions. Brain biopsy showed a well-demarcated area of demyelination in cerebral white matter. The patient improved clinically and radiologically after cessation of chemotherapy and a short course of steroids. There have been only 4 previously reported cases of multifocal leukoencephalopathy related to the use of combination 5-fluorouracil and levamisole. The extensive use of these agents as adjuvant treatment for colorectal carcinoma may result in more frequent recognition of this form of neurological toxicity.

Adenocarcinoma↗
PubMed1995

Phase II trial of ifosfamide, fluorouracil, and folinic acid (FIFO regimen) in relapsed and refractory urothelial cancer.

There is no known effective salvage chemotherapy for patients with refractory or relapsed urothelial tumors after methotrexate/cisplatin-based regimen. We report the results of a phase II trial with the FIFO regimen that includes from day 1 to 5: fluorouracil 350 mg/m2, folinic acid 20 mg/m2, and ifosfamide 1000 mg/m2, Q4W. Fifteen patients with metastatic measurable urothelial cancer were enrolled in this trial. Previous therapy included M-VAC regimen in 11 patients, CMV regimen in 3 patients, and both regimens in 1 patient. Thirty-one courses were delivered. Toxicity was moderate, including encephalopathy grade 2 in 2 patients and hematological toxicity grade 3 in 2 others. However, an early death occurred on day 1 in a patient who progressed rapidly and died from hepatic insufficiency after initial encephalopathy. No objective response was seen. Twelve patients progressed during FIFO therapy and 3 patients experienced a stable disease. Despite almost encouraging results of fluorouracil and ifosfamide in the literature, their combination according to our schedule is not active in urothelial cancer.

Adrenal Gland Neoplasms↗
PubMed1996

Cisplatin and continuous infusion of fluorouracil followed by radiation and weekly carboplatin in the treatment of locally advanced head and neck cancer: a Hellenic Cooperative Oncology Group study.

Induction chemotherapy followed by radiation has been extensively studied in an effort to improve local control and possibly overall survival of patients with locally advanced head and neck cancer. From June 1989 until May 1991, 39 patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with 3 cycles of induction chemotherapy, consisting of cisplatin (100 mg/m2 d 1) and fluorouracil (1000 mg/m2 d 2-6) followed by radiation potentiated by weekly administration of carboplatin (60 mg/m2). Surgery was performed in selected patients with residual disease after the combined modality approach. Four cycles of adjuvant chemotherapy with carboplatin (325 mg/m2) and bleomycin (15 u) were administered in those patients who demonstrated a partial response after locoregional treatment. There were 36 men and 3 women with a median age of 56 (range 39-74) years and Karnofsky performance status of 70 (range 60-100). The primary site of the tumor was nasopharynx (8), oropharynx (8), hypopharynx (3), oral cavity (4), larynx (13), paranasal sinus (2), and salivary glands (1). Thirty-two (82%) patients presented with stage IV disease. After the completion of induction chemotherapy, 14 (36%, 95% CI 21-53%) patients achieved a complete response (CR). This CR rate was increased to 56% (95% CI, 42-74%) after locoregional treatment. Main toxicities included nausea/vomiting (56%), leukopenia (40%), anemia (30%), thrombocytopenia (10%), stomatitis (28%), diarrhea (17%), and alopecia (12%). Median relapse-free survival was 18 (1-50) months, median time to progression was 13 (0.3-58.5) months, and median survival 19 (0.3-59) months. Induction chemotherapy with cisplatin and fluorouracil followed by radiation potentiated with carboplatin is feasible. However, this combined modality approach, as applied in the present study, does not appear to yield superior results than those reported with chemotherapy followed by radiation alone.

Animals↗
PubMed1986

Circadian modification of 5-fluorouracil-induced teratogenesis in mice.

Pregnant mice were treated intraperitoneally with 5-fluorouracil in a single dose of 30 mg/kg once on gestation day 11 at one of four selected times along the 24-hr time scale. All animals were kept under a lighting regimen of 12 hr (0600-1800) alternating with 12 hr of darkness. They were injected at the same circadian phase as they were mated. The developmental age of all fetuses was 264 +/- 1 hr at the time of injection. Fetuses collected on day 18 showed a circadian variation in teratogenic susceptibility to 5-fluorouracil. The lethal and teratogenic risk posed by the drug were highest among animals treated at the mid-light period until the onset of darkness.

Abnormalities, Drug-Induced↗
PubMed1992

A randomized comparison of intra-arterial versus intravenous BCNU, with or without intravenous 5-fluorouracil, for newly diagnosed patients with malignant glioma.

This Phase III trial tested the efficacy and safety of intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of newly resected malignant glioma, comparing intra-arterial BCNU and intravenous BCNU (200 mg/sq m every 8 weeks), each regimen without or with intravenous 5-fluorouracil (1 gm/sq m three times daily given 2 weeks after BCNU). All patients also received radiation therapy. A total of 505 patients were randomly assigned within the study. Fifty-seven patients were excluded, primarily because of neuropathology error, and the remaining 448 patients constituted the Valid Study Group. Of the total 505 patients, 190 patients could not receive intra-arterial BCNU and 315 patients were randomly assigned to receive intra-arterial (167 patients) and intravenous (148 patients) BCNU. Actuarial analysis (log-rank) demonstrated reduced survival for the intra-arterial group (p = 0.03). Serious toxicity was observed in the intra-arterial group; 16 patients (9.5%) developed irreversible encephalopathy with computerized tomography evidence of cerebral edema, and 26 patients (15.5%) developed visual loss ipsilateral to the infused carotid artery. Administration of 5-fluorouracil did not influence survival. The survival rate between the intravenous and the intra-arterial BCNU patients with glioblastoma multiforme did not differ, but was worse for intra-arterial BCNU patients with anaplastic astrocytoma than for those receiving intravenous BCNU (p = 0.002). Neuropathologically, intra-arterial BCNU produced white matter necrosis. It is concluded that intra-arterial BCNU is neither safe nor effective in prolonging survival when administered by the methods used in this study of newly diagnosed patients with malignant glioma.

Adolescent↗
PubMed2001

Combination of oxaliplatin, fluorouracil, and leucovorin in the treatment of fluoropyrimidine-pretreated patients with metastatic colorectal cancer.

There has been no standard therapy for patients with metastatic colorectal cancer who have failed to first-line fluorouracil-based treatment. The present study was designed to assess the efficacy and toxicities of a combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin in fluoropyrimidine-pretreated patients with metastatic colorectal cancer. Chemotherapy consisted of oxaliplatin 85 mg/m2 on day 1, followed by leucovorin 20 mg/m2 and 5-FU 1,200 mg/m2 on days 1 and 2. Treatment courses were repeated every two weeks. Thirty-nine patients were enrolled in this study. All patients previously received fluoropyrimidine-based chemotherapy. Thirty-one patients were assessable for response and 33 for treatment toxicity. Six patients required dose reduction of 5-FU due to grade III/IV cytopenia. Nausea/vomiting and peripheral neuropathy were common non-hematologic toxicities. Overall response rate was 42.0% including 3 complete response and 10 partial response. The median response duration was 91 days (range, 28-224+). The median duration of progression-free survival was 132 days (range, 40-308). A combination of oxaliplatin, 5-FU, and leucovorin showed high response rate in fluoropyrimidine-pretreated patients with metastatic colorectal cancer, but the duration of response was relatively short. It may be worthwhile to explore its therapeutic potential in the first-line treatment setting.

Adult↗
PubMed2002

Epirubicin, cisplatin, and protracted venous infusion of 5-fluorouracil for advanced gastric carcinoma.

To evaluate the activity and safety of a combination chemotherapy with epirubicin, cisplatin, and a protracted venous infusion of 5-fluorouracil (ECF) in unresectable or metastatic gastric cancer, a phase II study was performed. Thirty-five chemotherapy-naive patients were given ECF. Epirubicin (50 mg/m(2) intravenous, i.v.) and cisplatin (60 mg/m(2) i.v.) were administered every three weeks during a continuous intravenous infusion of 5-fluorouracil (250 mg/m(2) /day) using infusion pump. One complete response and 19 partial responses (response rate=62%) were achieved. Eight patients remained stable, whereas in four patients the disease progressed. The median duration of response was 22 weeks (95% confidence interval, 18-27 weeks). The median survival for all patients was 10 months (95% confidence interval, 6-14 months), with a 1-yr survival rate of 40%. A total of 184 cycles of chemotherapy were administered. Grade 3 or 4 emesis occurred in 3%, mucositis in 2%, anemia in 10%, and leukopenia in 3% of the cycles. Central venous catheter complications that required line removal occurred in 37% (n=13) of the patients. No patient died of toxicity. Overall, the ECF regimen showed high anti-tumor activity with a tolerable toxicity pattern.

Adult↗