• Journal of Pharmaceutical Investigation
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• v.34 no.3
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• pp.161-168
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• 2004

5-Fluorouracil (5-FU) is an antimetabolite anticancer agent active against many types of solid tumors. Tegafur (TF), a prodrug of 5-FU, is frequently used in combination with uracil as dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine. We studied the stability of 5-FU and TF in biological fluids of rats and determined their bioavailability (BA) and excretion into bile, and urine. The drug concentrations were analyzed by an HPLC method. At room temperature, there was a 14-30% decrease in the concentration of 5-FU and TF in bile, urine, and plasma specimen at 10 and $100\;{\mu}g/ml$ over 240 min. No significant difference was noted among the sample types or between two different concentrations of 10 and $100{\mu}g/ml$. The decrease in drug concentration was significantly less in samples kept on ice (6-12%) for both drugs. These data indicate that biological fluid samples containing 5-FU or TF in plasma, urine, or bile should be placed on ice during the sample collection. Following these storage guidelines, samples were collected after administration 50 mg/kg of each drug via i.v. or oral route. BA was 1.5 folds greater for TF (60%) than that of 5-FU (42%). Approximately 0.52 and 3.3% of the i.v. doses of 5-FU and TF was excreted into bile, respectively. Renal clearance of 5-FU was about 16% of its total body clearance. These results suggest that instability of 5-FU and TF in biological fluids should be considered in pharmacokinetic or pharmacogenomic studies.

• Radiation Oncology Journal
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• v.7 no.1
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• pp.1-13
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• 1989

Effects of ionizing radiation alone and combined with chemotherapy on tumor growth and it's clonal specificity monitored by changes in distribution of chromosome number were studies in A549 ceil line originated from human adenocarcinoma of the lung. Radiation (300 rad, 600 rad and 900 rad) were delivered with or without 5-FU. Forty eight hours later, 57.5% of growth inhibition of cell w8s seen in cells treated with 5-FU concentration of $0.4{\mu}g/ml$ for 24hr exposure. Cell survival curves after radiation with and without 5-FU were made. Chromosomal analysis of cells in metaphase in control, and in cells treated with 300 rad of radiation, or $0.4{\mu}g/ml$ of 5-FU treatment, and combined treatment of both were done to examine the changes in ploidy and number of chromosome. Radiation combined with S-FU enhanced growth inhibition of A549 cells. However, no evidence of synergegic effects in growth. inhibition was observed in the cells treated with the combination therapy. Pattern of chromosomal distribution of survived cells were shifted from hyperploidy to hypoploidy by single dose of radiation (300 rad). As radiation dose increased a large number of hypoploidy cells were observed. Following treatment of cells with 5-FU, chomosomal distribution of survived cells were also shifted to hypodiploidy which were seen in cells treated with radiation, The ceil treated with 5-FU and fellowed by radiation within 24 hrs had cell with increased number of hypodiploidy cells. Almost same type of chromosomal changes were reproduced in cells treated with combined treatment with radiation and 5-FU. Minor differences were that cells with fewer number of chromosome were more frequent in cells treated with combined therapy. Further increase in cells of hypoploidy (93%) having 1-10 chromosome were induced by additional radiation. Therefore, the enhanced therapeutic effect of 5-FU combined with radiation of A549 cells appeared to be additive rather than synergistic.

• YAKHAK HOEJI
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• v.40 no.5
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• pp.522-531
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• 1996

5-fluorouracil(5-FU) derivatives synthesized with four N-acyloxycarbonyl group such as 1-(N-t-butyloxycarbonyl)glycyloxymethyl-5-FU(BGFU), 1-(N-t-butyloxycarbonyl)leucyloxymethy l-5-FU(BLFU), 1-(N-t-carbobenzyloxymethyl)glycyoxymethyl-5-FU(CGFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU) were entrapped into liposomes with different lipid compositions. The entrapment efficiency and release rate of drugs from each liposomes were evaluated. The particle size of liposomes, cytotoxicity and stability of drug-entrapped in liposomes were evaluated. The entrapment efficiency in 5-FU derivatives liposomes was dependent on the lipophilicity of N-acyloxymethyl derivatives. The drug entrapment efficiency also increased on the content of lipid increased up to 200mcmol of lipid per milliliter of liposomal solution. However, inclusion of additives such as cholesterol, dicetylphosphate and stearylamine decreased the entrapment efficiency. The mean particle size and size distribution were varied with lipid compositions and lipophilicity of prodrugs. The release rates of drugs from liposomes were not affected by additives, but those of BGFU and CGFU entrapped in liposomes with cholesterol decreased. Cytotoxicity of BLFU and CLFU entrapped in liposomes decreased by 3~5 fold compared with those of free two prodrugs. Liposome-entrapped 5-FU prodrugs were more stable either at pH 7.4 or in human plasma. Especially, 5-FU prodrugs entrapped in liposome with dipalmitoylphosphatidylcholine(DMPC) was the most stable in human plasma. Compared with free BLFU, BLFU entrapped in DMPC liposome showed a superior antitumor activity at all doses used. In contrast, CLFU entapped in liposomes were more toxic than free prodrug.

• Biomolecules & Therapeutics
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• v.30 no.3
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• pp.257-264
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• 2022

Colorectal cancer (CRC) is one of the most common malignant tumor. 5-FU is commonly used for the treatment of CRC. However, the development of drug resistance in tumor chemotherapy can seriously reduce therapeutic efficacy of 5-FU. Recent data show that FoxM1 is associated with 5-FU resistance in CRC. FoxM1 plays a critical role in the carcinogenesis and drug resistance of several malignancies. It has been reported that urushiol V isolated from the cortex of Rhus verniciflua Stokes is cytotoxic to several types of cancer cells. However, the underlying molecular mechanisms for its antitumor activity and its potential to attenuate the chemotherapeutic resistance in CRC cells remain unknown. Here, we found that urushiol V could inhibit the cell proliferation and induced S-phase arrest of SW480 colon cancer cells. It inhibited protein expression level of FoxM1 through activation of AMPK. We also investigated the combined effect of urushiol V and 5-FU. The combination treatment reduced FoxM1 expression and consequently reduced cell growth and colony formation in 5-FU resistant colon cancer cells (SW480/5-FUR). Taken together, these result suggest that urushiol V from Rhus verniciflua Stokes can suppress cell proliferation by inhibiting FoxM1 and enhance the antitumor capacity of 5-FU. Therefore, urushiol V may be a potential bioactive compound for CRC therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.4039-4044
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• 2014

Background: The aim of this study was to investigate the anti-cancer effects and mechanisms of immunochemotherapy of 5-fluorouracil (5-FU) and interleukin-2 (IL-2) on non-small cell lung cancer (NSCLC) A549 cells. Materials and Methods: In order to detect whether 5-FU+IL-2 could effectively inhibit tumor growth in vivo, we established an A549-bearing nude mouse model. The cytotoxicity of natural killer (NK) cells was evaluated using a standard chromium release assay. To evaluate the relevance of NK cells in 5-FU+IL-2-mediated tumor inhibitory effects, we depleted NK cells in A549-bearing mice by injecting anti-asialo-GM-1 antibodies. Effects of 5-FU+IL-2 on the expression and promoter activity of NKG2D ligands (MICA/MICB) in A549 cells in vitro were also assessed. Results: In A549-bearing nude mice, combination therapy significantly inhibited tumor growth in comparison with monotherapy with 5-FU or IL-2 and enhanced the recognition and lysis of tumor cells by NK cells. Further study of mechanisms showed that NK cells played a vital role in the anticancer immune response of 5-FU+IL-2 immunochemotherapy. In addition, the combination therapy synergistically stimulated the expression and promoter activity of MICA/MICB. Conclusions: 5-FU and IL-2 immunochemotherapy significantly inhibited tumor growth and activated NK cytotoxicity in vivo, and these effects were partly impaired after depleting NK cells in tumor-bearing mice. Combination treatment of 5-FU and IL-2 upregulated the expression and the promoter activity of MICA/MICB in A549 cells, which enhanced the recognition of A549 cells by NK cells. All of the data indicated that immunochemotherapy of 5-FU and IL-2 may provide a new treatment option for patients with lung cancer.

• YAKHAK HOEJI
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• v.33 no.5
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• pp.267-272
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• 1989

The durg-macromolecule conjugates i.e. 5-fluorouracil-1-acetyl-human serum albumin(FU-AA-HSA, 8) and 5-fluorouracil-1-acetyl-poly-L-lysine(FU-AA-polylys, 9) have been synthesized and purified by sephadex G-25 gel filtration with 0.05M phosphate buffer(pH 7.5). The analyses of conjugates gave the molar ratio of FU-AA : HSA of 70-100:1 and FU-AA: poly-L-lysine of 109:1. The weight percent of FU-AA(as $FU-CH_2CO-$) in FU-AA-HSA conjugate was 16-22% and the one in FU-AA-polylys was 22.4%.

• Molecules and Cells
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• v.25 no.1
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• pp.119-123
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• 2008

Pyrimidine antagonists including 5-Fluorouracil (5-FU) have been used in chemotherapy for cancer patients for over 40 years. 5-FU, especially, is a mainstay treatment for colorectal cancer. It is a pro-drug that is converted to the active drug via the nucleic acid biosynthetic pathway. The metabolites of 5-FU inhibit normal RNA and DNA function, and induce apoptosis of cancer cells. One of the major obstacles to successful chemotherapy is the resistance of cancer cells to anti-cancer drugs. Therefore, it is important to elucidate resistance mechanisms to improve the efficacy of chemotherapy. We have used C. elegans as a model system to investigate the mechanism of resistance to 5-FU, which induces germ cell death and inhibits larval development in C. elegans. We screened 5-FU resistant mutants no longer arrested as larvae by 5-FU. We obtained 18 mutants out of 72,000 F1 individuals screened, and mapped them into three complementation groups. We propose that C. elegans could be a useful model system for studying mechanisms of resistance to anti-cancer drugs.

• Journal of Pharmaceutical Investigation
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• v.22 no.3
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• pp.185-196
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• 1992

To assess its suitability as a prodrug of 5-fluorouracil (5-FU), 1-glycyloxymethyl-5-FU HCl (GFU), a 5-fluorouracil derivative having a glycyloxymethyl group at the N-l position was synthetized. Its physicochemical properties and hydrolysis kinetics, in aqueous solution of pH $1{\sim}10$ and in the presence of human plasma or rat liver homogenate were studied. Its acute toxicity and antitumor activity against sarcoma 180 were also examined, GFU showed higher lipid/water partition coefficient than 5-FU. The calculated $pK_{\alpha}$ values of 5-FU and GFU were 8.02 and 7,20, respectively. The decomposition rates of GFU in aqueous solution showed a pH-dependence over the pH range used, which could be ascribed to solvent catalysed hydrolysis reaction at pH lower than 4,16 and to specific hydroxide ion hydrolysis reaction at pH higher than 4,16, The half-life of GFU was 6,9 min in 80% human plasma solution and less than 3 min in rat liver homogenate at $37^{\circ}C$, The $LD_{50}$ value of 5-FU was 240 mg/kg while that of GFU was 440.6 mg/kg (226 mg as 5-FU). Both of 5FU and GFU showed a strong antitumor activity, Therapeutic ratios of 5-FU and GFU were 3.07 and 3.55, respectively.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5127-5131
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• 2013

Background: 5-fluoro-uracil (FU) is a common agent in postoperative chemoradiation in gastric adenocarcinoma. However, FU is not well tolerated in a significant proportion of patients. Capecitabine (CA) is an orally administered fluoropyrimidine carbamate which is preferentially converted to active 5-FU and is one of the agents used instead of FU in such cases. We compared the toxicity, local and distant control and survival rates with FU or oral CA during the course of concurrent radiotherapy to assess the role of CA used instead of FU. Materials and Methods: We conducted an analysis of survival, disease control and toxicity data in 46 patients treated with postoperative chemoradiation following total or subtotal gastrectomy for gastric adenocarcinoma with either FU or CA between January 2008 and December 2012. Results: Median follow-up was 19 months (range: 3-59), median survival time was 23 ({\pm}6.08) months and 1-3 years overall survival (OS) rates were 64.9-39% for all patients. Compared with the CA regimen, the incidence of treatment interruption was higher with FU (p=0.023), but no significant differences were seen in local control (p=0.510), distant recurrences (p=0.721) and survival rates (p=0.866) among patients. Conclusions: Concurrent CA with radiotherapy seems to be a more tolerable and an equally effective regimen for the postoperative treatment of gastric adenocarcinoma when compared to FU.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4807-4814
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• 2012

Purpose: The chemoresistance of human hepatocellular carcinoma (HCC) to cytotoxic drugs, especially intrinsic or acquired multidrug resistance (MDR), still remains a major challenge in the management of HCC. In the present study, possible mechanisms involved in MDR of HCC were identified using a 5-fluorouracil (5-FU)-resistant human HCC cell line. Methods: BEL-7402/5-FU cells were established through continuous culturing parental BEL-7402 cells, imitating the pattern of chemotherapy clinically. Growth curves and chemosensitivity to cytotoxic drugs were determined by MTT assay. Doubling times, colony formation and adherence rates were calculated after cell counting. Morphological alteration, karyotype morphology, and untrastructure were assessed under optical and electron microscopes. The distribution in the cell cycle and drug efflux pump activity were measured by flow cytometry. Furthermore, expression of potential genes involved in MDR of BEL-7402/5-FU cells were detected by immunocytochemistry. Results: Compared to its parental cells, BEL-7402/5-FU cells had a prolonged doubling time, a lower mitotic index, colony efficiency and adhesive ability, and a decreased drug efflux pump activity. The resistant cells tended to grow in clusters and apparent changes of ultrastructures occurred. BEL-7402/5-FU cells presented with an increased proportion in S and G2/M phases with a concomitant decrease in G0/G1 phase. The MDR phenotype of BEL-7402/5-FU might be partly attributed to increased drug efflux pump activity via multidrug resistance protein 1 (MRP1), overexpression of thymidylate synthase (TS), resistance to apoptosis by augmentation of the Bcl-xl/Bax ratio, and intracellular adhesion medicated by E-cadherin (E-cad). P-glycoprotein (P-gp) might play a limited role in the MDR of BEL-7402/5-FU. Conclusion: Increased activity or expression of MRP1, Bcl-xl, TS, and E-cad appear to be involved in the MDR mechanism of BEL-7402/5-FU.