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PubMed2007

Pharmacokinetics of 5-fluorouracil in mutant Nagase analbuminemic rats: faster metabolism of 5-fluorouracil via CYP1A.

It has been reported that plasma albumin concentrations were significantly lower in cancer patients than those in the healthy volunteers, and the expression and mRNA level of hepatic microsomal cytochrome P450 (CYP) 1A2 increased in mutant Nagase analbuminemic rats (NARs). After intravenous administration of 5-fluorouracil at a dose of 30 mg/kg to NARs, the time-averaged nonrenal clearance (Clnr) of the drug was significantly faster than the controls (51.3 versus 28.8 ml/min/kg), possibly due to an increase in the expression and mRNA level of CYP1A2 in NARs. In order to determine whether 5-fluorouracil is metabolized via CYP1A2 in male Sprague-Dawley rats, the rats were pretreated with 3-methylcholanthrene (a main inducer of CYP1A1/2 in rats). The Clnr of 5-fluorouracil was significantly faster (34.3 versus 27.3 ml/min/kg) in rats pretreated with 3-methylcholanthrene. The aforementioned data indicate that CYP1A is involved in the metabolism of 5-fluorouracil in rats.

Acetylglucosaminidase↗
PubMed1991

Unusual serpentine hyperpigmentation associated with 5-fluorouracil. Case report and review of cutaneous manifestations associated with systemic 5-fluorouracil.

A variety of cutaneous reactions have been reported with the use of systemic 5-fluorouracil. Our patient had serpentine hyperpigmented streaks appearing 5 days after bolus infusion of 5-fluorouracil. The patient also had other skin eruptions, that is, inflammation of actinic keratoses and folliculitis limited to the forehead; these reactions have been reported previously with 5-fluorouracil medication. We report this case and review the literature on skin manifestations associated with 5-fluorouracil therapy.

Adenocarcinoma↗
PubMed2000

Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial.

BACKGROUND: Irinotecan is active against colorectal cancer in patients whose disease is refractory to fluorouracil. We investigated the efficacy of these two agents combined for first-line treatment of metastatic colorectal cancer. METHODS: 387 patients previously untreated with chemotherapy (other than adjuvant) for advanced colorectal cancer were randomly assigned open-label irinotecan plus fluorouracil and calcium folinate (irinotecan group, n=199) or fluorouracil and calcium folinate alone (no-irinotecan group, n=188). Infusion schedules were once weekly or every 2 weeks, and were chosen by each centre. We assessed response rates and time to progression, and also response duration, survival, and quality of life. Analyses were done on the intention-to-treat population and on evaluable patients. FINDINGS: The response rate was significantly higher in patients in the irinotecan group than in those in the no-irinotecan group (49 vs 31%, p<0.001 for evaluable patients, 35 vs 22%, p<0.005 by intention to treat). Time to progression was significantly longer in the irinotecan group than in the no-irinotecan group (median 6.7 vs 4.4 months, p<0.001), and overall survival was higher (median 17.4 vs 14.1 months, p=0.031). Some grade 3 and 4 toxic effects were significantly more frequent in the irinotecan group than in the no-irinotecan group, but effects were predictible, reversible, non-cumulative, and manageable. INTERPRETATION: Irinotecan combined with fluorouracil and calcium folinate was well-tolerated and increased response rate, time to progression, and survival, with a later deterioration in quality of life. This combination should be considered as a reference first-line treatment for metastatic colorectal cancer.

Adenocarcinoma↗
PubMed2002

Synthesis and release of 5-fluorouracil from poly(N-vinylpyrrolidinone) bearing 5-fluorouracil derivatives.

1-beta-allyloxycarbonyloxymethyl-5-fluorouracil (4) and 1,3-bis(beta-allyloxycarbonyloxymethyl)-5-fluorouracil (5) were synthesised by reacting 5-fluorouracil with formaldehyde followed by treating the product with isopropenyl chloroformate. The monomers 4 and 5 were copolymerized separately with N-vinylpyrrolidinone to form linear copolymers and cross-linked polymer networks, respectively. The monomer reactivity ratios in the copolymerization of 4 with NVP were evaluated by both linear and non-linear methods and the effect of monomer feed composition on copolymer molecular weight was examined. The degradation of the polymer networks in phosphate buffer (pH 7.4) was investigated. The hydrolytic scission of the carbonate groups resulted in release of 5-fluorouracil and a decrease in cross-linking density. The time-dependent fractional release of the 5-FU could be fitted by a power relationship with exponents between 0.10 and 0.25.

Antimetabolites, Antineoplastic↗
PubMed1978

Studies on antitumor agents, 2. Syntheses and antitumor activities of 1-(tetrahydro-2-furanyl)-5-fluorouracil and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil.

Convenient and efficient methods were developed for preparing 1-(tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU, 3) [trade name, Futraful (Ftorafur) or FT-207], which is used clinically as an antitumor agent, and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil (Thf2-FU, 4). For the syntheses, 2,4-bis(trimethylsily)-5-fluorouracil (Me3Si-FU, 1) and 2-acetoxytetrahydrofuran (Thf-OAc, 2) were condensed in the presence of Friedel-Crafts catalysts, such as SnCl4 and BF3-Et2O in dichloromethane, or in the presence of NaI in acetonitrile to give Thf-Fu or Thf2-FU depending on the reaction conditions and workup procedure. A trace of 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-Thf-FU, 5) was formed in these reactions. Thf2-FU was easily hydrolyzed to Thf-FU. 2-Methoxytetrahydrofuran can be used instead of Thf-OAc for preparation of Thf-FU under similar conditions. The optimal ratios of Me3Si-FU, Thf-OAc, and SnCl4 or NaI for preparation of Thf-FU and Thf2-FU were determined. In all cases, 2-2.5 equiv of Thf-OAc with respect to Me3Si-FU gave the best results. The yields of Thf-FU and more especially of Thf2-FU were greatly dependent on the relative amount of SnCl4, and 0.01-0.1 equiv of the catalyst with respect to Me3Si-FU gave the best results. Thf2-FU was found to be effective against murine solid tumors and it was less toxic than Thf-FU when given orally. The antitumor activity of 3-Thf-FU is also reported.

Animals↗
PubMed1989

19F NMR of 5-fluorouracil-substituted transfer RNA transcribed in vitro: resonance assignment of fluorouracil-guanine base pairs.

5-Fluorouracil is readily incorporated into active tRNA(Val) transcribed in vitro from a recombinant phagemid containing a synthetic E. coli tRNA(Val) gene. This tRNA has the expected sequence and a secondary and tertiary structure resembling that of native 5-fluorouracil-substituted tRNA(Val), as judged by 19F NMR spectroscopy. To assign resonances in the 19F spectrum, mutant phagemids were constructed having base changes in the tRNA gene. Replacement of fluorouracil in the T-stem with cytosine, converting a FU-G to a C-G base pair, results in the loss of one downfield peak in the 19F NMR spectrum of the mutant tRNA(Val). The spectra of other mutant tRNAs having guanine for adenine substitutions that convert FU-A to FU-G base pairs all have one resonance shifted 4.5 to 5 ppm downfield. These results allow assignment of several 19F resonances and demonstrate that the chemical shift of the 19F signal from base-paired 5-fluorouracil differs considerably between Watson-Crick and wobble geometry.

Anticodon↗
PubMed1981

The effect of fluorouracil on survival in metastatic colorectal cancer fluorouracil response improves survival.

We set out to define the place for therapy with fluorouracil in patients with advanced colorectal cancer. Sixty-three patients with stage D2 cancers were observed for seventeen months to five years from the time of diagnosis. Thirty patients received fluorouracil in various regimens. Nineteen patients were not referred for chemotherapy, a further eleven were excluded because their condition was terminal, and three could be evaluated. Ten patients had either partial or complete response to fluorouracil; their median survival was 25 months. Twenty patients who did not respond to fluorouracil had a median survival of 11 months, whereas the non-treated group had a median survival of 15 months. The difference between the responders and the other groups was highly significant.

Clinical Trials as Topic↗
PubMed1998

A phase II trial of carboplatin, methotrexate and fluorouracil in fluorouracil-pretreated colorectal cancer.

5-Fluorouracil and leucovorin combination is the most commonly applied chemotherapy treatment for colorectal cancer patients, both in the adjuvant setting and for advanced disease. Patients resistant or refractory to the 5-fluorouracil-leucovorin combination have been treated in this phase II trial with carboplatin plus methotrexate and fluorouracil in sequence. Twenty patients with measurable lesions from advanced colorectal cancer were entered in the trial. The treatment plan was carboplatin 300 mg/m2 day 1, methotrexate 40 mg/m2 day 1, fluorouracil 600 mg/m2 day 2, every 21 days. Two patients with liver metastasis had a partial response. Median survival was 12 months (range 4-24). Toxicity was acceptable and no patient had to be hospitalized because of the treatment. In this set of patients activity of the new combination is marginal.

Aged↗
PubMed1998

Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine the relative efficacy of an intensive cyclophosphamide, epirubicin, and fluorouracil (CEF) adjuvant chemotherapy regimen compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive breast cancer. PATIENTS AND METHODS: Premenopausal women with node-positive breast cancer were randomly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and fluorouracil 600 mg/m2 i.v. days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14; epirubicin 60 mg/m2 i.v. days 1 and 8; and fluorouracil 500 mg/m2 i.v. days 1 and 8. Each cycle was administered monthly for 6 months. Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy. RESULTS: The median follow-up was 59 months. One hundred sixty-nine of the 359 CMF patients developed recurrence compared with 132 of the 351 CEF patients. The corresponding 5-year relapse-free survival rates were 53% and 63%, respectively (P = .009). One hundred seven CMF patients died compared with 85 CEF patients. The corresponding 5-year actuarial survival rates were 70% and 77%, respectively (P = .03). The rate of hospitalization for febrile neutropenia was 1.1% in the CMF group compared with 8.5% in the CEF group. There was one case of congestive heart failure in a patient who received CMF compared with none in the CEF group. Acute leukemia occurred in five patients in the CEF group. CONCLUSION: The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer.

Adult↗
PubMed2005

Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study.

PURPOSE: A combination of docetaxel and fluorouracil (DF) was evaluated in an outpatient setting and compared with epirubicin, cisplatin, and fluorouracil (ECF), which served as an internal control arm to avoid selection bias. PATIENTS AND METHODS: Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were randomly assigned to receive either ECF (epirubicin 50 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks) or DF (docetaxel 75 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks). RESULTS: Ninety patients were randomly assigned. Toxicity was rarely severe. Major toxic effects included diarrhea, stomatitis, and leukopenia in the DF arm and nausea, vomiting, and leukopenia in the ECF arm. Forty-three of 45 patients in each arm were assessable. In the DF arm, two patients (4.4%, intent to treat) experienced a confirmed complete tumor remission as best response, and 15 patients (33.3%) experienced a confirmed partial remission (overall response rate [ORR], 37.8%; 95% CI, 25.9% to 51.9%). Two patients (4.4%) in the ECF arm showed confirmed complete remission, and 14 (31.1%) showed confirmed partial remission (ORR, 35.6%; 95% CI, 24.8% to 48.7%). For the DF and ECF arms, the median survival was 9.5 and 9.7 months, and the median time to tumor progression 5.5 and 5.3 months, respectively. CONCLUSION: DF can be safely given in an ambulant setting. Compared with ECF, the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin.

Adenocarcinoma↗
PubMed2006

Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group.

PURPOSE: In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part. PATIENTS AND METHODS: Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP). RESULTS: In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatment-related adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%). CONCLUSION: Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.

Adenocarcinoma↗
PubMed1982

Additive formation of antineoplastic 5-fluorouracil nucleosides from 5-fluorouracil by Ehrlich ascites tumor extracts in the presence of ribose 1-phosphate/uridine or deoxyribose 1-phosphate/deoxyuridine.

In order to acquire a biochemical fundamental knowledge on the enhancement of antitumor effect with 5-fluorouracil or its masked derivatives, this investigation was undertaken to determine the amounts of antineoplastic metabolic precursors formed from 5-fluorouracil-6-14C in the presence of various substrates by crude enzyme extracts from Ehrlich mouse ascites tumor cells and normal mouse liver. Combinations of uridine plus ribose 1-phosphate and deoxyuridine plus deoxyribose 1-phosphate were effective for the enhancement of 5-fluorouridine and 5-fluorodeoxyuridine formation, respectively. 5-Fluorouridine and 5-fluorodeoxyuridine are respectively utilizable for the syntheses of the antineoplastic compounds, 5-fluorouridine 5'-triphosphate and 5-fluoro-2'-deoxyuridine 5'-monophosphate. These results suggest that the coadministration of the above substrates together with 5-fluorouracil would be advantageous in the enhancement of the antitumor effect of 5-fluorouracil or its masked derivatives.

Animals↗
PubMed1989

[Randomized multicenter trial of sequential methotrexate and 5-fluorouracil versus 5-fluorouracil alone in advanced gastric cancer].

In a recent phase II trial we have shown a favorable response rate for sequential methotrexate-5-fluorouracil (MF) in advanced gastric and colorectal cancer. We determined the therapeutic effect of sequential MF in patients with advanced gastric cancer by comparing it to 5-fluorouracil alone (F) in a randomized multicenter trial. Since February 1987 to July 1988, 133 patients with advanced gastric cancer have been prospectively randomized to receive either MF (methotrexate 100 mg/m2 i.v. push, 5-fluorouracil 600 mg/m2 i.v. drip over 15 minutes one hour after methotrexate and leucovorin 15 mg p.o. q 6 hrs x 2 beginning 24 hrs after methotrexate) of F (the same 5-fluorouracil as described for MF). Each treatment was repeated weekly x 5, then q 2 weeks. The two treatment arms were balanced for 17 clinical characteristics. The response rate was 17.9% (10 of 56 patients) in the MF arm and 1.9% (one of 53 patients) in the F arm (p less than 0.01). Median duration of response was 6.8 weeks (MF) and 6 weeks (F), respectively. Median survival time was 7.9 months (MF) and 7.3 months (F) on interim findings. Leukocytopenia and GI toxicity were significantly more common in patients receiving MF, but the degree was similar for both arms. Other side effects were minimal and no different. This schedule of MF is more effective than F in inducing remission for patients with advanced gastric cancer.

Adult↗
PubMed1983

Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes.

There are two major R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) activation pathways to 5-fluorouracil, one that is mediated by microsomal cytochrome P-450 oxidation at C-5' of the tetrahydrofuran moiety and one that is mediated by soluble enzymes. This report demonstrates that the soluble enzyme pathway proceeds via enzymatic cleavage (possibly hydrolytic) of the N-1--C-2' bond to yield 5-fluorouracil and 4-hydroxybutanal, which is immediately further metabolized to gamma-butyrolactone or gamma-hydroxybutyric acid. The soluble activation pathway was present in liver, small intestine, and brain. Because of the limited distribution of cytochrome P-450 in body tissues and because of the lack of redistribution of 5-fluorouracil via the systemic circulation after ftorafur administration, we propose that the soluble enzyme pathway is at least in part responsible for organ toxicity and possibly antitumor effect. Distinction of the microsomal (C-5') and the soluble enzyme (C-2') activation pathways can be exploited in the design of more selective prodrug analogues.

Animals↗
PubMed1980

[Studies in vivo and in vitro on the influence of 5-fluorouracil and n'-(2'-furanidyl)-5-fluorouracil on the walker carcinosarcoma 256 in the rat (author's transl)].

We compare the effects of 5-fluorouracil and N'-(2'-furanidyl)-5-fluorouracil (Ftorafur) in vivo (tumor size) and in vitro ([6-3H]-deoxyuridine incorporation) on solid Walker carcinosarcoma of the rat. 5-Fluorouracil and Ftorafur have a dose-dependent effect on tumor size and on [6-3H]-deoxyuridine incorporation in vitro. The in vivo effects on tumor size are similar when the dose of Ftorafur calculated by its molecular weight is about 3 times higher than that of 5-fluorouracil. In vitro an about 650 times higher dose of Ftorafur is required to achieve a comparable reduction of [6-3H]-deoxyuridine incorporation in the tumor cells.

Animals↗
PubMed1977

A model for prediction of chemotherapy response to 5-fluorouracil based on the differential distribution of 5-[18F]fluorouracil in sensitive versus resistant lymphocytic leukemia in mice.

The distribution of 5-[18F]fluorouracil has been compared in two variants of the same tumor in c57bL X DBA/2 F1 mice: solid L1210 lymphocytic leukemia tumor susceptible to 5-fluorouracil treatment and the same tumor, made resistant to the drug over a 34-generation span. Significant differences in 5-[18F]fluorouracil distribution were observed, most notably in the tumor:blood ratios at 12 hr postinjection. The drug-responsive tumor showed a 20:1 concentration ratio, whereas the drug-resistant tumor only had a 4:1 concentration ratio. We postulate that these differences, observed here in this animal tumor model, may be a reflection of similar ratio differences in humans. This technique may allow, by noninvasive quantification of tumor:blood ratios following administration of 5-[18F]fluorouracil to man, the differentiation of those human tumors that are likely to respond to drug therapy from those in which the response will be minimal or nil.

Animals↗
PubMed1997

Mitoxantrone, 5-fluorouracil, and high dose leucovorin (NFL) versus intravenous cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in first-line chemotherapy for patients with metastatic breast carcinoma: a randomized phase II trial.

BACKGROUND: Previous Phase II studies using the combination of mitoxantrone, 5-fluorouracil, and high dose leucovorin (NFL) in the treatment of metastatic breast carcinoma have shown this regimen to be active and well tolerated. In this randomized Phase II study, the authors compared the NFL regimen with a standard CMF regimen in the first-line therapy of patients with metastatic breast carcinoma. METHODS: One hundred twenty-eight women receiving their first chemotherapy for metastatic breast carcinoma were entered into this randomized study. Sixty-four patients were treated with NFL: mitoxantrone 12 mg/m2 IV on Day 1; leucovorin 300 mg IV over 30-60 minutes on Days 1, 2, and 3, immediately preceding administration of 5-fluorouracil; and 5-fluorouracil 350 mg/m2 IV bolus on Days 1, 2, and 3. Sixty-four patients received CMF: cyclophosphamide 600 mg/m2 IV on Day 1; methotrexate 40 mg/m2 IV on Day 1; and 5-fluorouracil 600 mg/m2 IV on Day 1. Both regimens were repeated at 21-day intervals; responding patients received at least 8 courses. RESULTS: Patients treated with NFL had a higher response rate than patients treated with the CMF regimen (45% vs. 26%, respectively; P = 0.021). Median duration of response was 9 months with NFL and 6 months with CMF (P = 0.10); 11 patients had long responses (>12 months) with NFL versus 4 patients with CMF (P = 0.06). Median survival was similar for both groups. Both regimens were well tolerated, with infrequent Grade 3 or 4 toxicities. CONCLUSIONS: NFL is an active, well-tolerated regimen for the treatment of metastatic breast carcinoma; it produced a higher response rate than the CMF regimen used in this study. Although more intense CMF regimens or regimens containing doxorubicin would likely increase the response rate, they would almost certainly do so with the consequence of greater toxicity as compared with NFL. NFL is an excellent initial palliative treatment option for elderly patients or patients who have exhibited poor tolerance for other chemotherapy regimens.

Adult↗