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PubMed1988

Colorectal carcinoma in vitro is more sensitive to 1-hexylcarbamoyl-5-fluorouracil compared with six other antitumor drugs: carboquone, Adriamycin, mitomycin C, aclacinomycin A, cisplatin, 5-fluorouracil.

The sensitivity to 1-hexylcarbamoyl-5-fluorouracil (HCFU) of 25 colorectal cancer tissues was compared with that of six antitumor drugs: carboquone (CQ), Adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), cisplatin (DDP), and 5-fluorouracil (5-FU), using the in vitro succinate dehydrogenase inhibition (SDI) test. Chemosensitivity was determined to be positive when the succinate dehydrogenase (SD) activity of the drug-exposed cells, at ten times the peak plasma concentration, was decreased to below 50 percent of that of control cells on day 3 of exposure. Decrease in SD activity was remarkable in cases of exposure to HCFU, compared with six other drugs. The sensitivity rates were 32 percent for CQ, 40 percent for ADM, 24 percent for MMC, 28 percent for ACR, 32 percent for DDP, 16 percent for 5-FU, and 68 percent for HCFU. The sensitivity rate for at least one of the six drugs (CQ, ADM, MMC, ACR, DDP, and 5-FU) was 52 percent, but was 80 percent when HCFU was taken into account. Since colorectal cancer tissues are resistant to various antitumor drugs, the chemosensitivity test of HCFU should aid in determining the effects of a particular drug for an individual patient.

Aclarubicin↗
PubMed1987

Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma.

The pharmacokinetics of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a bi-exponential function (C = Ae-alpha t + Be-beta t), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups. The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 +/- 0.05 mumol/g liver protein/30 min) and four of those without it (0.13 +/- 0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 X g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2004

Concurrent chemoradiotherapy for esophageal cancer: comparison between intermittent standard-dose cisplatin with 5-fluorouracil and daily low-dose cisplatin with continuous infusion of 5-fluorouracil.

BACKGROUND: Although current standard treatment for advanced esophageal cancer is intermittent standard-dose cisplatin with 5-fluorouracil (5-FU) (ISD-FP), daily low-dose cisplatin with continuous infusion of 5-FU (CLD-FP) is advocated for equivalent effectiveness and lower toxicity. The feasibility of these two concurrent chemoradiotherapeutic protocols was retrospectively reviewed for local control rate, overall survival, toxicity, and compliance in a single institutional situation. METHODS: Concurrent chemoradiotherapy, using 60 Gy of radiation and ISD-FP or CLD-FP was non-randomly scheduled for 29 patients between June 1994 and March 2001. RESULTS: Complete response in the irradiated volume at the end of primary treatment was shown by 8 of 15 and 9 of 14 patients in the ISD-FP and CLD-FP groups, respectively. The projected overall survival rate at 2 years was 55% for stage III patients and 13% for stage IV. Median survival times were 14 months versus 15 months in the ISD-FP and CLD-FP groups, with no significant difference. Toxicities were similar, including two treatment-related deaths in each group. Chemotherapy was completed for 10 of 15 and 11 of 14 patients in the ISD-FP and CLD-FP groups, respectively. Modification of the planned regimen was more often required for the CLD-FP group. CONCLUSION: CLD-FP therapy has no apparent advantage over ISD-FP therapy from the perspective of compliance and safety. A randomized phase II clinical trial comparing ISD-FP and CLD-FP, currently being performed, is expected to provide further information. Although current standard treatment for advanced esophageal cancer is intermittent standard-dose cisplatin with 5-fluorouracil (5-FU) (ISD-FP), daily low-dose cisplatin with continuous infusion of 5-FU (CLD-FP) is advocated for equivalent effectiveness and lower toxicity. The feasibility of these two concurrent chemoradiotherapeutic protocols was retrospectively reviewed for local control rate, overall survival, toxicity, and compliance in a single institutional situation.

Adenocarcinoma↗
PubMed1984

Drug interactions in biotransformation of 1-phthalidyl 5-fluorouracil to 5-fluorouracil in rat liver.

Two rat liver hydrolases were found to be involved in the metabolism of 1-phthalidyl 5-fluorouracil (PH-FU) to 5-fluorouracil (5-FU), one of which was induced by phenobarbital (PB) treatment of rats. Both inducible and constitutive enzyme were soluble and showed different characteristics in gel filtration and response to inhibitors. Further study showed that the blood level of PH-FU could be modulated by PB-pretreatment or coadministration of enzyme inhibitors to rats.

Animals↗
PubMed1987

1-Hexylcarbamoyl-5-fluorouracil is more cytostatic than 5-fluorouracil against human tumors in vitro.

The sensitivity of HeLa cells and 15 human tumors, including eight gastric cancers, five colorectal cancers and two lung cancers to 1-hexylcarbamoyl-5-fluorouracil (HCFU) was compared with that to 5-fluorouracil (5-FU) in vitro. HeLa cells were doubly sensitive to HCFU, as compared to 5-FU. After the HeLa cells had been treated with 5-FU or HCFU at 77 microM for 1-5 h, the intracellular levels of 5-FU and HCFU were determined, using gas chromatographic-mass spectrometric methods. The level of HCFU plus 5-FU in the HCFU-treated cells was twice as high as the level of 5-FU in the 5-FU-treated cells. The sensitivity to HCFU in 15 tumor tissues varied with the tissue; however, all tissues tested were more sensitive to HCFU than to 5-FU, assessed using the succinate dehydrogenase inhibition test. These results suggest that the hexylcarbamoyl structure facilitates the rapid uptake of HCFU through the cell membrane. HCFU may prove to be more effective for treating each individual patient with a malignant lesion.

Antineoplastic Agents↗
PubMed1988

Cisplatin + 5-fluorouracil versus 5-fluorouracil alone in advanced colorectal cancer: a randomized study.

Sixty patients with advanced colorectal cancer were randomized between cisplatin (60 mg/mq i.v. every 3 weeks) + 5-fluorouracil (600 mg/mq i.v. bolus/weekly) and 5-fluorouracil alone (same schedule). In the 54 evaluable patients, no CR was observed. PR rate was 19.2% for the combination, and 14.5% for the monochemotherapy. Also the overall median survival time was similar for the two arms (10 and 13 months, respectively). Toxicity was acceptable, with more side-effects in the combination arm. Both treatments are of limited activity in advanced colorectal cancer and no advantage comes out from the use of this polychemotherapy.

Adult↗
PubMed1989

Hyperthermia enhances the in vitro activity of 1-hexylcarbamoyl-5-fluorouracil compared to that of 5-fluorouracil.

The synergic effects on HeLa cells between 1-hexylcarbamoyl-5-fluorouracil (HCFU), a lipophilic masked compound of 5-fluorouracil (5-FU), and hyperthermia were investigated, with the following results: (1) After the cells had been exposed to the drug at 77 microM for 1, 2 or 3 days, with or without heat (43 degrees C) for 2 h, treatment with HCFU and heat inhibited cell growth by 9.2% on day 3, compared to control cells, HCFU alone, heat alone or the combined treatment with 5-FU plus heat. (2) The cells were exposed to the drugs at 77 microM or heat (43 degrees C) for 15-45 min and the colonies counted on day 14. Combined treatment with HCFU plus heat inhibited the clonogenicity of HeLa cells to 22.4% of findings in the control cells and as compared to findings with other treatments. The combination of 5-FU, n-hexylamine and heat had much the same effect as the combined effect of the treatment of HCFU plus heat. (3) Intracellular levels of the drugs did not increase with hyperthermic treatment. Our findings suggest that it is the hexylcarbamoyl structure of HCFU that relates to the synergic effect between HCFU and hyperthermia. This combination is expected to have positive effects for treating patients with malignancy.

Antineoplastic Agents↗
PubMed1984

Fluorescence determination of 5-fluorouracil and 1-(tetrahydro-2-furanyl)-5-fluorouracil in blood serum by high-performance liquid chromatography.

Fluorescence derivatization of 5-fluorouracil (5-FU) and 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur, FT) with 4-bromomethyl-7-methoxycoumarin using 18-crown-6 as a catalyst is studied with aim of developing a sensitive and selective liquid chromatographic method. 5-FU and FT form virtually substituted derivatives which possess maxima in their fluorescence emission spectra near 400 nm. These derivatives are separated by thin-layer chromatography and high-performance liquid chromatography to confirm the completion of reaction. For the determination of 5-FU and FT in serum, the reversed-phase high-performance liquid chromatographic separation of the derivatives is studied with a C13 column. This chromatography is of importance for the accurate determination of 5-FU and FT, which are, respectively, an important antitumour agent for the treatment of solid tumours in clinical medicine and a masked form of 5-FU generated in vivo.

Chromatography, High Pressure Liquid↗
PubMed1996

High-performance liquid chromatographic determination of 5-fluorouracil and its prodrugs, tegafur and 4-deoxy-5-fluorouracil, in rat plasma.

A rapid, sensitive and reproducible ion-pair, reversed-phase high-performance liquid chromatographic (HPLC) method was developed to simultaneously quantitate 5-fluorouracil (5FU) and its prodrugs, tegafur (TF) and 4-deoxy-5-fluorouracil (DFU), in rat plasma. 5FU, TF, and internal standard 2', 3'-didehydro-2'-deoxythymidine (D4T, stavudine), were detected by UV absorption at 254 nm, and DFU was detected at 313 nm. Extraction recoveries for all compounds ranged between 80% and 92%. Retention times of 5FU, D4T, DFU and TF were 4.6, 5.5, 6.8 and 11.5 min, respectively. Calibration plots were linear over the range of 0.1 microgram/ml to 50 micrograms/ml for 5FU, and 0.25 microgram/ml to 50 micrograms/ml for TF and DFU. The limit of quantitation was 0.1 microgram/ml for 5FU and 0.25 microgram/ml for TF and DFU. The intra- and inter-day variations were less than 10% and accuracy was greater than 90%. This method was applied to plasma samples collected from rats that were administered 5FU, TF and DFU intravenously.

Animals↗
PubMed2006

Synthesis and properties of N-nicotinoyl-2-(5-fluorouracil-1-yl)-D,L-glycine ester as a prodrug of 5-fluorouracil for rectal administration.

N-Nicotinoyl-2-(5-fluorouracil-1-yl)-D,L-glycine (NFG) methyl-(NFGM), ethyl-(NFGE) and isopropyl esters (NFGIp) were synthesized and their potential as a prodrug of 5-fluorouracil (5-FU) for rectal administration was investigated. Chemical conversion proceeded either by elimination of (5-FU) or by hydrolysis of ester group. 5-FU was released from NFGIp, NFGE and NFGM 90.5%, 71.3% and 48.5% of the dose, respectively, in 80% human plasma and 79.8%, 56.3% and 31.6%, respectively, in pH 7.4 buffer solution after 48 h of incubation at 37 degrees C. Release of 5-FU occurred mainly from NFG esters but very slightly from NFG, which suggested that release of 5-FU was greatly dependent on the stability of the ester group against hydrolysis. Solubility (M) in pH 7.4 buffer solution was 0.13, 0.09 and 0.04 and apparent partition coefficient in 1-octanol/pH 7.4 buffer solution was 0.76, 1.61 and 4.2, respectively, for NFGM, NFGE and NFGIp, which were in the ranges suitable for rectal absorption. Plasma concentration (microg/mL) of NFGM, NFGE and NFGIp at 50 min after rectal administration to rats was 1.9, 4.6 and 6.7, respectively, and that for 5-FU was below the limit of detection. Their potential as prodrugs of 5-FU for rectal administration is suggested.

Administration, Rectal↗
PubMed2003

Fluorouracil prodrugs for the treatment of proliferative vitreoretinopathy: formulation in silicone oil and in vitro release of fluorouracil.

Three new N(1)-alkylcarbonyl-5-fluorouracil derivatives that are prodrugs of 5-fluorouracil (FU), one of them being a co-drug FU-retinoic acid (RA), were studied as potentially effective drugs against postsurgical proliferative vitreoretinopathy (PVR). The stability of N(1)-octenoylFU (3), N(1)-lauroylFU (2), and N(1)-retinoylFU (4) in aqueous medium, their solubility in silicone oil (SiO), the kinetics of FU release in an in vitro system were determined. Compound 3 is very rapidly soluble in SiO. Its saturation concentration, reached after 6h, is 233 +/- 13 microg g(-1) SiO. Compound 2 is not very soluble in SiO but its kinetic of solubilization is fast. Its saturation concentration, reached after 2 days, is 27 +/- 2 microg g(-1) SiO. Compound 4 is poorly soluble in SiO. A concentration plateau, with a mean value of 4 microg g(-1) SiO, is reached after 4 days. The addition in SiO of 5% of a perfluorinated perhydrogenated alkene greatly improves the solubilization of compound 4. Two different types of FU release are observed. For compound 3, the release is fast and is achieved after 1 day. For compounds 2 and 4, the release is slower and is ended at 10 and 27 days, respectively. The solubility of the prodrugs in SiO is not correlated with their lipophilicity, whereas the release rate of FU decreased with increased lipophilicity of the prodrug. The most promising prodrug is compound 4 that slowly releases two active drugs (FU and RA) with a t (1/2 release) of 5.8 days. It might be interesting for the treatment of PVR. However, an in vivo study on an animal model of PVR is necessary to prove the efficacy of this formulation and to study its toxicity.

Chemistry, Pharmaceutical↗
PubMed2000

Is salvage chemotherapy for metastatic breast cancer always effective and well tolerated? A phase II randomized trial of vinorelbine versus 5-fluorouracil plus leucovorin versus combination of mitoxantrone, 5-fluorouracil plus leucovorin.

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A - vinorelbine 30 mg/m2 i.v. weekly; Arm B - leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 5, q 28 days; Arm C - mitoxantrone 12 mg/m2 i.v. only day 1 + leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 3, q 28 days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3-4 toxicities. Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.

Adult↗
PubMed2003

Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate the impact of a dose-dense primary chemotherapy on pathological response rate (pCR) in patients with locally advanced breast cancer (LABC) treated with combined modality therapy. PATIENTS AND METHODS: Stage IIIA/IIIB patients received three courses of induction chemotherapy (ICT) with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by local therapy (total mastectomy or segmental mastectomy with axillary nodes dissection) and adjuvant chemotherapy (ACT) with three courses of CEF alternated with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Patients were randomized to receive ICT and ACT every 3 weeks (arm A, 'standard treatment') or every 2 weeks with granulocyte-macrophage colony-stimulating factor (GM-CSF) support (arm B, 'dose-dense treatment'). In both arms radiotherapy was administered after the end of chemotherapy (in selected cases) and patients with hormonal receptor-positive tumors received tamoxifen for 5 years. RESULTS: A total of 150 patients were randomized (77 arm A and 73 arm B) and demographics were well balanced between the two arms. Compliance to treatment was excellent: 95% and 93% of patients in arms A and B, respectively, completed the treatment program with no modification or delay. Median duration of treatment (ICT+local+ACT) was 183 days (range 0-265) in arm A and 139 days (0-226) in arm B. The average relative dose intensity (ARDI) of chemotherapy was 1.3 with a 30% increase in the dose intensity in arm B in comparison with arm A. No difference in clinical [62%; 95% confidence interval (CI) 49% to 73.2%] and pathological response rates to ICT was observed between the two arms. Median follow-up was 5 years (range 1-96 months); median disease-free survivals were 4.8 years in arm A and 4.5 years in arm B. Median overall survival was 7.8 years in standard therapy: this figure has not yet been reached in the dose-dense treatment. CONCLUSIONS: In LABC a dose-dense regimen, while allowing a 30% increase in the dose intensity of chemotherapy, did not provide significant improvement in pathological response rates. However, accelerated chemotherapy reduced the duration of the combined-modality program (6.1 versus 4.6 months) with no additional toxicities.

Adult↗
PubMed1994

FAC (fluorouracil, doxorubicin, cyclophosphamide) as second line chemotherapy in patients with metastatic breast cancer progressing under FEC (fluorouracil, epirubicin, cyclophosphamide) chemotherapy.

BACKGROUND: The cross-over resistance between different anthracyclines in breast carcinoma has not been largely evaluated in clinical trials. PATIENTS AND METHODS: Nineteen patients with metastatic breast cancer who had failed prior first line FEC chemotherapy (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 cyclophosphamide 500 mg/m2, every 4 weeks) were treated with a combination of fluorouracil 500 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 4 weeks (FAC). RESULTS: Five patients achieved partial responses, ranging in duration from 5 to 8 months. The main toxicity was cardiac, with congestive heart failure documented in five patients. CONCLUSION: The findings indicate an absence of cross resistance of doxorubicin in some epirubicin-resistant patients.

Adult↗
PubMed2002

CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus CNF (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: results by demographic and clinical subgroups.

A multicenter phase III randomized study comparing the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer: the standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), and an experimental protocol, CNF (cyclophosphamide, mitoxantrone [Novantrone], 5-fluorouracil) in which mitoxantrone replaced methotrexate. The finding of a significant advantage ( p= 0.04) in the disease-free survival for those receiving mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF) led the authors to break the data down in subpopulations to determine exactly which groups of women responded more favorably to CNF than CMF. An advantage in disease-free survival was found, most notable in four subgroups: Sephardic women, women less than 45 years of age, premenopausal women, and women with 4 to 10 positive axillary lymph nodes. Although the small numbers of women in each of these subgroups rule out drawing definitive conclusions, the trend merits further study to confirm these observations.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

A protein-bound polysaccharide immunomodulator, PSK, does not suppress the conversion from 1-(2-tetrahydrofuryl)-5-fluorouracil to 5-fluorouracil in patients with gastric cancer.

Effects of the immunomodulator PSK on the metabolism of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) to 5-fluorouracil (5-FU) were examined in 10 patients with advanced gastric cancer and who had undergone curative resection. PSK is a protein-bound preparation, extracted from Coriolus versicolor and belongs to Basidiomycetes. The 5-FU concentration in the plasma was 0.024 micrograms/ml at 15 min after the intravenous injection of 400 mg of tegafur and the area under the curve of 5-FU was 0.58 micrograms.h/ml. Following administration of PSK, 3 g/day for 8-14 months, there was no change in the plasma level of 5-FU, in any patient. As the clinical dose of PSK had no apparent influence on the metabolism of tegafur to 5-FU, the combination of PSK and tegafur can be prescribed to treat patients with advanced gastric cancer.

Antibiotics, Antineoplastic↗
PubMed1992

Metabolism of 1-(2-tetrahydrofuryl)-5-fluorouracil to 5-fluorouracil in partially hepatectomized rats.

Changes in the metabolism of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) to 5-fluorouracil (5-FU) were examined in the plasma, lung, liver, stomach, small intestine, spleen and kidney in two-thirds partially hepatectomized rats. Concentrations of tegafur and 5-FU in plasma and tissues were determined 30 min after injecting 100 mg/kg of tegafur via the tail vein. The 5-FU concentration in the plasma remained unchanged for the first 7 days after hepatectomy. The tissue level of 5-FU was higher in the liver and kidney than in other organs examined, but there were no changes in levels of 5-FU in each organ examined. Our observations support the proposal that the conversion of tegafur to 5-FU is maintained in partially hepatectomized rats.

Animals↗
PubMed1993

A preliminary report of a pilot randomized trial comparing cyclophosphamide, methotrexate and 5-fluorouracil with cyclophosphamide, mitoxantrone and 5-fluorouracil in the adjuvant therapy of stage II breast cancer with four or more positive axillary nodes.

Thirty-eight patients with stage II breast cancer with four or more positive axillary lymph nodes were randomized to receive CMF (cyclophosphamide, methotrexate and 5-fluorouracil, every 3 weeks) or CXF (cyclophosphamide, mitoxantrone and 5-fluorouracil, every 3 weeks). Pretreatment characteristics were similar for both groups. The actuarial 5 year disease-free survival (DFS) was 36% for the CMF group and 23% for the CXF group. The actuarial 5 year survival was 60% for the CMF arm and 66% for the CXF arm. These differences were not statistically significant. Partial alopecia was observed in 42% of patients in the CMF arm and in 100% of those receiving CXF (p = 0.0002). No episodes of leucopenic fever were observed in patients receiving CMF, while they were present in 53% of patients treated with CXF (p = 0.0006). No stomatitis occurred in the CMF group, but it was observed in 90% of patients who received CXF (p < 0.0001). Treatment with CXF had to be discontinued in two patients because of toxicity. In this small group of patients with poor prognosis, it seems that CXF at the doses given here is more toxic but not more effective than CMF, as represented by a similar DFS and survival.

Adult↗