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Sample records for 5-fluorouracil 5-fu enhances

  1. Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery

    PubMed Central

    De Angelis, Paula M; Svendsrud, Debbie H; Kravik, Katherine L; Stokke, Trond

    2006-01-01

    Background Treatment of cells with the anti-cancer drug 5-fluorouracil (5-FU) causes DNA damage, which in turn affects cell proliferation and survival. Two stable wild-type TP53 5-FU-resistant cell lines, ContinB and ContinD, generated from the HCT116 colon cancer cell line, demonstrate moderate and strong resistance to 5-FU, respectively, markedly-reduced levels of 5-FU-induced apoptosis, and alterations in expression levels of a number of key cell cycle- and apoptosis-regulatory genes as a result of resistance development. The aim of the present study was to determine potential differential responses to 8 and 24-hour 5-FU treatment in these resistant cell lines. We assessed levels of 5-FU uptake into DNA, cell cycle effects and apoptosis induction throughout treatment and recovery periods for each cell line, and alterations in expression levels of DNA damage response-, cell cycle- and apoptosis-regulatory genes in response to short-term drug exposure. Results 5-FU treatment for 24 hours resulted in S phase arrests, p53 accumulation, up-regulation of p53-target genes on DNA damage response (ATF3, GADD34, GADD45A, PCNA), cell cycle-regulatory (CDKN1A), and apoptosis-regulatory pathways (FAS), and apoptosis induction in the parental and resistant cell lines. Levels of 5-FU incorporation into DNA were similar for the cell lines. The pattern of cell cycle progression during recovery demonstrated consistently that the 5-FU-resistant cell lines had the smallest S phase fractions and the largest G2(/M) fractions. The strongly 5-FU-resistant ContinD cell line had the smallest S phase arrests, the lowest CDKN1A levels, and the lowest levels of 5-FU-induced apoptosis throughout the treatment and recovery periods, and the fastest recovery of exponential growth (10 days) compared to the other two cell lines. The moderately 5-FU-resistant ContinB cell line had comparatively lower apoptotic levels than the parental cells during treatment and recovery periods and a recovery time

  2. Assessment of surface concentrations in resorbable ocular implants: controlled drug delivery devices for 5-fluorouracil (5-FU)

    NASA Astrophysics Data System (ADS)

    Milne, Peter J.; Gautier, Sandrine; Parel, Jean-Marie A.; Jallet, Valerie

    1997-05-01

    The antineoplastic drug 5-fluorouracil (5-fluoro- 2,4,(1H,3H)-pyrimidinedione; 5-FU) has been used to control proliferation of penetrating fibroblasts and to prevent channel closure following glaucoma filtration surgery (trabeculectomy) or laser sclerectomy. Because of the toxicity of the drug, administration of low dosages slowly over time, at the site of the desired treatment, is indicated for optimum efficacy. Repeated injections of low dosages of the drug represent an undesirable intervention and may also result in unwanted toxicity to the corneal epithelium. A suitable biocompatible and resorbable polymer matrix composed of a poly (D,L-lactic-co-glycolic acid: PLGA) has been admixed with varying amounts of 5-FU and cast as shapes suitable for intracorneal implantation. Slow biodegradation of this polymer over a one to two week period has been shown to result in an acceptably slow drug release mechanism. An issue arising during the clinical evaluation of the efficacy of this drug delivery system was how best to quantify the concentration of 5-FU and its distribution spatially in the solid implant. FT-IR and FT-Raman spectroscopies distinguishes between the drug and the polymer matrix and were used to differentiate and quantitate the 5-FU concentration of the implants.

  3. Cerivastatin enhances the cytotoxicity of 5-fluorouracil on chemosensitive and resistant colorectal cancer cell lines.

    PubMed

    Wang, Weiguang; Collie-Duguid, Elaina; Cassidy, James

    2002-11-20

    Cerivastatin is one of the synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors used for the treatment and prevention of hypercholesterolaemia. The observation that patients receiving this drug had a lower incidence at cancer led to our interest in using it as a putative anticancer agent. In this study, we tested the cytotoxicity of cerivastatin on a panel of 5-fluorouracil (5FU) sensitive and resistant cell lines in vitro. Cerivastatin was cytotoxic to both 5FU sensitive and resistant cells. Cerivastatin significantly augmented the cytotoxic effect of 5FU on drug sensitive (6-22-fold) and resistant (229-310-fold) cell lines. Cerivastatin and 5FU acted synergistically. Cerivastatin inhibited nuclear factor kappaB DNA binding activity. The enhancing effect of cerivastatin on 5FU was partially mevalonate pathway independent. Cerivastatin may allow successful 5FU therapy in chemoresistant patients. PMID:12435585

  4. Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells.

    PubMed

    González-Vallinas, Margarita; Molina, Susana; Vicente, Gonzalo; de la Cueva, Ana; Vargas, Teodoro; Santoyo, Susana; García-Risco, Mónica R; Fornari, Tiziana; Reglero, Guillermo; Ramírez de Molina, Ana

    2013-06-01

    5-Fluorouracil (5-FU) is the most used chemotherapeutic agent in colorectal cancer. However, resistance to this drug is relatively frequent, and new strategies to overcome it are urgently needed. The aim of this work was to determine the antitumor properties of a supercritical fluid rosemary extract (SFRE), alone and in combination with 5-FU, as a potential adjuvant therapy useful for colon cancer patients. This extract has been recognized as a healthy component by the European Food Safety Authority (EFSA). The effects of SFRE both alone and in combination with 5-FU were evaluated in different human colon cancer cells in terms of cell viability, cytotoxicity, and cell transformation. Additionally, colon cancer cells resistant to 5-FU were used to assay the effects of SFRE on drug resistance. Finally, qRT-PCR was performed to ascertain the mechanism by which SFRE potentiates the effect of 5-FU. Our results show that SFRE displays dose-dependent antitumor activities and exerts a synergistic effect in combination with 5-FU on colon cancer cells. Furthermore, SFRE sensitizes 5-FU-resistant cells to the therapeutic activity of this drug, constituting a beneficial agent against both 5-FU sensitive and resistant tumor cells. Gene expression analysis indicates that the enhancement of the effect of 5-FU by SFRE might be explained by the downregulation of TYMS and TK1, enzymes related to 5-FU resistance. PMID:23557932

  5. Surface-enhanced Raman spectral measurements of 5-fluorouracil in saliva.

    PubMed

    Farquharson, Stuart; Gift, Alan; Shende, Chetan; Inscore, Frank; Ordway, Beth; Farquharson, Carl; Murren, John

    2008-01-01

    The ability of surface-enhanced Raman spectroscopy (SERS) to measure 5-fluorouracil (5-FU) in saliva is presented. The approach is based on the capacity of Raman spectroscopy to provide a unique spectral signature for virtually every chemical, and the ability of SERS to provide microg/mL sensitivity. A simple sampling method, that employed 1-mm glass capillaries filled with silver-doped sol-gels, was developed to isolate 5-FU from potential interfering chemical components of saliva and simultaneously provide SERSactivity. The method involved treating a 1 mL saliva sample with 1 mL of acetic acid, drawing 10 microL of sample into a SERS-active capillary by syringe, and then measuring the SER spectrum. Quality SER spectra were obtained for samples containing as little as 2 microg of 5-FU in 1 mL saliva. The entire process, the acid pretreatment, extraction and spectral measurement, took less than 5 minutes. The SERS of 5-fluorouridine and 5-fluoro-2'-deoxyuridine, two major metabolites of 5-FU, were also measured and shown to have unique spectral peaks. These measurements suggest that disposable SERS-active capillaries could be used to measure 5-FU and metabolite concentrations in chemotherapy patient saliva, thereby providing metabolic data that would allow regulating dosage. Tentative vibrational mode assignments for 5-FU and its metabolites are also given. PMID:18946423

  6. Anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin in 5-fluorouracil-resistant human gastric cancer cell line SNU620/5-FU

    SciTech Connect

    Kim, Nam Hyun; Kim, Su-Nam; Oh, Joa Sub; Lee, Seokjoon; Kim, Yong Kee

    2012-02-24

    Highlights: Black-Right-Pointing-Pointer DBC exerts antiproliferative potential against 5FU-resistant human gastric cancer cells. Black-Right-Pointing-Pointer This effect is mediated by destabilization of microtubules and subsequent mitotic arrest. Black-Right-Pointing-Pointer DBC enhances apoptosis via caspase activation and downregulation of antiapoptotic genes. -- Abstract: In this study, we investigate an anti-mitotic potential of the novel synthetic coumarin-based compound, 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin, in 5-fluorouracil-resistant human gastric cancer cell line SNU-620-5FU and its parental cell SNU-620. It exerts the anti-proliferative effects with similar potencies against both cancer cells, which is mediated by destabilization of microtubules and subsequent mitotic arrest. Furthermore, this compound enhances caspase-dependent apoptotic cell death via decreased expression of anti-apoptotic genes. Taken together, our data strongly support anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin against drug-resistant cancer cells which will prompt us to further develop as a novel microtubule inhibitor for drug-resistant cancer chemotherapy.

  7. CDK inhibitor enhances the sensitivity to 5-fluorouracil in colorectal cancer cells.

    PubMed

    Takagi, Koichi; Sowa, Yoshihiro; Cevik, Ozgur Muhammer; Nakanishi, Ryoko; Sakai, Toshiyuki

    2008-05-01

    Thymidylate synthase (TS) is a dNTP synthetic enzyme and is also a target enzyme of 5-fluorouracil (5-FU). 5-FU is one of the anticancer agents most frequently used for the treatment of colorectal cancers. However, the clinical rate of response to its use as a single agent is not exceptionally high. Therefore, various combination chemotherapies have been devised. The elevated expression of TS in cancer cells is a serious obstacle in the clinical use of 5-FU. In the present study, TS expression was up-regulated by the knockout of the p21WAF1/CIP1 gene in human colorectal cancer HCT116 cells, suggesting that TS expression is mediated through the inhibition of cyclin-dependent kinase (CDK). Based on these findings, we tested whether the CDK inhibitor (CDKI) SU9516, acted as a suppressor of TS. SU9516 effectively reduced the expression of TS in a dose-dependent manner. Furthermore, the reduction of TS expression resulted in enhancement of the sensitivity to 5-FU in human colon cancer DLD-1 cells. Thus, SU9516 might be a promising compound for combination chemotherapy with 5-FU. PMID:18425338

  8. Depletion of Bmi-1 enhances 5-fluorouracil-induced apoptosis and autophagy in hepatocellular carcinoma cells.

    PubMed

    Wu, Jing; Hu, Dong; Zhang, Rongbo

    2012-10-01

    5-fluorouracil (5-FU) is one of the standard chemoradiotherapy regimens for hepatocellular carcinoma (HCC) treatment. B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) has been demonstrated to regulate proliferation. Additionally, Bmi-1 overexpression has been identified in HCC cell lines and correlates with the advanced invasive stage of tumor progression and poor prognosis. In this study, we examined the effects of 5-FU treatment on cell growth in HCC cells with or without Bmi-1 depletion. The IC(50) values of 5-FU were significantly decreased to a greater extent in cells with Bmi-1 knockdown. Depletion of Bmi-1 increased sensitivity of the cells to 5-FU and increased apoptosis. Knockdown of endogenous Bmi-1 led to a substantial reduction in the levels of phospho-AKT and Bcl-2 with a concomitant increase in the levels of Bax. Additionally, 5-FU induced the conversion/turnover of microtubule-associated protein 1 light chain 3 (LC3). Knockdown of endogenous Bmi-1 led to an increase in the levels of Beclin-1 and the accumulation of LC3-II. Together, these findings reveal that Bmi-1 depletion enhanced the chemosensitivity of HCC cells by inducing apoptosis and autophagy, which is associated with the PI3K/AKT and Bcl-2/Beclin-1 pathways. PMID:23205090

  9. Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells

    PubMed Central

    Wang, Chong-Zhi; Luo, Xiaoji; Zhang, Bin; Song, Wen-Xin; Ni, Ming; Mehendale, Sangeeta; Xie, Jing-Tian; Aung, Han H.; He, Tong-Chuan

    2009-01-01

    Purpose Panax notoginseng is a commonly used Chinese herb. Although a few studies have found that notoginseng shows anti-tumor effects, the effect of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil (5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer that interferes with the growth of cancer cells. However, this compound has serious side effects at high doses. In this study, using HCT-116 human colorectal cancer cell line, we investigated the possible synergistic anti-cancer effects between notoginseng flower extract (NGF) and 5-FU on colon cancer cells. Methods The anti-proliferation activity of these modes of treatment was evaluated by MTS cell proliferation assay. Apoptotic effects were analyzed by using Hoechst 33258 staining and Annexin-V/PI staining assays. The anti-proliferation effects of four major single compounds from NGF, ginsenosides Rb1, Rb3, Rc and Rg3 were also analyzed. Results Both 5-FU and NGF inhibited proliferation of HCT-116 cells. With increasing doses of 5-FU, the anti-proliferation effect was slowly increased. The combined usage of 5-FU 5 μM and NGF 0.25 mg/ml, significantly increased the anti-proliferation effect (59.4 ± 3.3%) compared with using the two medicines separately (5-FU 5 μM, 31.1 ± 0.4%; NGF 0.25 mg/ml, 25.3 ± 3.6%). Apoptotic analysis showed that at this concentration, 5-FU did not exert an apoptotic effect, while apoptotic cells induced by NGF were observed, suggesting that the anti-proliferation target(s) of NGF may be different from that of 5-FU, which is known to inhibit thymidilate synthase. Conclusions This study demonstrates that NGF can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment. PMID:17009031

  10. Design and development of folate appended liposomes for enhanced delivery of 5-FU to tumor cells.

    PubMed

    Gupta, Yashwant; Jain, Anekant; Jain, Priyanka; Jain, Sanjay K

    2007-04-01

    Folate appended sterically-stabilized liposomes (FA-SL) were investigated for tumor targeting. Liposomes were prepared using HSPC, cholesterol and FA-polyethylene glycol (PEG)-SA. The liposomes with polyethylene glycol (PEG) without folic acid which has similar lipid composition were used for comparison. Liposomal preparations were characterized for shape, size and percent entrapment. The average size of liposomes was found to be in range 124-163 nm and maximum drug entrapment was found to be 34.2-40.3%. In vitro drug release from the formulations is obeying fickian release kinetics. Cellular uptake and IC(50) values of the FR-targeted formulation were determined in vitro in FR (+) B16F10 melanoma cells. In vitro cell binding of FA-SL exhibits 11-folds higher binding to B16F10 melanoma cells in comparison to SL. In vivo cytotoxicy assay on FR targeted liposomes gave IC(50) of 1.87 microM and non-targeted liposomes gave IC(50) of 4.02 microM. In therapeutic experiments 5-fluorouracil (5-FU), SL and FA-SL were administered at the dose of 10 mg 5-FU/kg body weight to B16F10 tumor bearing Balb/c mice. Administration of FA-SL formulation results in effective reduction in tumor growth as compared with free 5-FU and SL. Results indicate that folic acid appended SL bearing 5-FU are significantly (P < 0.01) active against primary tumor and metastasis than non-targeted sterically-SL. Thus, it could be concluded that folate coupled liposomal formulations enhanced drug uptake by tumor cells. PMID:17454361

  11. Hydrogen–water enhances 5-fluorouracil-induced inhibition of colon cancer

    PubMed Central

    Runtuwene, Joshua; Amitani, Marie; Asakawa, Akihiro; Cheng, Kai-Chun; Inui, Akio

    2015-01-01

    Oxidative stress is involved in cancer development. Hydrogen (H2) is a potent antioxidant and exhibits anti-inflammatory and potentially anticancer-like activities. This study aimed to investigate the role of H2 incombination with 5-fluorouracil (5-FU) in cancer treatment both in vitro and in vivo using the colon 26 cell line. The survival rate was determined using the Kaplan–Meier survival test, and cell viability was assessed using cell viability imaging kit and the MTT assay, and activation of the cell apoptosis pathway (Phosphorylated adenosine monophosphate activated protein kinase (p-AMPK), Apoptosis-inducing factor (AIF) and Caspase 3) were characterized by western blots. Hydrogen water administration improved the survival of mice with colon 26-induced cancer. Furthermore, hydrogen water enhanced cell apoptosis in cancer cells, resulting in a marked increase in the expression of p-AMPK, AIF and Caspase 3 in colon 26 cells. Hydrogen water also increased the inhibitory effect of 5-FU on colon 26 cells with spect to cell survival rate and anticancer functions. Additionally, high-content hydrogen water exhibited stronger antioxidative and anticancer activity than did the natural hydrogen water. In conclusion, high-content hydrogen water can inhibit colon cancer, particularly in combination with 5-fluorouracil. PMID:25870767

  12. Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil.

    PubMed

    Cornwell, P A; Barry, B W

    1994-04-01

    Twelve sesquiterpene compounds, derived from natural volatile oils, were investigated as putative skin penetration enhancers for human skin. Pretreatment of epidermal membranes with sesquiterpene oils, or solid sesquiterpenes saturated in dimethyl isosorbide, increased the rate of absorption of the model hydrophilic permeant, 5-fluorouracil (5-FU). Enhancers with polar functional groups were generally more potent than pure hydrocarbons. Furthermore, enhancers with the least bunched structures were the most active. The largest effect was observed following pretreatment with nerolidol, which increased pseudo-steady-state 5-FU flux over 20-fold. Molecular modelling suggested that terpenes with structures suitable for alignment within lipid lamellae were the most potent enhancers. Sesquiterpene enhancers had long durations of action implying that they did not wash out of the skin easily. This study attempted to improve enhancer clearance by replacing the aqueous donor and receptor phases by ethanol:water (1:1) solutions. Ethanol increased the permeability coefficient for 5-FU 13-fold, demonstrating that, in aqueous solution, it is a moderately potent penetration enhancer. Sesquiterpene and ethanol enhancement effects were approximately additive. Sesquiterpene effects were almost fully maintained for at least 4.5 days following pretreatment, illustrating poor reversibility. Stratum corneum/water drug partitioning studies suggested that an important mechanism of action of the enhancers was to increase the apparent drug diffusivity in the stratum corneum. Increases in drug partitioning into the entire stratum corneum following enhancer pretreatment were relatively small. Diffusivity increases were directly related to overall rises in permeability. This study has shown that sesquiterpene compounds, which are of low toxicity and cutaneous irritancy, can promote 5-FU absorption across human skin. Sesquiterpene compounds, therefore, show promise as clinically-acceptable skin

  13. 5-Fluorouracil as an enhancer of aminolevulinate-based photodynamic therapy for skin cancer: New use for a venerable agent?

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay; Wilson, Clara; Iyer, Karthik

    2011-02-01

    5-Fluorouracil (5-FU) was developed in the 1950s as an anticancer drug and is now widely used to treat many cancers, including colon and breast carcinoma. 5-FU causes fluoronucleotide misincorporation into RNA and DNA, inhibits thymidylate synthase, and leads to growth arrest and apoptosis. For skin precancers (actinic keratoses; AK), 5-FU is prescribed as a topical agent and was essentially the only option for treating widespread AK of the skin prior to FDA approval of photodynamic therapy (PDT) in 1999. PDT is now gradually replacing 5-FU as a preferred treatment for AK, but neither PDT nor 5-FU are effective for true skin cancers (basal or squamous cell), particularly for tumors >1 mm in depth. In our ongoing work to improve the efficacy of PDT for skin cancer, we previously showed that PDT efficacy can be significantly enhanced by preconditioning tumors with methotrexate (MTX), which leads to increased production of protoporphyrin IX (PpIX) in target cells. However, because MTX must be given orally or intravenously, it is considered unacceptable for widespread human use due to potential toxicity. MTX and 5-FU exert similar effects on the thymidylate synthesis pathway, so we reasoned that topical 5-FU could be a potential alternative to MTX. In this paper, exploratory studies that test 5-FU as a preconditioning agent for PDT are presented. In a cutaneous model of squamous cell carcinoma (chemically-induced papillomatous tumors in mice), 5-FU significantly enhances PpIX accumulation and therefore emerges as a new candidate agent for combination therapy with PDT.

  14. Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer

    PubMed Central

    YANG, CHAO; CUI, XIAOXIAN; DAI, XIAOQIN; LIAO, WENTING

    2016-01-01

    The chemotherapy drug 5-fluorouracil (5-FU) is fundamental for the treatment of colorectal cancer (CRC); however, drug resistance to 5-FU may occasionally occur. Abnormal expression of Forkhead box C2 gene (Foxc2) has been identified in several human cancers, but the role of Foxc2 in the progression of CRC remains unclear. The present study established a stable Foxc2-short hairpin (sh)RNA cell line, which was confirmed by western blot analysis and quantitative polymerase chain reaction. The Foxc2-shRNA cells were treated with 5-FU and the cell viability was determined by an MTT assay. Western blot analysis was performed to investigate the signaling pathway involved in 5-FU treatment. The present study identified that 5-FU increased the percentage of apoptotic CRC cells among the Foxc2/RNA interference-transfected cells compared with cells transfected with an empty vector. Therefore, the downregulation of Foxc2, induced by 5-FU, may enhance apoptosis by the downregulation of apoptotic factors, including B cell lymphoma-2 and pro-caspase-3, in Foxc2-shRNA CRC cells. Furthermore, the mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT) pathways were essential for the sensitization effect of Foxc2 to 5-FU treatment. Overall, these findings reveal the mechanisms behind Foxc2 depletion and 5-FU treatment of CRC and suggest that Foxc2 enhances resistance to apoptosis, induced by 5-FU, through the activation of MAPK and P13K/AKT pathways, and may serve as a valuable clinical prognostic marker for CRC. PMID:26893778

  15. Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301)

    PubMed Central

    Bonnetain, Frank; Ychou, Marc; Mitry, Emmanuel; Gasmi, Mohamed; Raoul, Jean-Luc; Cattan, Stéphane; Phelip, Jean-Marc; Hammel, Pascal; Chauffert, Bruno; Michel, Pierre; Legoux, Jean-Louis; Rougier, Philippe; Bedenne, Laurent; Seitz, Jean-François

    2010-01-01

    Purpose Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted. Methods Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0–2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%). Results 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0–1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018). Conclusion This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy. PMID:20947887

  16. Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration.

    PubMed

    Choi, Jung-Hye; Yoon, Jin Sun; Won, Young-Woong; Park, Byeong-Bae; Lee, Young Yiul

    2012-07-01

    Autophagy is a conserved catabolic process that degrades cytoplasmic proteins and organelles for recycling. The role of autophagy in tumorigenesis is controversial because autophagy can be either protective or damaging to tumor cells, and its effects may change during tumor progression. A number of cancer cell lines have been exposed to chloroquine, an anti-malarial drug, with the aim of inhibiting cell growth and inducing cell death. In addition, chloroquine inhibits a late phase of autophagy. This study was conducted to investigate the anti-cancer effect of autophagy inhibition, using chloroquine together with 5-fluorouracil (5-FU) in a colon cancer cell line. Human colon cancer DLD-1 cells were treated with 5-FU (10 μΜ) or chloroquine (100 μΜ), or a combination of both. Autophagy was evaluated by western blot analysis of microtubule-associated protein light chain3 (LC3). Proliferative activity, alterations of the cell cycle, and apoptosis were measured by MTT assays, flow cytometry, and western blotting. LC3-II protein increased after treatment with 5-FU, and chloroquine potentiated the cytotoxicity of 5-FU. MTT assays showed that 5-FU inhibited proliferation of the DLD-1 cells and that chloroquine enhanced this inhibitory effect of 5-FU. The combination of 5-FU and chloroquine induced G1 arrest, up-regulation of p27 and p53, and down-regulation of CDK2 and cyclin D1. These results suggest that chloroquine may potentiate the anti-cancer effect of 5-FU via cell cycle inhibition. Chloroquine potentiates the anti-cancer effect of 5-FU in colon cancer cells. Supplementation of conventional chemotherapy with chloroquine may provide a new cancer therapy modality. PMID:22716215

  17. Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells*

    PubMed Central

    Ng, Pek Leng; Rajab, Nor Fadilah; Then, Sue Mian; Mohd Yusof, Yasmin Anum; Wan Ngah, Wan Zurinah; Pin, Kar Yong; Looi, Mee Lee

    2014-01-01

    Objective: The combination effect of Piper betle (PB) and 5-fluorouracil (5-FU) in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. Methods: HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography (HPLC) was performed to exclude any possible chemical interaction between the compounds. Results: In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose (IC50 12.5 μmol/L) and a shorter time (24 h) in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively. Conclusions: In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway. PMID:25091987

  18. Inhibition of phosphoserine phosphatase enhances the anticancer efficacy of 5-fluorouracil in colorectal cancer.

    PubMed

    Li, Xin; Xun, Zhe; Yang, Yong

    2016-09-01

    Most colorectal cancer (CRC) cell lines are identified to overexpress phosphoserine phosphatase (PSPH), which regulates the intracellular synthesis of serine and glycine, and supports tumor growth. In this study, the effect of PSPH on 5-fluorouracil (5-FU) efficacy was evaluated. CRC cells exposed to 5-FU acquire metabolic remodeling, resulting in increased glucose flux for PSPH-mediated serine synthesis. Then serine is converted into GSH, which promotes cell survival through the detoxification of 5-FU-induced reactive oxygen species (ROS). Consequently, repression of PSPH by the use of shRNAs for PSPH impaired the defense against drug-induced oxidative stress, thereby sensitizing cells to 5-FU. The importance of the PSPH in supporting tumor growth during 5-FU treatment was also demonstrated in an in vivo tumor model of CRC. These findings indicate that the PSPH could serve as a target for increasing the anticancer efficacy of conventional therapy in patients with CRC. PMID:27349874

  19. Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

    PubMed Central

    LI, QIONGYU; WANG, XIANGFENG; SHEN, ALING; ZHANG, YUCHEN; CHEN, YOUQIN; SFERRA, THOMAS J.; LIN, JIUMAO; PENG, JUN

    2015-01-01

    Previous studies have demonstrated that Hedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5-fluorouracil (5-FU); however, less is known with regard to the activity of HDW against 5-FU-resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (EEHDW) were investigated on a multidrug-resistant CRC HCT-8/5-FU cell line. Using an MTT cell proliferation assay, EEHDW treatment was shown to significantly reduce the cell viability of HCT-8/5-FU cells in a dose- and time-dependent manner. Furthermore, EEHDW significantly increased the retention of the ATP-binding cassette (ABC) transporter substrate, rhodamine-123, as compared with the untreated controls. To further investigate the molecular mechanisms targeted by EEHDW in the resistant cells, the expression levels of the ABC drug transporter protein, P-glycoprotein (P-gp), and ABC subfamily G member 2 (ABCG2), were analyzed using reverse-transcription polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of P-gp and ABCG2 were reduced in the HCT-8/5-FU cells following EEHDW treatment, indicating that EEHDW inhibits ABCG2-mediated drug resistance by downregulating the expression of ABCG2 and P-gp. Therefore, the potential application of EEHDW as a chemotherapeutic adjuvant represents a promising alternative approach to the treatment of drug-resistant CRC. PMID:26640560

  20. Silencing of CD59 enhanced the sensitivity of HT29 cells to 5-Fluorouracil and Oxaliplatin.

    PubMed

    Yin, Haipeng; Li, Cuiling; Wang, Shaoyu; Guo, Qiang; Ren, Xia; Jiang, Guosheng

    2015-01-01

    Complement regulatory proteins (CD55 and CD59) were known to be expressed in many tumors and tumor cell lines including colorectal carcinoma, and were proposed as immunotherapy targets, however whether knocking down of CD55 and CD59 will affect the sensitivity of HT-29 cells to chemotherapy drugs for example, 5-Fluorouracil and Oxaliplatin and their possible mechanisms haven't been studied. To address this question, SiRNAs targeting CD55 and CD59 were chemically synthesized and transfected into HT-29 cells by lipofectamine. HT-29 growth curves of CD55 and CD59 knockdown cells were detected by MTT assay, HT29 inhibition curves to chemotherapy drugs (5-Fu and Oxaliplatin) were also assayed, in addition, chemotherapy sensitivity changes of HT29 affected by CD55 and CD59 knockdown were equally detected. Complement mediated lysis was examined by calcein-AM. We found that silencing CD59 in HT-29 cells could significantly enhance their sensitivity to 5-FU (P < 0.05) and Oxaliplatin (P < 0.05), and significantly reduced their IC50 concentration. On the contrary, knocking down of CD55 could inhibit HT-29 growth (P < 0.05). Mechanisms included increasing apoptosis rate of HT-29 by CD59 knocking down and G1/G0 blocking by silencing CD55. Our results thus shed light on the novel mechanism of chemotherapy resistance and provide an alternative strategy to overcome the resistance problem. PMID:25444672

  1. Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma.

    PubMed

    Dai, Wei; Gao, Quangen; Qiu, Jianping; Yuan, Jianmao; Wu, Guoliang; Shen, Genhai

    2016-05-01

    Quercetin (Q), a flavonoid compound, which is obtained in variety of fruits, seeds, and vegetables, has been reported to possess many pharmacological properties including cancer-preventive and anticancer effects. However, studies on the anticancer effects and underlying mechanisms of Q in human hepatocellular carcinoma (HCC) are still limited. The present study is conducted to investigate the anticancer efficacy and adjuvant chemotherapy action of Q in HCC. HCC cell lines HepG2 and SMCC-7721 were treated with different concentrations of Q. The antiproliferative effects of Q were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the apoptosis and cell cycle dynamics were assessed by flow cytometry; the expression of apoptosis-associated proteins were evaluated by Western blot and immunohistochemistry staining; the tumor growth in vivo was evaluated in a xenograft mouse model. Our results showed that Q effectively inhibited human HCC cell proliferation and induced apoptosis by upregulating the expression of Bad and Bax and downregulating the expression of Bcl-2 and Survivin in vitro. Furthermore, Q obviously inhibited the tumor growth and enhanced the 5-fluorouracil (5-FU) therapeutic efficacy in vitro and in vivo. Taken together, our findings highlight that Q effectively inhibited the growth of tumor and enhanced the sensitivity to thermotherapy, indicating Q is a potential treatment option for HCC. PMID:26628295

  2. Neo-adjuvant chemo-(immuno-)therapy of advanced squamous-cell head and neck carcinoma: a multicenter, phase III, randomized study comparing cisplatin + 5-fluorouracil (5-FU) with cisplatin + 5-FU + recombinant interleukin 2.

    PubMed

    Mantovani, G; Gebbia, V; Airoldi, M; Bumma, C; Contu, P; Bianchi, A; Ghiani, M; Dessì, D; Massa, E; Curreli, L; Lampis, B; Lai, P; Mulas, C; Testa, A; Proto, E; Cadeddu, G; Tore, G

    1998-11-01

    We carried out an open, randomized, phase III, multicenter clinical trial to compare, in neo-adjuvant setting, the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c. recombinant interleukin-2 (rIL-2) in patients with advanced (stage III IV) head and neck squamous-cell carcinoma (HNSCC). Regimen A was the classical Al Sarraf treatment: 100 mg/m2 cisplatin i.v. on day 1 plus 1000 mg m(-2) day(-1) 5-FU on days 1-5 as a continuous infusion. Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c. on days 8-12 and 15-19. Treatment was repeated every 3 weeks for three cycles. A total of 33 patients were enrolled in the study; 30 were evaluable for toxicity and 28 for response. Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients (20%) of group A and 4 (31%) of group B had a complete response, 9 patients (60%) of group A and 6 (46%) of group B had a partial response, with an overall response rate of 12 patients (80%) for group A and 10 patients (77%) for group B. Two patients (13%) of group A and 3 patients (23%) group B had stable disease; 1 patient (7%) of group A had progressive disease. Thus, there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the standard chemotherapy. Both regimens were well tolerated. There were 2 toxic deaths (6.7%), 1 from hematological causes in group A and I from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity, mainly nausea/vomiting and stomatitis, were the most frequent toxicities. The calculated number of patients for the sample has not yet been reached; however, the projection of our present results suggests that it is highly improbable that a clinically significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved

  3. Lupeol enhances inhibitory effect of 5-fluorouracil on human gastric carcinoma cells.

    PubMed

    Liu, Yan; Bi, Tingting; Dai, Wei; Wang, Gang; Qian, Liqiang; Shen, Genhai; Gao, Quangen

    2016-05-01

    Lupeol, a dietary triterpene present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including cancer-preventive and anti-cancer effects in vitro and in vivo. Here, we investigated the anti-cancer efficacy and adjuvant chemotherapy action of lupeol in gastric cancer (GC) cells (SGC7901 and BGC823) and explored the underlying mechanisms. Cells were treated with lupeol and/or 5-fluorouracil (5-Fu) and subjected to cell viability, colony formation, apoptosis, western blot, semiquantitative RT-PCR, and xenograft tumorigenicity assay. Our results showed that lupeol and 5-Fu inhibited the proliferation of SGC7901 and BGC823 cells, and combination treatment with lupeol and 5-Fu resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with lupeol and 5-Fu induced apoptosis through up-regulating the expressions of Bax and p53 and down-regulating the expressions of survivin and Bcl-2. Furthermore, co-treatment displayed more efficient inhibition of tumor weight and volume on BGC823 xenograft mouse model than single-agent treatment with 5-Fu or lupeol. Taken together, our findings highlight that lupeol sensitizes GC to 5-Fu treatment, and combination treatment with lupeol and 5-Fu would be a promising therapeutic strategy for human GC treatment. PMID:26892272

  4. Enhancing effect of N-dodecyl-2-pyrrolidone on the percutaneous absorption of 5-fluorouracil derivatives.

    PubMed

    Sato, S; Hirotani, Y; Ogura, N; Sasaki, E; Kitagawa, S

    1998-05-01

    The enhancing effects of N-dodecyl-2-pyrrolidone (NDP) on the percutaneous absorption of doxifluridine (DOX), 5-fluorouracil (5-FU), tegafur (TEG) and carmofur (CAR) were examined using an in vitro penetration technique and rat skin. Phosphate buffered isotonic saline (PBS), propylene glycol (PG) and PG containing 0.4M NDP (PGNDP) were applied as the donor solution. The correlation between the n-octanol/water partition coefficients and the permeability coefficients of DOX, 5-FU and TEG was investigated using both logarithmic plots. It was determined that the permeability coefficients are significantly correlated with their n-octanol/water partition coefficients on PBS. This result suggested that the non-polar stratum corneum lipid lamella in the skin might act as a rate limiting step on the skin penetration of DOX, 5-FU and TEG. The permeability coefficient of DOX, 5-FU and TEG was increased on PGNDP. The enhancing effect of NDP on the permeability coefficient was more effective at higher hydrophilic drugs, the values of the permeability coefficient had almost the same values on PGNDP and the dependency of the permeability coefficient on the n-octanol/water partition coefficient disappeared in the presence of NDP. These results indicated that the enhancing effect of NDP on the percutaneous absorption of DOX, 5-FU and TEG might be closely related to the perturbation of stratum corneum lipid lamella. Since it has been well recognized that CAR is decomposed into 5-FU in neutral and alkaline solution, the decomposition rate of CAR was measured using PBS solution and was found to be very rapid (Kd = 3.17 h-1, t1/2 = 13.1 min). The total concentrations of CAR plus 5-FU in the acceptor compartment were used to determine the permeability coefficient of CAR. The obtained value of the permeability coefficient of CAR on PG was almost the same as that of TEG on PG (CAR: 1.11 x 10(-3) cm/h, TEG: 1.24 x 10(-3) cm/h), while that of CAR on PGNDP was smaller than that of TEG on

  5. Enhanced in vivo delivery of 5-fluorouracil by ethosomal gels in rabbit ear hypertrophic scar model.

    PubMed

    Wo, Yan; Zhang, Zheng; Zhang, Yixin; Zhang, Zhen; Wang, Kan; Mao, Xiaohui; Su, Weijie; Li, Ke; Cui, Daxiang; Chen, Jun

    2014-01-01

    Applying Ethosomal Gels (EGs) in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs) was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 ± 1 °C had a better size stability than that at 25 ± 1 °C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI) of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future. PMID:25501333

  6. Enhanced in Vivo Delivery of 5-Fluorouracil by Ethosomal Gels in Rabbit Ear Hypertrophic Scar Model

    PubMed Central

    Wo, Yan; Zhang, Zheng; Zhang, Yixin; Zhang, Zhen; Wang, Kan; Mao, Xiaohui; Su, Weijie; Li, Ke; Cui, Daxiang; Chen, Jun

    2014-01-01

    Applying Ethosomal Gels (EGs) in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs) was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 ± 1 °C had a better size stability than that at 25 ± 1 °C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI) of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future. PMID:25501333

  7. Combination photodynamic therapy using 5-fluorouracil and aminolevulinate enhances tumor-selective production of protoporphyrin IX and improves treatment efficacy of squamous skin cancers and precancers

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay

    2016-03-01

    In combination photodynamic therapy (cPDT), a small-molecule drug is used to modulate the physiological state of tumor cells prior to giving aminolevulinate (ALA; a precursor for protoporphyrin IX, PpIX). In our laboratory we have identified three agents (methotrexate, 5-fluorouracil, and vitamin D) that can enhance therapeutic effectiveness of ALAbased photodynamic therapy for cutaneous squamous cell carcinoma (SCC). However, only one (5-fluorouracil; 5-FU) is FDA-approved for skin cancer management. Here, we describe animal and human studies on 5-FU mechanisms of action, in terms of how 5-FU pretreatment leads to enhanced PpIX accumulation and improves selectivity of ALA-PDT treatment. In A431 subcutaneous tumors in mice, 5-FU changed expression of heme enzyme (upregulating coproporphyrinogen oxidase, and down-regulating ferrochelatase), inhibited tumor cell proliferation (Ki-67), enhanced differentiation (E-cadherin), and led to strong, tumor-selective increases in apoptosis. Interestingly, enhancement of apoptosis by 5-FU correlated strongly with an increased accumulation of p53 in tumor cells that persisted for 24 h post- PDT. In a clinical trial using a split-body, bilaterally controlled study design, human subjects with actinic keratoses (AK; preneoplastic precursors of SCC) were pretreated on one side of the face, scalp, or forearms with 5-FU cream for 6 days, while the control side received no 5-FU. On the seventh day, the levels of PpIX in 4 test lesions were measured by noninvasive fluorescence dosimetry, and then all lesions were treated with PDT using methyl-aminolevulinate (MAL) and red light (635 nm). Relative amounts of PpIX were found to be increased ~2-fold in 5-FU pretreated lesions relative to controls. At 3 months after PDT, the overall clinical response to PDT (reduction in lesion counts) was 2- to 3-fold better for the 5-FU pretreated lesions, a clinically important result. In summary, 5-FU is a useful adjuvant to aminolevulinate-based PDT

  8. AOT water-in-oil microemulsions as a penetration enhancer in transdermal drug delivery of 5-fluorouracil.

    PubMed

    Gupta, Reeta R; Jain, Swantrant K; Varshney, Manoj

    2005-03-10

    In vitro transdermal permeation of 5-fluorouracil (antineoplastic), a hydrophilic drug encapsulated in AOT/water/isopropylmyristate water-in-oil microemulsions (MEs), were studied using a modified Keshary and Chien diffusion cell. AOT (aerosol-OT or sodium bis(2-ethylhexyl) sulfosuccinate) is an anionic surfactant, which forms 'water-in-oil' ME in non-aqueous medium. The effect of water and AOT concentrations in MEs to the transdermal permeation of 5-fluorouracil through hairless mouse skin was investigated. MEs with 5:95 weight ratio of AOT:isopropylmyristate, containing 0.9, 1.8, 2.7 and 3.6% w/w of water have showed 1.68-, 2.36-, 3.58- and 3.77-fold increases in the skin flux of 5-fluorouracil (5-FU) respectively, compared to the aqueous solution of drug. The MEs with 5:95, 9:91 and 13:87 weight ratio of AOT:isopropyl myristate at fixed water content W0=15 (W0=[H2O]/AOT]) gave 3.58-, 5.04- and 6.3-fold enhancement of drug. In addition, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy was used to examine the effect of ME on lipid alkyl chain, hydration level, and corneocyte cells of the stratum corneum (SC). Results reveal that the ME interacts with a component of the SC and perturbs its architectural structure. The extent of perturbation in the SC depends on the concentration of water and AOT in the ME. Preliminary dermal toxicity studies indicate that the AOT/water/isopropylmyristate ME be safe for the transdermal permeation of 5-FU. PMID:15698753

  9. Epigallocatechin-3-gallate targets cancer stem-like cells and enhances 5-fluorouracil chemosensitivity in colorectal cancer

    PubMed Central

    Toden, Shusuke; Tran, Hanh-My; Tovar-Camargo, Oscar A.; Okugawa, Yoshinaga; Goel, Ajay

    2016-01-01

    Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. A small subset of cancer cells, termed “cancer stem cells” (CSCs), are believed to be key contributors of chemoresistance and tumor recurrence. Recently, epigallocatechin-3-gallate (EGCG), an active catechin present in green tea, has been shown to suppress CSC growth in various cancers, but whether it can specifically target CSCs and subsequently sensitize chemoresistant CRC cells to standard of care chemotherapeutic treatments remains unknown. Herein, we investigated the chemosensitizing effects of EGCG in 5-fluorouracil (5FU)-resistant (5FUR) CRC cells and spheroid-derived CSCs (SDCSCs), and interrogated the underlying molecular mechanisms responsible for its chemopreventive activity. EGCG enhanced 5FU-induced cytotoxicity and inhibited proliferation in 5FUR cell lines through enhancement of apoptosis and cell cycle arrest. The 5FUR cells showed higher spheroid forming capacity compared to parental cells, indicating higher CSC population. EGCG treatment in these cells resulted in suppression of SDCSC formation and enhanced 5FU sensitivity to SDCSCs. Furthermore, EGCG suppressed Notch1, Bmi1, Suz12, and Ezh2, and upregulated self-renewal suppressive-miRNAs, miR-34a, miR-145, and miR-200c, which are some of the key pathways targeted in 5FUR CRC cells. These findings were validated in vivo, wherein EGCG treatment resulted in inhibited tumor growth in a SDCSC xenograft model. Collectively our data provide novel and previously unrecognized evidence for EGCG-induced sensitization to 5FU through targeting of CSCs in CRC. Our data highlight that in addition to its chemopreventive ability, EGCG may serve as an adjunctive treatment to conventional chemotherapeutic drugs in CRC patients. PMID:26930714

  10. Protocol of a randomised phase III clinical trial of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab in advanced colorectal cancer: the C-cubed (C3) study

    PubMed Central

    Mishima, Hideyuki; Sawaki, Akira; Shimokawa, Mototsugu; Inukai, Michio; Shinozaki, Katsunori; Tanioka, Hiroaki; Nasu, Junichiro; Nishina, Tomohiro; Hazama, Shoichi; Okajima, Masazumi; Yamaguchi, Yoshiyuki

    2016-01-01

    Introduction Results from several randomised trials suggest that the sequential use of cytotoxic agents in patients with metastatic colorectal cancer (mCRC) has the potential to improve overall survival compared with combination chemotherapy. This study is designed to investigate whether sequential treatment with bevacizumab-based first-line treatment with oxaliplatin is superior to combination treatment of mCRC. Methods and analysis The C-cubed (C3) study is a two-arm, multicentre, open-label, randomised phase III trial in Japan comparing the efficacy and safety of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) with escalation to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab as the first-line treatment of mCRC. In the sequential arm (Arm A: oxaliplatin ‘wait-and-go’), treatment escalation from Cape/5-FU-Bmab to CapeOX/mFOLFOX6-Bmab is recommended in the case of progressive disease. In the combination arm (Arm B: oxaliplatin ‘stop-and-go’), de-escalation from CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin after 12 weeks of treatment not caused by oxaliplatin-associated toxicity. A target sample size of 304 evaluable patients is considered sufficient to validate an expected HR for time to failure of strategy of the sequential approach ‘wait-and-go’ compared to the combination approach ‘stop-and go’ with 80% power and 2-sided 5% α in case of a true HR<0.69. Ethics and dissemination This study is conducted according to the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki 2013 and local regulations, and has been submitted and approved by the Ethical Committee of the Non-Profit Organization MINS Institutional Review Board. The protocol

  11. White light-mediated Cu (II)-5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study.

    PubMed

    Chibber, Sandesh; Farhan, Mohd; Hassan, Iftekhar; Naseem, Imrana

    2011-10-01

    5-Fluorouracil (5-FU) is a potent photosensitizer used in colon and rectal cancers. 5-FU on galvanostatic electrolysis or radiation-induced oxidation of aqueous solution yields N(1)-C(5)-linked dimmer hydrate of 5-FU. Copper is presently associated with chromatin; in cancer cells the concentration of copper is very high. It has been shown to be capable of mediating the action of several anticancer drugs through the production of reactive oxygen species (ROS). The objective of the present study is to determine the Cu (II)-mediated anticancer mechanism of 5-FU under photo-illumination as well as 5-FU alone. We have shown that a pro-oxidant action was enhanced when Cu (II) was used with 5-FU as compared to 5-FU alone. This may be due to the inhibition of dimerization of 5-FU when present in combination with Cu (II) under photo-illumination. It was also shown that 5-FU alone as well as in combination with Cu (II) was able to generate oxidative stress in lymphocyte which is inhibited by scavengers of ROS. Moreover, the results of Fourier-transformed infrared spectra lead to the conclusion that the dimerization of 5-FU was inhibited when used in combination with Cu (II). It was due to the interaction of 5-FU with Cu (II). Hence, we propose that during chemoradiotherapy with 5-FU, the endogenous copper is mobilized by 5-FU, leading to the generation of ROS which cause oxidative stress and possibly cancer cell death by apoptosis. PMID:21618035

  12. Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats.

    PubMed

    El-Shemi, Adel Galal; Refaat, Bassem; Kensara, Osama Adnan; Mohamed, Amr Mohamed; Idris, Shakir; Ahmad, Jawwad

    2016-06-01

    Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), whereas paricalcitol (2.5 μg/kg/day; 3 days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, β-catenin, DKK-1, CDNK-1A, NF-κB, and COX-2 genes, and ELISA was used to quantify the protein levels of β-catenin, COX-2, HSP90, and VEGF. IHC was additionally used to measure β-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. ©2016 AACR. PMID:27020656

  13. Recent studies of 5-fluorouracil resistance in pancreatic cancer

    PubMed Central

    Wang, Wei-Bin; Yang, Yu; Zhao, Yu-Pei; Zhang, Tai-Ping; Liao, Quan; Shu, Hong

    2014-01-01

    Resistance to 5-fluorouracil (5-FU), an important anticancer drug, is a serious challenge in the treatment of pancreatic cancer. Equilibrative nucleoside transporter 1 and multidrug-resistance protein (MRP) 5 and MRP8, rather than P-glycoprotein, play important roles in 5-FU transport. Thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidine phosphorylase are four key enzymes involved in 5-FU metabolism. Other metabolic enzymes, including uridine monophosphate synthetase, also contribute to chemoresistance. Intracellular signaling pathways are an integrated network, and nuclear factor kappa-light-chain-enhancer of activated B cells, AKT and extracellular signal-regulated kinases are signaling pathways that are particularly relevant to 5-FU resistance. In addition, recent reports indicate that STAT-3 is a crucial survival protein. Proteomic assays provide a powerful tool for identifying target proteins and understanding the role of microRNAs and stromal factors to facilitate the development of strategies to combat 5-FU resistance. PMID:25400452

  14. Recent studies of 5-fluorouracil resistance in pancreatic cancer.

    PubMed

    Wang, Wei-Bin; Yang, Yu; Zhao, Yu-Pei; Zhang, Tai-Ping; Liao, Quan; Shu, Hong

    2014-11-14

    Resistance to 5-fluorouracil (5-FU), an important anticancer drug, is a serious challenge in the treatment of pancreatic cancer. Equilibrative nucleoside transporter 1 and multidrug-resistance protein (MRP) 5 and MRP8, rather than P-glycoprotein, play important roles in 5-FU transport. Thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidine phosphorylase are four key enzymes involved in 5-FU metabolism. Other metabolic enzymes, including uridine monophosphate synthetase, also contribute to chemoresistance. Intracellular signaling pathways are an integrated network, and nuclear factor kappa-light-chain-enhancer of activated B cells, AKT and extracellular signal-regulated kinases are signaling pathways that are particularly relevant to 5-FU resistance. In addition, recent reports indicate that STAT-3 is a crucial survival protein. Proteomic assays provide a powerful tool for identifying target proteins and understanding the role of microRNAs and stromal factors to facilitate the development of strategies to combat 5-FU resistance. PMID:25400452

  15. Oxymatrine synergistically enhances the inhibitory effect of 5-fluorouracil on hepatocellular carcinoma in vitro and in vivo.

    PubMed

    Liu, Yan; Bi, Tingting; Dai, Wei; Wang, Gang; Qian, Liqiang; Gao, Quangen; Shen, Genhai

    2016-06-01

    Oxymatrine (OMT), one of the main active components of extracts from the dry roots of Sophora flavescens, has long been employed clinically to treat cancers. Here, we investigated the synergistic effect of OMT with 5-fluorouracil (5-Fu) on the tumor growth inhibition of hepatocellular carcinoma cells (HCC; Hep-G2 and SMMC-7721) and explored the underlying mechanism. Cells were treated with OMT and/or 5-Fu and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay, and immunohistochemistry. OMT and 5-Fu inhibited the proliferation of Hep-G2 and SMMC-7721 cells, and combination treatment with OMT and 5-Fu resulted in a combination index <1, indicating a synergistic effect. Co-treatment with OMT and 5-Fu caused G0/G1 phase arrest by upregulating P21 and P27 and downregulating cyclin D, and induced apoptosis through increasing the production of reactive oxygen species (ROS) and decreasing the levels of p-ERK. In addition, the inhibition of ROS respectively reversed the cell death induced by 5-Fu + OMT, suggesting the key roles of ROS in the process. More importantly, 5-Fu and OMT in combination exhibit much superior tumor weight and volume inhibition on SMMC-7721 xenograft mouse model in comparison to 5-Fu or OMT alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which was consistent with our in vitro results. Taken together, our findings indicated that OMT sensitizes HCC to 5-Fu treatment by the suppression of ERK activation through the overproduction of ROS, and combination treatment with OMT and 5-Fu would be a promising therapeutic strategy for HCC treatment. PMID:26687645

  16. Teng-Long-Bu-Zhong-Tang, a Chinese herbal formula, enhances anticancer effects of 5 - Fluorouracil in CT26 colon carcinoma

    PubMed Central

    2013-01-01

    Background Colorectal cancer remains one of the leading causes of cancer death worldwide. Traditional Chinese Medicine (TCM) has played a positive role in colorectal cancer treatment. There is a great need to establish effective herbal formula for colorectal cancer treatment. Based on TCM principles and clinical practices, we have established an eight herbs composed formula for colorectal cancer treatment, which is Teng-Long-Bu-Zhong-Tang (TLBZT). We have demonstrated the anticancer effects of TLBZT against colorectal carcinoma in vitro. In present study, we evaluated the anticancer potential of TLBZT, used alone or in combination with low dose of 5-Fluorouracil (5-Fu), in CT26 colon carcinoma in vivo. Methods CT26 colon carcinoma was established in BALB/c mice and treated with TLBZT, 5-Fu, or TLBZT plus 5-Fu. The tumor volumes were observed. Apoptosis was detected by TUNEL assay. Caspases activities were detected by colorimetric assay. Cell senescence was indentified by senescence β-galactosidase staining. Gene expression and angiogenesis was observed by immunohistochemistry or western blot. Results TLBZT significantly inhibited CT26 colon carcinoma growth. TLBZT elicited apoptosis in CT26 colon carcinoma, accompanied by Caspase-3, 8, and 9 activation and PARP cleavage, and downregulation of XIAP and Survivin. TLBZT also induced cell senescence in CT26 colon carcinoma, with concomitant upregulation of p16 and p21 and downregulation of RB phosphorylation. In addition, angiogenesis and VEGF expression in CT26 colon carcinoma was significantly inhibited by TLBZT treatment. Furthermore, TLBZT significantly enhanced anticancer effects of 5-Fu in CT26 colon carcinoma. Conclusions TLBZT exhibited significantly anticancer effect, and enhanced the effects of 5-Fu in CT26 colon carcinoma, which may correlate with induction of apoptosis and cell senescence, and angiogenesis inhibition. The present study provides new insight into TCM approaches for colon cancer treatment

  17. Methyl-{beta}-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: Involvement of Akt, NF-{kappa}B and Bcl-2

    SciTech Connect

    Upadhyay, Ankur Kumar; Singh, Sandeep; Chhipa, Rishi Raj; Vijayakumar, Maleppillil Vavachan; Ajay, Amrendra Kumar; Bhat, Manoj Kumar . E-mail: manojkbhat@nccs.res.in

    2006-10-15

    The response rates of extensively used chemotherapeutic drugs, carboplatin (Carb) or 5-fluorouracil (5-FU) are relatively disappointing because of considerable side effects associated with their high-dose regimen. In the present study, we determined whether treatment with a cholesterol depleting agent, methyl-{beta}-cyclodextrin (MCD), enhances the weak efficacy of low doses of Carb or 5-FU in human breast cancer cells. Data demonstrate that pretreatment with MCD significantly potentiates the cytotoxic activity of Carb and 5-FU in both MCF-7 and MDA-MB-231. Furthermore, we explored the molecular basis of enhanced cytotoxicity, and our data revealed that low-dose treatment with these drugs in MCD pretreated cells exhibited significantly decreased Akt phosphorylation, NF-{kappa}B activity and down-regulation in expression of anti-apoptotic protein Bcl-2. In addition, MCD pretreated cells demonstrated an increased intracellular drug accumulation as compared to cells treated with drugs alone. Taken together, our data provide the basis for potential therapeutic application of MCD in combination with other conventional cytotoxic drugs to facilitate reduction of drug dosage that offers a better chemotherapeutic approach with low toxicity.

  18. Lin28A enhances chemosensitivity of colon cancer cells to 5-FU by promoting apoptosis in a let-7 independent manner.

    PubMed

    Wang, Tianzhen; Han, Peng; He, Yan; Zhao, Ci; Wang, Guangyu; Yang, Weiwei; Shan, Ming; Zhu, Yuanyuan; Yang, Chao; Weng, Mingjiao; Wu, Di; Gao, Lin; Jin, Xiaoming; Wei, Yunwei; Cui, BinBin; Shen, Guomin; Li, Xiaobo

    2016-06-01

    RNA-binding protein Lin28A is frequently over-expressed in human malignant tumors and is associated with tumor advance and poor prognosis. However, the expression pattern and functions of Lin28A in colon cancer are unknown. In this study, we detected the expression of Lin28A in colon cancer patients and tested the effect of Lin28A on the chemotherapeutic sensitivity of colon cancer cells to 5-fluorouracil (5-FU). As expected, we showed that Lin28A is up-regulated in 73.3 % of colon cancer patients. However, to our surprise, we found that oncogenic protein Lin28A-enforced expression in colon cancer cells enhanced the chemosensitivity of cancer cells to 5-FU via promoting the cell apoptosis. Further mechanisms study revealed that the effect of Lin28A increasing chemosensitivity of cancer cells is in a let-7 independent manner, but which is associated with decreasing the expression of DNA damage repair protein H2AX. Conclusively, here we reported an unexpected function of Lin28A, which may shed lights on fully understanding the physiological and pathological roles of this oncogene. PMID:26687759

  19. MK-2206 co-treatment with 5-fluorouracil or doxorubicin enhances chemosensitivity and apoptosis in gastric cancer by attenuation of Akt phosphorylation

    PubMed Central

    Jin, Piaopiao; Wong, Chi Chun; Mei, Sibin; He, Xingkang; Qian, Yun; Sun, Leimin

    2016-01-01

    The anticancer effect of MK-2206, an Akt inhibitor, has been explored in some types of cancers, but its effect on gastric cancer is unclear. In this study, we aimed to investigate its anticancer effect in gastric cancer cells. Cell viability and colony formation assays showed that MK-2206 effectively inhibited the proliferation of SGC-7901 and MKN45 cells. The 50% inhibitory concentration values after 24, 48, and 72 hours’ treatment were 22.92, 13.68, and 8.55 μM in SGC-7901 cells and 19.21, 13.10, and 9.11 μM in MKN45 cells, respectively. Treatment with MK-2206 induced apoptosis in SGC-7901 cells as indicated by flow cytometry assay. The combination indexes of MK-2206 and doxorubicin were 0.59 in SGC-7901 cells and 0.57 in MKN45 cells, whereas for 5-fluorouracil (5-FU) the indexes were 0.17 in SGC-7901 cells and 0.73 in MKN45 cells, indicating that MK-2206 could work synergistically with doxorubicin or 5-FU to inhibit cell growth. Furthermore, a small dose (1 μM) of MK-2206 co-treatment with doxorubicin or 5-FU was sufficient for complete inhibition of chemotherapeutic alteration of phosphorylated Akt expression and significant enhancement of pro-apoptosis effect through the activation of caspase pathway. Therefore, MK-2206 effectively inhibits gastric cancer cell growth by attenuation of Akt phosphorylation and synergistically enhances the antitumor effect of doxorubicin and 5-FU via caspase-dependent apoptosis. PMID:27499633

  20. Symptomatic 5-fluorouracil-induced sinus bradycardia.

    PubMed

    Lee, A D; McKay, M J

    2011-07-01

    5-Fluorouracil (5-FU) is a commonly used anti-neoplastic agent. 5-FU has been not uncommonly associated with cardiotoxicity, although the many potentially causative mechanisms are yet to be established. Here, we present the case of a 61-year-old gemstone miner who developed symptomatic sinus bradycardia while receiving a continuous 5-FU infusion combined with radiotherapy for locally advanced rectal cancer. This dysrhythmia is an unusual type of 5-FU toxicity, our case being the second described. We review the actions of 5-FU and the various proposed mechanisms of its cardiotoxic effects. PMID:21762335

  1. Combination chemotherapy with 5-fluorouracil (5FU) and 1,3-bis(2-chloro-ethyl)-1-nitrosourea (BCNU) prolongs survival of rats with dimethylhydrazine-induced colon cancer.

    PubMed Central

    Danzi, M; Lewin, M R; Cruse, J P; Clark, C G

    1983-01-01

    The effects of combination chemotherapy with 5FU and BCNU on rats with dimethylhydrazine (DMH)-induced colon cancer were investigated in a long term survival study. Eighty Wistar rats received a colon cancer producing regimen on DMH (40 mg/kg body weight/week, subcutaneously for 10 weeks). After presenting with signs of colonic disease, all rats underwent diagnostic laparotomy and colonoscopy when colon tumours were located, measured and the extent of the disease staged. Only animals with tumours (n = 63) were included and allocated to one of three tumour stages. Stage A (n = 17), had colonic tumours without serosal involvement; stage B (n = 28) had serosal involvement without metastases; stage C (n = 18) had serosal involvement with lymphadenopathy and/or metastases. Each group was randomly allocated into two subgroups, one serving as untreated controls while the other received 5FU (300 mg/m2 weekly intragastrically for life) together with BCNU (40 mg/m2 intraperitoneally on days 0, 42 and 84). The effect of chemotherapy on tumour growth was measured sequentially by colonoscopy. Animals were observed until death and necropsied, when colon carcinoma was histologically confirmed and survival analysed. The results indicate that chemotherapy significantly prolongs the survival of rats with the least advanced disease (stage A) but was of no benefit to rats with locally advanced or metastatic disease (stages B and C). Furthermore, chemotherapy was associated with a significant reduction in tumour size. Survival analyses in untreated animals show that the laparotomy staging system adopted provides accurate prognostic information. This study shows that DMH-induced colon tumours are chemosensitive, and suggests that this animal model may be a valuable testing ground for new chemotherapeutic agents. PMID:6629114

  2. Knockdown of EpCAM Enhances the Chemosensitivity of Breast Cancer Cells to 5-fluorouracil by Downregulating the Antiapoptotic Factor Bcl-2

    PubMed Central

    Liu, Shuai; Yang, Xuesong

    2014-01-01

    Resistance to fluoropyrimidine-based chemotherapy is the main reason for the failure of cancer treatment, and drug resistance is associated with an inability of tumor cells to undergo apoptosis in response to treatment. Alterations in the expression of epithelial cell adhesion molecule (EpCAM) affect the sensitivity or resistance of tumor cells to anticancer treatment and the activity of intracellular signaling pathways. However, the role of EpCAM in the induction of apoptosis in breast cancer cells remains unclear. Here, we investigated the effect of EpCAM gene knockdown on chemosensitivity to 5-fluorouracil (5-FU) in MCF-7 cells and explored the underlying mechanisms. Our results showed that knockdown of EpCAM promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest. EpCAM knockdown enhanced the cytotoxic effect of 5-FU, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro-apoptotic proteins Bax, and caspase3 via the ERK1/2 and JNK MAPK signaling pathways in MCF-7 cells. These results indicate that knockdown of EpCAM may have a tumor suppressor effect and suggest EpCAM as a potential target for the treatment of breast cancer. PMID:25019346

  3. Development of sulfadiazine-decorated PLGA nanoparticles loaded with 5-fluorouracil and cell viability.

    PubMed

    Guimarães, Pedro Pires Goulart; Oliveira, Sheila Rodrigues; de Castro Rodrigues, Gabrielle; Gontijo, Savio Morato Lacerda; Lula, Ivana Silva; Cortés, Maria Esperanza; Denadai, Ângelo Márcio Leite; Sinisterra, Rubén Dario

    2015-01-01

    The aim of this work was to synthesize sulfadiazine-poly(lactide-co-glycolide) (SUL-PLGA) nanoparticles (NPs) for the efficient delivery of 5-fluorouracil to cancer cells. The SUL-PLGA conjugation was assessed using FTIR, 1H-NMR, 13C-NMR, elemental analysis and TG and DTA analysis. The SUL-PLGA NPs were characterized using transmission and scanning electron microscopy and dynamic light scattering. Additionally, the zeta potential, drug content, and in vitro 5-FU release were evaluated. We found that for the SUL-PLGA NPs, Dh = 114.0 nm, ZP = -32.1 mV and the encapsulation efficiency was 49%. The 5-FU was released for up to 7 days from the NPs. Cytotoxicity evaluations of 5-FU-loaded NPs (5-FU-SUL-PLGA and 5-FU-PLGA) on two cancer cell lines (Caco-2, A431) and two normal cell lines (fibroblast, osteoblast) were compared. Higher cytotoxicity of 5-FU-SUL-PLGA NPs were found to both cancer cell lines when compared to normal cell lines, demonstrating that the presence of SUL could significantly enhance the cytotoxicity of the 5-FU-SUL-PLGA NPs when compared with 5-FU-PLGA NPs. Thus, the development of 5-FU-SUL-PLGA NPs to cancer cells is a promising strategy for the 5-FU antitumor formulation in the future. PMID:25580685

  4. Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells.

    PubMed

    Zeng, Quan; Wang, Zhihai; Liu, Chuan; Gong, Zhitao; Yang, Li; Jiang, Liang; Ma, Zuxia; Qian, Yi; Yang, Yucheng; Kang, Houyong; Hong, Suling; Bu, Youquan; Hu, Guohua

    2016-07-01

    Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer that is prevalent among people of southern Chinese ancestry in southern China and Southeast Asia. Radiotherapy and cisplatin (CDDP)-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to CDDP and radiotherapy. NFBD1 functions in cell cycle checkpoint activation and DNA repair following DNA damage. In this study, we identified the NFBD1 as a tractable molecular target to chemosensitize NPC cells. NFBD1 expression in NPC CNE1 cell lines was depleted using lentivirus-mediated short hairpin RNA, and the elevated sensitivity of these NFBD1-inhibited NPC cells to therapeutic reagent CDDP and 5-fluorouracil (5-FU) was evaluated using MTS assays. Flow cytometry analysis also showed that NFBD1 knockdown led to an obvious induction of apoptosis in CDDP- or 5-FU-treated CNE1 cells. Furthermore, we implicated the involvement of NFBD1 in Rad51 and DNA-PKcs foci formation following CDDP or 5-FU chemotherapy. In conclusion, NFBD1 knockdown improves the chemosensitivity of NPC cells by inhibiting cell growth and promoting apoptosis through the impairment of DNA damage repair, suggesting NFBD1 as a novel therapeutic target for NPC. PMID:27334757

  5. Ciprofloxacin decreases survival in HT-29 cells via the induction of TGF-β1 secretion and enhances the anti-proliferative effect of 5-fluorouracil

    PubMed Central

    Bourikas, Leonidas A; Kolios, George; Valatas, Vassilis; Notas, George; Drygiannakis, Ioannis; Pelagiadis, Iordanis; Manousou, Pinelopi; Klironomos, Stefanos; Mouzas, Ioannis A; Kouroumalis, Elias

    2009-01-01

    Background and purpose: Fluoroquinolones are potent anti-microbial agents with multiple effects on host cells and tissues. Previous studies have highlighted their pro-apoptotic effect on human cancer cells and an immunoregulatory role in animal models of inflammatory bowel disease. We examined the effect of ciprofloxacin on proliferation, cell cycle and apoptosis of HT-29 cells, a human colonic epithelial cell line sensitive to transforming growth factor (TGF)-β1-mediated growth inhibition and its role in TGF-β1 production. We also examined the effect of ciprofloxacin on proliferation of HT-29 cells in combination with 5-fluorouracil (5-FU), a well-established pro-apoptotic agent. Experimental approach: Using subconfluent cultures of HT-29 and Caco-2 cells, we studied the effect of ciprofloxacin, TGF-β1 and 5-FU on proliferation, apoptosis, necrosis and cell cycle. The effect of ciprofloxacin on TGF-β1 mRNA expression and production was studied in RNA extracts and cell culture supernatants respectively, using confluent cultures. Key results: Ciprofloxacin decreased proliferation of HT-29 cells in a concentration- and time-dependent manner. This was mediated by accumulation of HT-29 cells into the S-phase but without any effect on apoptosis or necrosis. Additionally, ciprofloxacin enhanced the antiproliferative effect of 5-FU. Interestingly, ciprofloxacin was found to up-regulate TGF-β1 production by HT-29 cells and its anti-proliferative effect was abolished when TGF-β1 was blocked. Confirming this mechanism further, ciprofloxacin had no effect on Caco-2, a human colonic epithelial cell line that lacks functional TGF-β1 receptors. Conclusions and implications: We demonstrate a novel anti-proliferative and immunoregulatory effect of ciprofloxacin on human intestinal epithelial cells mediated via TGF-β1. PMID:19371339

  6. Preparation and passive target of 5-fluorouracil solid lipid nanoparticles.

    PubMed

    Du, Bin; Yan, Ying; Li, Ying; Wang, Shuyu; Zhang, ZhenZhong

    2010-01-01

    This work studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with 5-fluorouracil (5-FU). The goal was to design longer drug residence in vivo and passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects. Based on the optimized results of uniform design experiment, 5-FU-SLNs were prepared by multiple emulsion-ultrasonication (w/o/w). The SLNs were found to be relatively uniform in size (182.1 +/- 25.8 nm) with a negative zeta potential (-27.89 +/- 5.1 mV). The average drug entrapment efficiency and loading were 74% and 10%, respectively. Compared with the 5-FU solution (t(1/2beta), 0.593h; MRT, 0.358h) after intravenous injection to rats, the pharmacokinetic parameters of 5-FU-SLNs exhibited a longer retention time. (t(1/2beta), 4.0628h; MRT, 3.5321h). The area under curve of plasma concentration-time (AUC) of 5-FU-SLNs was 1.48 times greater than that of free drugs. The overall targeting efficiency (TE(C)) of the 5-FU-SLNs was enhanced from 13.25-20.45% in the lung and from 11.48-23.16% in kidney while the spleen distribution of 5-FU was significantly reduced as compared with that of the 5-FU solution. These results indicated that 5-FU-SLNs were promising passive targeting therapeutic agents for curing primary lung carcinoma. PMID:19769532

  7. Glycyrrhetinic acid-modified chitosan nanoparticles enhanced the effect of 5-fluorouracil in murine liver cancer model via regulatory T-cells

    PubMed Central

    Cheng, Mingrong; Xu, Hongzhi; Wang, Yong; Chen, Houxiang; He, Bing; Gao, Xiaoyan; Li, Yingchun; Han, Jiang; Zhang, Zhiping

    2013-01-01

    Modified chitosan nanoparticles are a promising platform for drug, such as 5-fluorouracil (5-FU), gene, and vaccine delivery. Here, we used chitosan and hepatoma cell-specific binding molecule glycyrrhetinic acid (GA) to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared spectroscopy and hydrogen nuclear magnetic resonance. By combining GA-CTS and 5-FU, we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 193.7 nm, drug loading of 1.56%, and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained-release system comprising three distinct phases of quick, steady, and slow release. In vitro data indicated that it had a dose- and time-dependent anticancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited cancer cell proliferation, resulting in increased survival time. The antitumor mechanisms for GA-CTS/5-FU nanoparticle were possibly associated with an increased expression of regulatory T-cells, decreased expression of cytotoxic T-cell and natural killer cells, and reduced levels of interleukin-2 and interferon gamma. PMID:24187487

  8. Folate-functionalized nanoparticles for controlled 5-Fluorouracil delivery.

    PubMed

    Zhang, Yan; Li, Jiashi; Lang, Meidong; Tang, Xiaolin; Li, Lei; Shen, Xizhong

    2011-02-01

    In this paper, folate conjugated poly(ε-caprolactone-co-4-maleate-ε-caprolactone) (P(CL-co-MCL)-folate) was prepared by a carbodiimide coupling reaction, i.e., the vitamin folic acid (FA) was covalently linked to the main chain of the maleate-functionalized polymer, poly(ε-caprolactone-co-4-maleate-ε-caprolactone) (P(CL-co-MCL)). Then the 5-Fluorouracil (5-FU) loaded nanoparticles of P(CL-co-MCL)-folate were achieved by solvent-evaporation method. Their properties were extensively studied by dynamic light scattering (DLS) and scan electron microscopy (SEM). DLS and SEM showed that the nanoparticles were in a well-defined spherical shape with a uniform size distribution. We also investigated the entrapment and in vitro release behavior, which indicated that the release speed of 5-FU could be well controlled and the release half-life period could reach 16.86h, which was 26.4 times longer than that of pure 5-FU. The in vitro targeting test displayed that the 5-FU loaded P(CL-co-MCL)-folate nanoparticles exhibited an enhanced cell inhibition because folate targeting increased the concentration of 5-FU loaded P(CL-co-MCL)-folate nanoparticles in the tumor cells with folate receptor overexpressed. Meanwhile, the tumor inhibition of 5-FU loaded P(CL-co-MCL)-folate nanoparticles was much higher than that of pure 5-FU and that of 5-FU loaded P(CL-co-MCL) nanoparticles. Therefore, P(CL-co-MCL)-folate nanoparticles would be highly beneficial for biomedical and pharmaceutical applications. PMID:21094493

  9. PX-12 inhibits the growth of hepatocelluar carcinoma by inducing S-phase arrest, ROS-dependent apoptosis and enhances 5-FU cytotoxicity

    PubMed Central

    Li, Guang-Zhen; Liang, Hui-Fang; Liao, Bo; Zhang, Lei; Ni, Ya-An; Zhou, Hong-Hao; Zhang, Er-Lei; Zhang, Bi-Xiang; Chen, Xiao-Ping

    2015-01-01

    Background: 1-methylpropyl 2-imidazolyl disulfide (PX-12), a thioredoxin 1 (Trx1) inhibitor, has been investigated in a number of ancers, but its effectiveness in the treatment of hepatocellular carcinoma (HCC) has not been reported. PX-12 has generated considerable interest in its use in a variety of solid tumors, yet most studies have confined their interests to using PX-12 as a single agent. The aim of this study is to investigate whether PX-12 inhibits cell growth and has a synergistic anti-tumor effect in combination with 5-fluorouracil (5-FU) in HCC. Methods: Cells were treated with different concentrations of PX-12 and 5-FU. Cell viability assays, colony formation assay, cell cycle assay, reactive oxygen species (ROS) assay, apoptosis analysis, western blot assay, immunohistochemistry and xenograft tumorigenicity assay were performed. Results: Treatment with PX-12 inhibited cell growth, induced S-phase arrest, and increased ROS levels. PX-12-induced apoptosis and inhibition of colony formation were associated with the generation of ROS, and inhibition of ROS attenuated PX-12-induced apoptosis and inhibition of colony formation. Treatment with PX-12 increased the expression of bax and reduced the expression of bcl-2, indicating that PX-12-mediated apoptosis is mitochondria-dependent. PX-12 also exerted a synergistic effect with 5-FU tosignificantly suppress tumorigenicity both in vitro and in vivo. Inhibition of ROS accumulation reduced the synergistic effect of PX-12 and 5-FU. Conclusions: PX-12 has anti-tumor activity and a synergistic effect in combination with 5-FU in HCC. Treatment with PX-12 alone or in combination with 5-FU may have clinical use in the treatment of HCC and other cancers. PMID:26550453

  10. Free radical derivatives formed from cyclooxygenase-catalyzed dihomo-γ-linolenic acid peroxidation can attenuate colon cancer cell growth and enhance 5-fluorouracil׳s cytotoxicity

    PubMed Central

    Xu, Yi; Qi, Jin; Yang, Xiaoyu; Wu, Erxi; Qian, Steven Y.

    2014-01-01

    Dihomo-γ-linolenic acid (DGLA) and its downstream fatty acid arachidonic acid (AA) are both nutritionally important ω–6 polyunsaturated fatty acids (ω–6s). Evidence shows that, via COX-mediated peroxidation, DGLA and its metabolites (1-series prostaglandins) are associated with anti-tumor activity, while AA and its metabolites (2-series prostaglandins) could be tightly implicated in various cancer diseases. However, it still remains a mystery why DGLA and AA possess contrasting bioactivities. Our previous studies showed that DGLA could go through an exclusive C-8 oxygenation pathway during COX-catalyzed lipid peroxidation in addition to a C-15 oxygenation pathway shared by both DGLA and AA, and that the exclusive C-8 oxygenation could lead to the production of distinct DGLA׳s free radical derivatives that may be correlated with DGLA׳s anti-proliferation activity. In the present work, we further investigate the anti-cancer effect of DGLA׳s free radical derivatives and their associated molecular mechanisms. Our study shows that the exclusive DGLA׳s free radical derivatives from C-8 oxygenation lead to cell growth inhibition, cell cycle arrest and apoptosis in the human colon cancer cell line HCA-7 colony 29, probably by up-regulating the cancer suppressor p53 and the cell cycle inhibitor p27. In addition, these exclusive radical derivatives were also able to enhance the efficacy of 5-Fluorouracil (5-FU), a widely used chemo-drug for colon cancer. For the first time, we show how DGLA׳s radical pathway and metabolites are associated with DGLA׳s anti-cancer activities and able to sensitize colon cancer cells to chemo-drugs such as 5-FU. Our findings could be used to guide future development of a combined chemotherapy and dietary care strategy for colon cancer treatment. PMID:25114837

  11. Cytotoxicity and antitumour activity of 5-fluorouracil-loaded polyhydroxybutyrate and cellulose acetate phthalate blend microspheres.

    PubMed

    Chaturvedi, Kiran; Tripathi, Santosh Kumar; Kulkarni, Anandrao R; Aminabhavi, Tejraj M

    2013-01-01

    Pharmacokinetics, biodistribution and antitumour activity of 5-fluorouracil (5-FU)-loaded polyhydroxybutyrate (PHB) and cellulose acetate phthalate (CAP) blend microspheres were investigated in chemically induced colorectal cancer in albino male Wistar rats and compared with pristine 5-FU given as a suspension. The microspheres were characterised for particle size, encapsulation efficiency, in vitro release and in vitro cytotoxicity on human HT-29 colon cancer cell line. Spherical particles with a mean size of 44 ± 11 µm were obtained that showed sustained release of 5-FU. A high concentration of 5-FU was achieved in colonic tissues and significant reduction in tumour volume and multiplicity were observed in animals treated with 5-FU-loaded microspheres. The decreased levels of plasma albumin, creatinine, leucocytopenia and thrombocytopenia were observed in animals for 5-FU microspheres compared to the standard 5-FU formulation. The results suggest the extended release of 5-FU from the PHB-CAP blend microspheres in colonic region to enhance the antitumour efficacy. PMID:23078151

  12. Analysis of chemotherapy drug 5-fluorouracil and its metabolites by surface-enhanced Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Gift, Alan D.; Shende, Chetan S.; Inscore, Frank E.; Farquharson, Stuart

    2004-12-01

    Chemotherapy drug dosage is based on the limited statistics of the response of previously treated patients and administered according to body surface area. Considerably better dose regulation could be performed if the drug metabolism of each patient could be monitored. Unfortunately, current technologies require multiple withdrawals of blood to determine metabolism, a precious fluid in limited supply. Saliva analysis has long been considered an attractive alternative, but unfortunately standard techniques require large quantities that are difficult to obtain. In an effort to overcome this limitation we have been investigating the ability of metal-doped sol-gels to both separate drugs and their metabolites from saliva and generate surface-enhanced Raman spectra. Surface-enhanced Raman spectroscopy has the potential to perform this analysis with just a few drops of sample due to its extreme sensitivity. Preliminary measurements are presented for the chemotherapy drug, 5-fluorouracil, and its two metabolites 5-fluorouridine and 5-fluoro-2'-deoxyuridine, and the potential of determining metabolism on a patient-by-patient basis.

  13. Distinct TRPV1- and TRPA1-based mechanisms underlying enhancement of oral ulcerative mucositis-induced pain by 5-fluorouracil.

    PubMed

    Yamaguchi, Kiichiro; Ono, Kentaro; Hitomi, Suzuro; Ito, Misa; Nodai, Tomotaka; Goto, Tetsuya; Harano, Nozomu; Watanabe, Seiji; Inoue, Hiromasa; Miyano, Kanako; Uezono, Yasuhito; Matoba, Motohiro; Inenaga, Kiyotoshi

    2016-05-01

    In many patients with cancer, chemotherapy-induced severe oral ulcerative mucositis causes intractable pain, leading to delays and interruptions in therapy. However, the pain mechanism in oral ulcerative mucositis after chemotherapy has not been extensively studied. In this study, we investigated spontaneous pain and mechanical allodynia in a preclinical model of oral ulcerative mucositis after systemic administration of the chemotherapy drug 5-fluorouracil, using our proprietary pain assay system for conscious rats. 5-Fluorouracil caused leukopenia but did not induce pain-related behaviors. After 5-fluorouracil administration, oral ulcers were developed with topical acetic acid treatment. Compared with saline-treated rats, 5-fluorouracil-exposed rats showed more severe mucositis with excessive bacterial loading due to a lack of leukocyte infiltration, as well as enhancements of spontaneous pain and mechanical allodynia. Antibacterial drugs, the lipid A inhibitor polymyxin B and the TRPV1/TRPA1 channel pore-passing anesthetic QX-314, suppressed both the spontaneous pain and the mechanical allodynia. The cyclooxygenase inhibitor indomethacin and the TRPV1 antagonist SB-366791 inhibited the spontaneous pain, but not the mechanical allodynia. In contrast, the TRPA1 antagonist HC-030031 and the N-formylmethionine receptor FPR1 antagonist Boc MLF primarily suppressed the mechanical allodynia. These results suggest that 5-fluorouracil-associated leukopenia allows excessive oral bacterial infection in the oral ulcerative region, resulting in the enhancement of spontaneous pain through continuous TRPV1 activation and cyclooxygenase pathway, and mechanical allodynia through mechanical sensitization of TRPA1 caused by neuronal effects of bacterial toxins. These distinct pain mechanisms explain the difficulties encountered with general treatments for oral ulcerative mucositis-induced pain in patients with cancer and suggest more effective approaches. PMID:26808144

  14. Synergistic enhancement of 5-fluorouracil cytotoxicity by deoxyuridine analogs in cancer cells

    PubMed Central

    Matsumoto, Yoshihiro; Rodriguez, Victoria; Whitford, Tracy A.; Beeharry, Neil; Ide, Hiroshi; Tomkinson, Alan E.

    2015-01-01

    5-Fluorouracil (FU) is a halogenated nucleobase analog that is widely used in chemotherapy. Here we show that 5-hydroxymethyl-2′-deoxyuridine (hmUdR) synergistically enhances the activity of FU in cell lines derived from solid tumors but not normal tissues. While the cytotoxicity of FU and hmUdR was not directly related to the amount of the modified bases incorporated into cellular DNA, incubation with this combination resulted in dramatic increase in the number of single strand breaks in replicating cancer cells, leading to NAD-depletion as consequence of poly(ADP-ribose) synthesis and S phase arrest. Cell death resulting from the base/nucleoside combination did not occur by apoptosis, autophagy or necroptosis. Instead, the cells die via necrosis as a result of NAD depletion. The FU-related nucleoside analog, 5-fluoro-2′-deoxyuridine, also displayed synergy with hmUdR, whereas hmUdR could not be replaced by 5-hydroxymethyluracil. Among other 5-modified deoxyuridine analogs tested, 5-formyl-2′-deoxyuridine and, to a lesser extent, 5-hydroxy-2′-deoxyuridine, also acted synergistically with FU, whereas 5-hydroxyethyl-2′-deoxyuridine did not. Together, our results have revealed an unexpected synergistic interaction between deoxyuridine analogs and FU in a cancer cell-specific manner, and suggest that these novel base/nucleoside combinations could be developed into improved FU-based chemotherapies. PMID:25897430

  15. Acute hyperammonemic encephalopathy after 5-fluorouracil based chemotherapy

    PubMed Central

    Yi, Hee Jung; Hong, Kyung Sook; Moon, Nara; Chung, Soon Sup; Lee, Ryung-Ah

    2016-01-01

    5-Fluorouracil (5-FU) based chemotherapy has been commonly used to treat metastatic or advanced colon cancer as an adjuvant chemotherapy. Although the side effects of 5-FU such as gastrointestinal problems and neutropenia and thrombocytopenia are common, not many cases of 5-FU related encephalopathy are reported. Hyperammonemic encephalopathy is a rare central nervous system toxicity following 5-FU chemotherapy manifesting as altered mental status with elevated ammonia levels with no radiologic abnormality. We report one case of 5-FU induced hyperammonemic encephalopathy occurring after Folfox4 (oxaliplatin, folinic acid and 5-fluorouracil) chemotherapy in a colon cancer patient who presented with confused mental status soon after the chemotherapy and review the 5-FU related encephalopathy. PMID:26942162

  16. Acute hyperammonemic encephalopathy after 5-fluorouracil based chemotherapy.

    PubMed

    Yi, Hee Jung; Hong, Kyung Sook; Moon, Nara; Chung, Soon Sup; Lee, Ryung-Ah; Kim, Kwang Ho

    2016-03-01

    5-Fluorouracil (5-FU) based chemotherapy has been commonly used to treat metastatic or advanced colon cancer as an adjuvant chemotherapy. Although the side effects of 5-FU such as gastrointestinal problems and neutropenia and thrombocytopenia are common, not many cases of 5-FU related encephalopathy are reported. Hyperammonemic encephalopathy is a rare central nervous system toxicity following 5-FU chemotherapy manifesting as altered mental status with elevated ammonia levels with no radiologic abnormality. We report one case of 5-FU induced hyperammonemic encephalopathy occurring after Folfox4 (oxaliplatin, folinic acid and 5-fluorouracil) chemotherapy in a colon cancer patient who presented with confused mental status soon after the chemotherapy and review the 5-FU related encephalopathy. PMID:26942162

  17. A Case of Neurotoxicity Following 5-Fluorouracil-based Chemotherapy

    PubMed Central

    Ki, Seung Seog; Jeong, Jin Mo; Kim, Seong Ho; Jeong, Sook Hyang; Lee, Jin Hyuk; Han, Chul Ju; Kim, You Cheol; Lee, Jhin Oh; Hong, Young Joon

    2002-01-01

    5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent. However, its neurotoxicity is rare and not well recognized. We report a case of 5-FU neurotoxicity with organic brain syndrome and progression to multifocal leukoencephalopathy in a 44-year-old male patient having malignant gastrointestinal stromal tumor. 5-FU-induced neurotoxicity should, therefore, be considered as an important differential diagnosis in cancer patients with neurological abnormality and history of chemotherapy. PMID:12014219

  18. Degradation of cyclophosphamide and 5-fluorouracil by UV and simulated sunlight treatments: Assessment of the enhancement of the biodegradability and toxicity.

    PubMed

    Lutterbeck, Carlos Alexandre; Wilde, Marcelo Luís; Baginska, Ewelina; Leder, Christoph; Machado, Ênio Leandro; Kümmerer, Klaus

    2016-01-01

    The presence of pharmaceuticals in the environment has triggered concern among the general population and received considerable attention from the scientific community in recent years. However, only a few publications have focused on anticancer drugs, a class of pharmaceuticals that can exhibit cytotoxic, genotoxic, mutagenic, carcinogenic and teratogenic effects. The present study investigated the photodegradation, biodegradation, bacterial toxicity, mutagenicity and genotoxicity of cyclophosphamide (CP) and 5-fluorouracil (5-FU). The photodegradation experiments were performed at a neutral to slight pH range (7-7.8) using two different lamps (medium-pressure mercury lamp and a xenon lamp). The primary elimination of the parent compounds was monitored by means of liquid chromatography tandem mass spectrometry (LC-IT-MS/MS). NPOC (non-purgeable organic carbon) analyses were carried out in order to assess mineralization rates. The Closed Bottle Test (CBT) was used to assess ready biodegradability. A new method using Vibrio fischeri was adopted to evaluate toxicity. CP was not degraded by any lamp, whereas 5-FU was completely eliminated by irradiation with the mercury lamp but only partially by the Xe lamp. No mineralization was observed for the experiments performed with the Xe lamp, and a NPOC removal of only 18% was registered for 5-FU after 256 min using the UV lamp. Not one of the parent compounds was readily biodegradable in the CBT. Photo transformation products (PTPs) resulting from photolysis were neither better biodegradable nor less toxic than the parent compound 5-FU. In contrast, the results of the tests carried out with the UV lamp indicated that more biodegradable and non-toxic PTPs of 5-FU were generated. Three PTPs were formed during the photodegradation experiments and were identified. The results of the in silico QSAR predictions showed positive mutagenic and genotoxic alerts for 5-FU, whereas only one of the formed PTPs presented positive alerts

  19. EFFECTS OF 5-FLUOROURACIL ON EMBRYONIC RAT PALATE IN VITRO: FUSION IN THE ABSENCE OF PROLIFERATION

    EPA Science Inventory

    5-Fluorouracil (5-FU) inhibits the enzyme thymidylate synthetase (TS) which results in inhibition of DNA synthesis. 5-FU is teratogenic in many species, inducing cleft palate, limb, and tail defects. n the present study, GD 14 embryonic rat palates were exposed to 5-FU in organ c...

  20. Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity.

    PubMed Central

    Köhne, C. H.; Thuss-Patience, P.; Friedrich, M.; Daniel, P. T.; Kretzschmar, A.; Benter, T.; Bauer, B.; Dietz, R.; Dörken, B.

    1998-01-01

    Two patients with proven 5-fluorouracil (5-FU)-associated cardiotoxicity were treated with the specific thymidylate synthase inhibitor raltitrexed safely, without evidence of cardiotoxicity. Raltitrexed might be an alternative for patients with advanced colorectal cancer and 5-FU-associated cardiotoxicity. 5-FU cardiotoxicity is not due to the antineoplastic mechanisms via thymidilate synthase. Images Figure 3 Figure 4 PMID:9528843

  1. Intermediate dose 5-fluorouracil-induced encephalopathy.

    PubMed

    Kim, Yeon-A; Chung, Hyun Cheol; Choi, Hye Jin; Rha, Sun Young; Seong, Jin Sil; Jeung, Hei-Cheul

    2006-01-01

    As an acute neurotoxicity, high dose 5-fluorouracil (5-FU)-induced encephalopathy is well-known, but encephalopathy associated with lower dose is rarely reported. Here, we report a case of a male with anal cancer who was treated with 5-FU 1000 mg/m(2), continuous infusion for 5 days q4 weeks. At the second and the fourth cycles of chemotherapy, sudden confusion, cognitive dysfunction and disorientation occurred during 5-FU infusion. They were accompanied by hyperammonemia in the absence of focal neurological deficits or structural abnormalities. These symptoms completely disappeared and the serum ammonia level returned to normal after discontinuation of 5-FU and conservative care. In order to investigate a possible deficit of dihydropyrimidine dehydrogenase (DPD), we checked its mRNA level before and after treatment using real-time PCR. The patient's pre-treatment level was 80% compared with reference group, and it was elevated up to 187% of initial after 5-FU treatment, implying that that his encephalopathy may be 5-FU catabolite type rather than DPD deficiency. In conclusion, we report that encephalopathy can develop even with the dose of 5-FU lower than ever reported, and it should be considered as a differential diagnosis for proper management. PMID:16436463

  2. Dynamics of uracil and 5-fluorouracil in DNA.

    PubMed

    Parker, Jared B; Stivers, James T

    2011-02-01

    The prodrug 5-fluorouracil (5-FU), after activation into 5-F-dUMP, is an extensively used anticancer agent that inhibits thymidylate synthase and leads to increases in dUTP and 5-F-dUTP levels in cells. One mechanism for 5-FU action involves DNA polymerase mediated incorporation of dUTP and 5-F-dUTP into genomic DNA leading to U/A, 5-FU/A, or 5-FU/G base pairs. These uracil-containing lesions are recognized and excised by several human uracil excision repair glycosylases (hUNG2, hSMUG2, and hTDG) leading to toxic abasic sites in DNA that may precipitate cell death. Each of these enzymes uses an extrahelical base recognition mechanism, and previous studies with UNG have shown that extrahelical recognition is facilitated by destabilized base pairs possessing kinetically enhanced base pair opening rates. Thus, the dynamic properties of base pairs containing 5-FU and U are an important unknown in understanding the role of these enzymes in damage recognition and prodrug activation. The pH dependence of the (19)F NMR chemical shift of 5-FU imbedded in a model trinucleotide was used to obtain a pK(a) = 8.1 for its imino proton (10 °C). This is about 1.5 units lower than the imino protons of uracil or thymine and indicates that at neutral pH 5-FU exists significantly as an ionized tautomer that can mispair with guanine during DNA replication. NMR imino proton exchange measurements show that U/A and 5-FU/A base pairs open with rate constants (k(op)) that are 6- and 13-fold faster than a T/A base pair in the same sequence context. In contrast, these same base pairs have apparent opening equilibrium constants (αK(op)) that differ by less than a factor of 2, indicating that the closing rates (k(cl)) are enhanced by nearly equal amounts as k(op). These dynamic measurements are consistent with the previously proposed kinetic trapping model for extrahelical recognition by UNG. In this model, the enhanced intrinsic opening rates of destabilized base pairs allow the bound

  3. Phase II trial of cyclophosphamide, leucovorin, 5-fluorouracil 24-hour infusion and tamoxifen in pancreatic cancer.

    PubMed

    Eckel, F; Lersch, C; Lippl, F; Assmann, G; Schulte-Frohlinde, E

    2000-09-01

    Leucovorin modulates the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. 24-hour infusion of 5-FU has been shown to enhance antitumor activity in colorectal cancer compared to bolus infusion. According to experimental data cyclophosphamide and tamoxifen may enhance the effectiveness of leucovorin and 5-FU. A phase II trial was initiated to evaluate the effect of a combination of low-dose cyclophosphamide (C), leucovorin (L), 5-FU (F) and tamoxifen (T) (CLFT) in advanced pancreatic cancer. Fifty patients were treated monthly with 300 mg/m2 cyclophosphamide and weekly with 500 mg/m2 leucovorin followed by a 24-hour infusion of 2000 mg/m2 5-FU and tamoxifen 20 mg bid. Three patients had a partial response (6%), two a minor response (4%) and 32 (64%) no change of disease. The median survival time was 8.5 months for all patients, the median time to progression of disease was 4.6 months and the 1-year survival rate was 28%. CLFT was fairly well tolerated. These data suggest that biochemical modulation of 24-hour infusional 5-FU with leucovorin together with cyclophosphamide and tamoxifen has some positive effects in the treatment of pancreatic cancer. PMID:11144522

  4. The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

    PubMed Central

    Naguib, Youssef W.; Kumar, Amit; Cui, Zhengrong

    2014-01-01

    Topical 5-fluorouracil (5-FU) is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter). In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5%) was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy. PMID:25313350

  5. Factors derived from Escherichia coli Nissle 1917, grown in different growth media, enhance cell death in a model of 5-fluorouracil-induced Caco-2 intestinal epithelial cell damage.

    PubMed

    Wang, Hanru; Bastian, Susan E P; Lawrence, Andrew; Howarth, Gordon S

    2015-01-01

    We evaluated supernatants (SNs) from Escherichia coli Nissle 1917 (EcN) grown in commonly used growth media for their capacity to affect the viability of Caco-2 colon cancer cells in the presence and absence of 5-Fluorouracil (5-FU) chemotherapy. EcN was grown in Luria-Bertani (LB), tryptone soya (TSB), Man Rogosa Sharpe (MRS), and M17 broth supplemented with 10% (v/v) lactose solution (M17). Human Caco-2 colon cancer cells were treated with DMEM (control), growth media alone (LB, TSB, MRS, and M17) or EcN SNs derived from these 4 media, in the presence and absence of 5-FU. Cell viability, reactive oxygen species (ROS), and cell monolayer permeability were determined. EcN SN in LB medium reduced Caco-2 cell viability significantly, to 51% at 48 h. The combination of this EcN SN and 5-FU further reduced cell viability to 37% at 48 h, compared to 5-FU control. MRS broth and EcN SN in MRS, together with 5-FU, generated significantly lower levels of ROS compared to 5-FU control. However, all 5-FU treatments significantly disrupted the Caco-2 cell barrier compared to control; with no significant differences observed among any of the 5-FU treatments. EcN SNs (LB+) was most effective at decreasing the viability of Caco-2 cells. This could indicate a potential role for this EcN SN in chemoprevention for colon cancer. PMID:25625670

  6. B7-H3 upregulates BRCC3 expression, antagonizing DNA damage caused by 5-Fu.

    PubMed

    Sun, Zhang Zhang; Zhang, Ting; Ning, Kuan; Zhu, Ruan; Liu, Fen; Tang, Shou-Ching; Jiang, Bo; Hua, Dong

    2016-07-01

    5-fluorouracil (5-Fu) is still recognized as the mainstay in colorectal cancer chemotherapy, but the response rate of 5-Fu in colorectal cancer is less than 50%. Our previous mRNA microarray data revealed that BRCC3, a component of the BRCA1-BRCA2-BRCC3 DNA repair complex, had a direct relationship with B7-H3, an immunoglobulin that is upregulated in tumor tissue and associated with metastasis and poor prognosis. Real-time PCR and western blot analysis confirmed that the expression of both BRCC3 mRNA and protein, respectively, were elevated following B7-H3 overexpression in SW480 cells; likewise, BRCC3 expression decreased after B7-H3 was knocked down in HCT-8 cells. DNA comet assay results indicate an inverse correlation between the extent of 5-Fu-induced DNA damage and the expression level of B7-H3 in both SW480- and HCT-8-based cell lines. In SW480 cells that overexpress B7-H3, knockdown of BRCC3 similarly permitted greater 5-Fu-induced DNA damage. Altogether, results suggest that BRCC3 may play a role in B7-H3-induced 5-Fu resistance, such that B7-H3 upregulates BRCC3 expression, enhancing DNA repair in colorectal cancer cells. PMID:27175567

  7. Allicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathway.

    PubMed

    Zou, Xuejing; Liang, Jiyun; Sun, Jingyuan; Hu, Xiaoyun; Lei, Ling; Wu, Dehua; Liu, Li

    2016-08-01

    Drug resistance and hepatic dysfunction are the two major factors that limit the application of chemotherapy for hepatocellular carcinoma (HCC). It has been reported that allicin has the hepatic protective effect and antitumor activity. Hence allicin may be an ideal enhancer to chemotherapy regimen of HCC. In the present study, we demonstrated that allicin enhanced 5-fluorouracil (5-FU) inducing cytotoxicity in HCC cells. In vivo experiment, combined treatment group with allicin (5 mg/kg/d; every two days for 3 weeks) and 5-FU (20 mg/kg/d; 5 consecutive days) showed a dramatic inhibitory effect on the growth of HCC xenograft tumors in nude mice. The co-treatment group showed highly apoptotic level compared with 5-FU treated alone. Cells combined treatment with allicin and 5-FU increased intracellular reactive oxygen species (ROS) level, reduced mitochondrial membrane potential (ΔΨm), activated caspase-3 and PARP, and down-regulated Bcl-2 compared with DMSO, allicin and 5-FU treated alone. Moreover, the increase of activated caspase-3 and PARP was blocked by the ROS inhibitor antioxidant N-acetyl cysteine (NAC). In conclusion, this is the first study to demonstrate that allicin sensitized HCC cells to 5-FU induced apoptosis through ROS-mediated mitochondrial pathway. These results provided evidences for the combination used of allicin and 5-FU as a novel chemotherapy regimen in HCC. PMID:27177453

  8. Self-assembly of a 5-fluorouracil-dipeptide hydrogel.

    PubMed

    Sun, Yuan; Kaplan, Jonah A; Shieh, Aileen; Sun, Hui-Lung; Croce, Carlo M; Grinstaff, Mark W; Parquette, Jon R

    2016-04-18

    The self-assembly of 5-fluorouracil dilysine conjugates into self-supporting hydrogels, comprised of entangled nanofibers or rigid nanotubes with diameters of 10 and 16 nm, respectively, is reported. The rate of release of 5-Fu from the conjugates was highly dependent on concentration in solution, whereas, release from the fully formed hydrogels was significantly slower. The 5-Fu conjugate also exhibited promising in vitro cytotoxicity against human tumor cell lines A549, H460 and H23. PMID:26996124

  9. Phase I and pharmacologic study of 72-hour infused 5-fluorouracil and hyperfractionated cyclical radiation

    SciTech Connect

    Byfield, J.E.; Frankel, S.S.; Sharp, T.R.; Hornbeck, C.L.; Callipari, F.B.

    1985-04-01

    The authors have studied 21 patients infused for 72 hours with 5- Fluorouracil (5-FU) at progressive doses combined with hyperfractionated radiation. The schedule was chosen as being one capable of inducing 5-FU radiosensitization (RS). All patients were started at a daily 5-FU dose of 40 mg/kg/24 hours; doses were then escalated with each subsequent treatment cycle to limiting toxicity or until taken off study. Patients received between one and six infusion cycles. Every treatment cycle included coincident hyperfractionated radiation to various body areas including the abdomen, chest, and head and neck region. Radiation fractionation was invariant; 1,000 rad were delivered in four equal fractions. Two fractions of 250 rad each were given on days 1 and 2 of each three day 5-FU cycle, i.e. at approximately 0, 8, 24, and 32 hours into the drug infusion. Patients were followed for toxicity; serum 5-FU concentrations were determined using a high pressure liquid chromatographic assay. 5-FU clearances were calculated from the mean serum drug levels and the infused drug dose. The toxicity spectrum was not found to be significantly different from infused drug alone in this dose range except when the head and neck region received coincident irradiation. In that region the two anticipated toxicities combined in what appears to be a synergistic fashion to enhance mucositis. Most toxicities including gastrointestinal and bone marrow appeared dependent on the mean serum 5-FU level as did mucositis itself. 5-FU clearance was found to be non-linear in this dose region but did not appear influenced by radiation to any part of the body.

  10. A Case of 5-Fluorouracil Induced Encephalopathy

    PubMed Central

    Kwon, Kyung A; Kwon, Hyuk-Chan; Kim, Min Chan; Kim, Sung-Hyun; Oh, Sung Yong; Lee, Suee

    2010-01-01

    Patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at risk for experiencing serious adverse effects following 5-fluorouracil (5-FU) based chemotherapy. Neurotoxicity is considered an extremely rare side effect of 5-FU. We report here on an unusual case of 5-FU induced encephalopathy. A 38-year-old woman with advanced gastric carcinoma was treated with adjuvant chemotherapy that consisted of infused 5-FU (1,000 mg/m2) for 5 days and cisplatin (60 mg/m2) on day 1 following total gastrectomy. Nineteen days after starting chemotherapy, the patient displayed a sudden onset of slurred speech, confusion, cognitive disturbances and paranoia. A magnetic resonance image (MRI) of the brain showed no structural abnormalities, and the other laboratory tests provided no explanations for her symptoms, other than a slightly elevated ammonia level. The patient was treated with a lactulose retention enema and thiamine infusion, the 5-FU was halted and her symptoms then recovered after 7 days. PMID:20622967

  11. 5-Fluorouracil modulation of radiosensitivity in cultured human carcinoma cells.

    PubMed

    Smalley, S R; Kimler, B F; Evans, R G

    1991-02-01

    We evaluated conventional pulse exposure versus continuous exposure models of 5-fluorouracil (5-FU) radiosensitization in HT-29 (human colon adenocarcinoma) and DU-145 (human prostate cancer adenocarcinoma) cell lines. Cell survival following treatment with drug and/or radiation was determined by colony formation assays. Radiation was delivered either by itself, approximately midway through a 1-hr exposure to 5-FU (10 micrograms/ml), or at various times following initiation of exposure to 5-FU (0.5 microgram/ml) present throughout the entire period of incubation. Drug concentrations were selected to approximate those achieved in vivo in humans. HT-29 cells showed a plating efficiency of 87% and similar cytotoxicity (survival reduced to 0.57-0.71) for all 5-FU conditions. The Do's of the radiation survival curves were not different for 1 hr of 5-FU exposure versus radiation alone. However, continuous exposure conditions demonstrated statistically significantly different Do's from radiation alone and pulse 5-FU exposure. DU-145 cells displayed a plating efficiency of 17% and cytotoxicities of 0.10-0.91 for the 5-FU conditions. DU-145 cells showed different radiation 5-FU interactions: 5-FU produced statistically significant changes in Do well as the differences between cell lines insofar as their radiosensitization by 5-FU underscore the caution required in extrapolating these radiobiologic models to the clinical setting. PMID:1991680

  12. Chromosome segregation and organization are targets of 5'-Fluorouracil in eukaryotic cells.

    PubMed

    Mojardín, Laura; Botet, Javier; Moreno, Sergio; Salas, Margarita

    2015-01-01

    The antimetabolite 5'-Fluorouracil (5FU) is an analog of uracil commonly employed as a chemotherapeutic agent in the treatment of a range of cancers including colorectal tumors. To assess the cellular effects of 5FU, we performed a genome-wide screening of the haploid deletion library of the eukaryotic model Schizosaccharomyces pombe. Our analysis validated previously characterized drug targets including RNA metabolism, but it also revealed unexpected mechanisms of action associated with chromosome segregation and organization (post-translational histone modification, histone exchange, heterochromatin). Further analysis showed that 5FU affects the heterochromatin structure (decreased levels of histone H3 lysine 9 methylation) and silencing (down-regulation of heterochromatic dg/dh transcripts). To our knowledge, this is the first time that defects in heterochromatin have been correlated with increased cytotoxicity to an anticancer drug. Moreover, the segregation of chromosomes, a process that requires an intact heterochromatin at centromeres, was impaired after drug exposure. These defects could be related to the induction of genes involved in chromatid cohesion and kinetochore assembly. Interestingly, we also observed that thiabendazole, a microtubule-destabilizing agent, synergistically enhanced the cytotoxic effects of 5FU. These findings point to new targets and drug combinations that could potentiate the effectiveness of 5FU-based treatments. PMID:25483073

  13. 5-Fluorouracil sensitizes colorectal tumor cells towards double stranded DNA breaks by interfering with homologous recombination repair

    PubMed Central

    Srinivas, Upadhyayula Sai; Dyczkowski, Jerzy; Beißbarth, Tim; Gaedcke, Jochen; Mansour, Wael Y.; Borgmann, Kerstin; Dobbelstein, Matthias

    2015-01-01

    Malignant tumors of the rectum are treated by neoadjuvant radiochemotherapy. This involves a combination of 5-fluorouracil (5-FU) and double stranded DNA-break (DSB)-inducing radiotherapy. Here we explored how 5-FU cooperates with DSB-induction to achieve sustainable DNA damage in colorectal cancer (CRC) cells. After DSB induction by neocarzinostatin, phosphorylated histone 2AX (γ-H2AX) rapidly accumulated but then largely vanished within a few hours. In contrast, when CRC cells were pre-treated with 5-FU, gammaH2AX remained for at least 24 hours. GFP-reporter assays revealed that 5-FU decreases the efficiency of homologous recombination (HR) repair. However, 5-FU did not prevent the initial steps of HR repair, such as the accumulation of RPA and Rad51 at nuclear foci. Thus, we propose that 5-FU interferes with the continuation of HR repair, e. g. the synthesis of new DNA strands. Two key mediators of HR, Rad51 and BRCA2, were found upregulated in CRC biopsies as compared to normal mucosa. Inhibition of HR by targeting Rad51 enhanced DNA damage upon DSB-inducing treatment, outlining an alternative way of enhancing therapeutic efficacy. Taken together, our results strongly suggest that interfering with HR represents a key mechanism to enhance the efficacy when treating CRC with DNA-damaging therapy. PMID:25909291

  14. Application of artificial neural network to investigate the effects of 5-fluorouracil on ribonucleotides and deoxyribonucleotides in HepG2 cells.

    PubMed

    Guo, Jianru; Chen, QianQian; Lam, Christopher Wai Kei; Wang, Caiyun; Wong, Vincent Kam Wai; Xu, Fengguo; Jiang, ZhiHong; Zhang, Wei

    2015-01-01

    Endogenous ribonucleotides and deoxyribonucleotides are essential metabolites that play important roles in a broad range of key cellular functions. Their intracellular levels could also reflect the action of nucleoside analogues. We investigated the effects of 5-fluorouracil (5-FU) on ribonucleotide and deoxyribonucleotide pool sizes in cells upon exposure to 5-FU for different durations. Unsupervised and supervised artificial neural networks were compared for comprehensive analysis of global responses to 5-FU. As expected, deoxyuridine monophosphate (dUMP) increased after 5-FU incubation due to the inhibition of thymine monophosphate (TMP) synthesis. Interestingly, the accumulation of dUMP could not lead to increased levels of deoxyuridine triphosphate (dUTP) and deoxyuridine diphosphate (dUDP). After the initial fall in intracellular deoxythymidine triphosphate (TTP) concentration, its level recovered and increased from 48 h exposure to 5-FU, although deoxythymidine diphosphate (TDP) and TMP continued to decrease compared with the control group. These findings suggest 5-FU treatment caused unexpected changes in intracellular purine polls, such as increases in deoxyadenosine triphosphate (dATP), adenosine-triphosphate (ATP), guanosine triphosphate (GTP) pools. Further elucidation of the mechanism of action of 5-FU in causing these changes should enhance development of strategies that will increase the anticancer activity of 5-FU while decreasing its resistance. PMID:26578061

  15. Application of artificial neural network to investigate the effects of 5-fluorouracil on ribonucleotides and deoxyribonucleotides in HepG2 cells

    PubMed Central

    Guo, Jianru; Chen, QianQian; Lam, Christopher Wai Kei; Wang, Caiyun; Wong, Vincent Kam Wai; Xu, Fengguo; Jiang, ZhiHong; Zhang, Wei

    2015-01-01

    Endogenous ribonucleotides and deoxyribonucleotides are essential metabolites that play important roles in a broad range of key cellular functions. Their intracellular levels could also reflect the action of nucleoside analogues. We investigated the effects of 5-fluorouracil (5-FU) on ribonucleotide and deoxyribonucleotide pool sizes in cells upon exposure to 5-FU for different durations. Unsupervised and supervised artificial neural networks were compared for comprehensive analysis of global responses to 5-FU. As expected, deoxyuridine monophosphate (dUMP) increased after 5-FU incubation due to the inhibition of thymine monophosphate (TMP) synthesis. Interestingly, the accumulation of dUMP could not lead to increased levels of deoxyuridine triphosphate (dUTP) and deoxyuridine diphosphate (dUDP). After the initial fall in intracellular deoxythymidine triphosphate (TTP) concentration, its level recovered and increased from 48 h exposure to 5-FU, although deoxythymidine diphosphate (TDP) and TMP continued to decrease compared with the control group. These findings suggest 5-FU treatment caused unexpected changes in intracellular purine polls, such as increases in deoxyadenosine triphosphate (dATP), adenosine-triphosphate (ATP), guanosine triphosphate (GTP) pools. Further elucidation of the mechanism of action of 5-FU in causing these changes should enhance development of strategies that will increase the anticancer activity of 5-FU while decreasing its resistance. PMID:26578061

  16. Role of peptide YY in 5-fluorouracil-induced reduction of dietary intake.

    PubMed

    Sakai, Hiroyasu; Kai, Yuki; Takase, Kazuhide; Sato, Ken; Kimura, Minami; Tabata, Shoko; Yaegashi, Miyabi; Sato, Fumiaki; Yomoto, Tetsuro; Narita, Minoru

    2016-08-01

    5-fluorouracil (5-FU) is part of the standard care for cancer treatment but is associated with high incidences of appetite loss and reduced food intake, which may contribute to chemotherapy-induced cachexia (weakness and wasting of tissue). The role of gastrointestinal satiety hormones in chemotherapy-induced appetite loss has not been intensively investigated. Peptide YY (PYY) and glucagon-like peptide (GLP)-1 are important signals of gastrointestinal satiety, so this study examined the roles of these gut hormones in 5-FU-induced reduction of dietary intake. Mice were given 5-FU (50 mg/kg, intraperitoneal [i.p.]) every day for 4 consecutive days. Gene expression levels of proglucagon (Pro-Gcg), a precursor of GLP-1, and PYY in the colon were examined by real-time RT-PCR. Serum levels of GLP-1 and PYY were measured by enzyme-linked immunosorbent assay. Some mice were pretreated with the GLP-1 receptor antagonist exendin9-39 (1 mg/kg) or the neuropeptide Y type 2 (NPY2) receptor antagonist BIIE0246 (2 mg/kg) via the i.p. route 30 minutes before 5-FU administration. Mice receiving 5-FU exhibited a significant reduction in food intake that was correlated with body weight loss. These mice also showed significantly enhanced expression levels of mRNAs encoding pro-GLP-1 and PYY in the transverse and distal colon as well as elevated serum concentrations of GLP-1 and PYY compared to vehicle-treated controls. The 5-FU-induced reduction in food intake was attenuated by BIIE0246 but not by exendin9-39. These data suggest that administration of a NPY2 receptor antagonist may be effective for attenuating the anorexia caused by 5-FU chemotherapy. PMID:27130783

  17. Development of novel ionic liquid-based microemulsion formulation for dermal delivery of 5-Fluorouracil.

    PubMed

    Goindi, Shishu; Arora, Prabhleen; Kumar, Neeraj; Puri, Ashana

    2014-08-01

    The present study was aimed at synthesizing an imidazole-based ionic liquid 1-butyl-3-methylimidazolium bromide (BMIMBr) and subsequent development of a novel ionic liquid-in-oil (IL/o) microemulsion (ME) system for dermal delivery of a poorly permeating drug 5-fluorouracil (5-FU). A significant enhancement in the solubility of 5-FU was observed in BMIMBr. IL/o MEs of 5-FU were prepared using isopropyl myristate, Tween 80/Span 20, and BMIMBr. Results of ex vivo skin permeation studies through mice skin indicated that the selected IL/o ME exhibited 4-fold enhancement in percent drug permeation as compared to aqueous solution, 2.3-fold as compared to hydrophilic ointment, and 1.6-fold greater permeation than water in oil (w/o) ME. The results of in vivo studies against dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice skin carcinogenesis demonstrated that the IL/o ME could effectively treat skin cancer in 4 weeks. In addition, the side effects such as erythema and irritation associated with the conventional formulations were not observed. Histopathological studies showed that the use of IL/o ME caused no anatomic and pathological changes in the skin structure of mice. These studies suggest that the use of IL-based ME system can efficiently enhance the solubility and permeability of 5-FU and hence its therapeutic efficacy. PMID:24668136

  18. SNAI2 modulates colorectal cancer 5-fluorouracil sensitivity through miR145 repression.

    PubMed

    Findlay, Victoria J; Wang, Cindy; Nogueira, Lourdes M; Hurst, Katie; Quirk, Daniel; Ethier, Stephen P; Staveley O'Carroll, Kevin F; Watson, Dennis K; Camp, E Ramsay

    2014-11-01

    Epithelial-to-mesenchymal transition (EMT) has been associated with poor treatment outcomes in various malignancies and is inversely associated with miRNA145 expression. Therefore, we hypothesized that SNAI2 (Slug) may mediate 5-fluorouracil (5FU) chemotherapy resistance through inhibition of miR145 in colorectal cancer and thus represents a novel therapeutic target to enhance current colorectal cancer treatment strategies. Compared with parental DLD1 colon cancer cells, 5FU-resistant (5FUr) DLD1 cells demonstrated features of EMT, including >2-fold enhanced invasion (P < 0.001) and migration, suppressed E-cadherin expression, and 2-fold increased SNAI2 expression. DLD1 and HCT116 cells with stable expression of SNAI2 (DLD1/SNAI2; HCT116/SNAI2) also demonstrated EMT features such as the decreased E-cadherin as well as significantly decreased miR145 expression, as compared with control empty vector cells. On the basis of an miR145 luciferase promoter assay, we demonstrated that SNAI2 repressed activity of the miR145 promoter in the DLD1 and HCT116 cells. In addition, the ectopic expressing SNAI2 cell lines demonstrated decreased 5FU sensitivity, and, conversely, miR145 replacement significantly enhanced 5FU sensitivity. In the parental SW620 colon cancer cell line with high SNAI2 and low miR145 levels, inhibition of SNAI2 directly with short hairpin sequence for SNAI2 and miR145 replacement therapy both decreased vimentin expression and increased in vitro 5FU sensitivity. In pretreatment rectal cancer patient biopsy samples, low miR145 expression levels correlated with poor response to neoadjuvant 5FU-based chemoradiation. These results suggested that the SNAI2:miR145 pathway may represent a novel clinical therapeutic target in colorectal cancer and may serve as a response predictor to chemoradiation therapy. PMID:25249558

  19. 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits

    PubMed Central

    Calvani, Maura; Taddei, Maria Letizia; Giannoni, Elisa; Kopetz, Scott; Kazmi, Syed Mohammad Ali; Pia, Morelli Maria; Pettazzoni, Piergiorgio; Sacco, Elena; Caselli, Anna; Vanoni, Marco; Landriscina, Matteo; Cirri, Paolo; Chiarugi, Paola

    2015-01-01

    Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer. PMID:26527315

  20. Autophagy in human skin squamous cell carcinoma: Inhibition by 3-MA enhances the effect of 5-FU-induced chemotherapy sensitivity.

    PubMed

    Zhang, Lili; Zhang, Jie; Chen, Li; Wang, Jianli

    2015-12-01

    Autophagy is an intracellular multi-step catabolic degradation process that involves the degradation and recycling of cellular proteins and cytoplasmic damaged organelles to maintain cellular homeostasis and reduction of metabolic stress. Numerous studies have indicated the importance of autophagy in cancer, but the role of autophagy in human skin squamous cell carcinoma (SSCC) development and response to therapy it is still unclear. In the present study, we investigated the role of autophagy in SSCC and the relationship with chemotherapy sensitivity. The present study demonstrated that autophagy related gene the microtubule-associated protein 1 light chain 3 (LC3) expression was low in SSCC. The negative correlation with Bcl2 and survivin, and the chemotherapy drug 5-FU increased the level of autophagy and the autophagy inhibitor 3-MA inhibited this effect in SSCC cells, time- and dose-dependently. When SSCC cells were treated first with 3-MA and then with 5-FU, the inhibition of proliferation, migration, invasion and apoptosis of SSCC cells was enhanced. Our results suggested the possibility of autophagy as a potential target in SSCC therapy and 3-MA and 5-FU combination treatment may be an effective SSCC therapy via autophagy modulating. PMID:26398820

  1. Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug-resistant human hepatocellular carcinoma cells to 5-FU

    PubMed Central

    TANG, BO; HU, ZHIGAO; LI, YANG; YUAN, SHENGGUANG; WANG, ZHENRAN; YU, SHUIPING; HE, SONGQING

    2016-01-01

    δ opioid receptor (DOR) was the first opioid receptor of the G protein-coupled receptor family to be cloned. Our previous studies demonstrated that DOR is involved in regulating the development and progression of human hepatocellular carcinoma (HCC), and is involved in the regulation of the processes of invasion and metastasis of HCC cells. However, whether DOR is involved in the development and progression of drug resistance in HCC has not been reported and requires further elucidation. The aim of the present study was to investigate the expression levels of DOR in the drug-resistant HCC BEL-7402/5-fluorouracil (BEL/FU) cell line, and its effects on drug resistance, in order to preliminarily elucidate the effects of DOR in HCC drug resistance. The results of the present study demonstrated that DOR was expressed at high levels in the BEL/FU cells, and the expression levels were higher, compared with those in normal liver cells. When the expression of DOR was silenced, the proliferation of the drug-resistant HCC cells were unaffected. However, when the cells were co-treated with a therapeutic dose of 5-FU, the proliferation rate of the BEL/FU cells was significantly inhibited, a large number of cells underwent apoptosis, cell cycle progression was arrested and changes in the expression levels of drug-resistant proteins were observed. Overall, the expression of DOR was upregulated in the drug-resistant HCC cells, and its functional status was closely associated with drug resistance in HCC. Therefore, DOR may become a recognized target molecule with important roles in the clinical treatment of drug-resistant HCC. PMID:26549838

  2. Chemoprevention of skin cancer using low HLB surfactant nanoemulsion of 5-fluorouracil: a preliminary study.

    PubMed

    Shakeel, Faiyaz; Haq, Nazrul; Al-Dhfyan, Abdullah; Alanazi, Fars K; Alsarra, Ibrahim A

    2015-01-01

    Oral delivery of 5-fluorouracil (5-FU) is difficult due to its serious adverse effects and extremely low bioavailability. Therefore, the aim of present investigation was to develop and evaluate low HLB surfactant nanoemulsion of 5-FU for topical chemoprevention of skin cancer. Low HLB surfactant nanoemulsions were prepared by oil phase titration method. Thermodynamically stable nanoemulsions were characterized in terms of droplet size distribution, zeta potential, viscosity and refractive index. Selected formulations and control were subjected to in vitro skin permeation studies through rat skin using Franz diffusion cells. Optimized formulation F9 was subjected to stability and in vitro cytotoxic studies on melanoma cell lines. Enhancement ratio was found to be 22.33 in formulation F9 compared with control and other formulations. The values of steady state flux and permeability coefficient for formulation F9 were found to be 206.40 ± 14.56 µg cm(-2) h(-1) and 2.064 × 10(-2) ± 0.050 × 10(-2 )cm h(-1), respectively. Optimized formulation F9 was found to be physical stable. In vitro cytotoxicity studies on SK-MEL-5 cancer cells indicated that 5-FU in optimized nanoemulsion is much more efficacious than free 5-FU. From these results, it can be concluded that the developed nanoemulsion might be a promising vehicle for chemoprevention of skin cancer. PMID:24350612

  3. Pterostilbine, an active component of blueberries, sensitizes colon cancer cells to 5-fluorouracil cytotoxicity.

    PubMed

    Tolba, Mai F; Abdel-Rahman, Sherif Z

    2015-01-01

    Although colorectal cancer (CRC) treatment with 5-fluorouracil (5-FU) is the first line of therapy for this debilitating disease, treatment effectiveness is often hampered by the development of drug resistance and toxicity at high doses. ER-β can play an important role in CRC development and possibly in its response to therapy. Pterostilbene (PT) possesses antioxidant and anticancer effects that are mediated by ER-β. In the current study, we test the hypothesis that PT sensitizes colon cancer cells to 5-FU and we examine the underlying mechanism(s) by which PT exerts its cytotoxic effects in CRC cells. Our data indicate that PT exhibited a more potent cytotoxic effect in Caco-2 compared to HCT-116 cells. PT/5-FU co-treatment was more effective in Caco-2 cells. Our data indicate that ER-β is expressed at higher levels in Caco-2 cells and its levels are further boosted with PT treatment. PT significantly suppressed Akt and ERK phosphorylations, and enhanced FOXO-1 and p27(kip1) levels in Caco-2 cells. PT also induced a significant increase in Caco-2 cells at pre-G phase coupled with increased Bax/Bcl-2 ratio and PARP cleavage. These results provide a rationale for novel combination treatment strategies, especially for patients with 5-FU-resistant tumors expressing ER-β protein. PMID:26472352

  4. Pterostilbine, an active component of blueberries, sensitizes colon cancer cells to 5-fluorouracil cytotoxicity

    PubMed Central

    Tolba, Mai F.; Abdel-Rahman, Sherif Z.

    2015-01-01

    Although colorectal cancer (CRC) treatment with 5-fluorouracil (5-FU) is the first line of therapy for this debilitating disease, treatment effectiveness is often hampered by the development of drug resistance and toxicity at high doses. ER-β can play an important role in CRC development and possibly in its response to therapy. Pterostilbene (PT) possesses antioxidant and anticancer effects that are mediated by ER-β. In the current study, we test the hypothesis that PT sensitizes colon cancer cells to 5-FU and we examine the underlying mechanism(s) by which PT exerts its cytotoxic effects in CRC cells. Our data indicate that PT exhibited a more potent cytotoxic effect in Caco-2 compared to HCT-116 cells. PT/5-FU co-treatment was more effective in Caco-2 cells. Our data indicate that ER-β is expressed at higher levels in Caco-2 cells and its levels are further boosted with PT treatment. PT significantly suppressed Akt and ERK phosphorylations, and enhanced FOXO-1 and p27kip1 levels in Caco-2 cells. PT also induced a significant increase in Caco-2 cells at pre-G phase coupled with increased Bax/Bcl-2 ratio and PARP cleavage. These results provide a rationale for novel combination treatment strategies, especially for patients with 5-FU-resistant tumors expressing ER-β protein. PMID:26472352

  5. Expression of ABCB6 is related to resistance to 5-FU, SN-38 and vincristine.

    PubMed

    Minami, Kentaro; Kamijo, Youhei; Nishizawa, Yukihiko; Tabata, Sho; Horikuchi, Fumito; Yamamoto, Masatatsu; Kawahara, Kohich; Shinsato, Yoshinari; Tachiwada, Tokushi; Chen, Zhe-Sheng; Tsujikawa, Kazutake; Nakagawa, Masayuki; Seki, Naohiko; Akiyama, Shin-Ichi; Arima, Kazunari; Takeda, Yasuo; Furukawa, Tatsuhiko

    2014-09-01

    A previously established arsenite-resistant cell line, KAS, is also resistant to a variety of anticancer drugs. In order to understand responsible molecules for the multidrug resistance phenotype of KAS cells, we examined the expressions of ATP-binding cassette (ABC) transporters and found that the ABCB6 and ABCC1/ multidrug resistance protein 1 (ABCC1/MRP1) were increased. ABCC1/MRP1 was not completely responsible for the drug resistance spectrum of KAS cells and several reports have suggested that ABCB6 is related to anticancer drug and metal resistance. We, therefore, established and examined ABCB6-expressing KB cells and ABCB6-knockdown KAS cells. ABCB6 expression enhanced resistance to 5-fluorouracil (5-FU), SN-38 and vincristine (Vcr) but not to arsenite. Conversely, down-regulation of ABCB6 in KAS cells increased the sensitivity of KAS cells to 5-FU, SN-38 and Vcr, but not to arsenite. Our findings suggest that ABCB6 is involved in 5-FU, SN-38 and Vcr resistance. PMID:25202056

  6. Effects of endogenous nitric oxide induced by 5-fluorouracil and L-Arg on liver carcinoma in nude mice

    PubMed Central

    Yin, Xiao-Yan; Jiang, Jun-Mei; Liu, Ji-Yong; Zhu, Ju-Ren

    2007-01-01

    AIM: To study the effects of endogeous nitric oxide induced by 5-fluorouracil (5-FU) and L-arginine (L-Arg) on the human liver carcinoma model in nude mice. METHODS: The human liver carcinoma model in nude mice was established with BEL-7402 cells and normal saline (NS), 5-FU and 5-FU + L-Arg injected intraperitoneally. The tumor size was measured. The necrotic degree and range were observed under microscope. The apoptosis of cancer cell was detected by turmina deoxynucleotidyl transferanse mediated dUTP nick end labeling (TUNEL) method. Immunohistochemical method was performed to determine the expression of iNOS, P16, BAX. The chemical colorimetry was used to test the activity and nitrate reductase method was adopted to test the concentration of nitric oxide (NO) in the tumor tissue. The BI2000 pathological image analyzer was used to analyze the result of immunohistochemistry. RESULTS: 5-FU combined with L-Arg could inhibit the tumor growth apparently. In NS, 5-FU and 5-FU+L-Arg groups, the changes of tumor volumes were 257.978 ± 59.0, 172.232 ± 66.0 and 91.523 ± 26.7 mm3, respectively (P < 0.05 5-FU vs 5-FU + L-Arg group; P < 0.05 NS vs 5-FU + L-Arg group; P < 0.05, NS vs 5-FU group). The necrotic range and apoptosis index were significantly increased after the drug injection. The necrotic range was biggest in 5-FU + L-Arg group (χ2 = 15.963, P < 0.05). The apoptosis indexes were as follows: NS, 17.4% ± 6.19%; 5-FU, 31.3% ± 12.3%; and 5-FU + L-Arg, 46% ± 15.24% (P < 0.05, 5-FU vs 5-FU + L-Arg; P < 0.05, NS vs 5-FU + L-Arg; P < 0.05, NS vs 5-FU). The expression and activity of iNOS were increased in the tumor tissue. The concentration of NO was also increased. F of optical density of iNOS, iNOS activity and NO concentration are 31.693, 21.949, and 33.909, respectively, P < 0.05. The concentration of NO was related to the expression of P16 and BAX. The correlation coefficient was 0.764 and 0.554. CONCLUSION: 5-FU combined with L-Arg can inhibit the growth of

  7. Studies on the prevention of 5-fluorouracil-induced oral mucositis.

    PubMed

    Loprinzi, C L; Dose, A M

    1990-01-01

    Oral mucositis is a major toxic effect related to 5-fluorouracil (5-FU) therapy. Clinical studies have attempted to identify an effective antidote for this untoward side effect. Early pilot studies suggested that an allopurinol mouthwash could lessen 5-FU-induced mucositis. However, a randomized, double-blinded, placebo-controlled crossover study did not suggest that an allopurinol mouthwash had any prophylactic value in this clinical situation. An ongoing, randomized clinical protocol is testing cryotherapy as a method of inhibiting 5-FU-induced stomatitis. No clinically appropriate prophylactic measure for preventing 5-FU-induced mucositis has been found to date. PMID:2342597

  8. Engineering of lipid prodrug-based, hyaluronic acid-decorated nanostructured lipid carriers platform for 5-fluorouracil and cisplatin combination gastric cancer therapy

    PubMed Central

    Qu, Chun-Ying; Zhou, Min; Chen, Ying-wei; Chen, Mei-mei; Shen, Feng; Xu, Lei-Ming

    2015-01-01

    Purpose The first-line chemotherapy treatment protocol for gastric cancer is combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP). The aim of this study was to engineer prodrug-based nanostructured lipid carriers (NLC) platform for codelivery of 5-FU and CDDP to enhance therapy and decrease toxicity. Methods First, 5-FU-stearic acid lipid conjugate was synthesized by two steps. Second, 5-FU-stearic acid prodrug and CDDP were loaded in NLC. Finally, hyaluronic acid (HA) was coated onto NLC surface. Average size, zeta potential, and drug loading capacity of NLC were evaluated. Human gastric cancer cell line BGC823 (BGC823 cells) was used for the testing of in vitro cytotoxicity assays. In vivo antitumor activity of NLC was evaluated in mice bearing BGC823 cells model. Results HA-coated 5-FU-stearic acid prodrug and CDDP-loaded NLC (HA-FU/C-NLC) showed a synergistic effect in combination therapy and displayed the greatest antitumor activity than all of the free drugs or uncoated NLC in vitro and in vivo. Conclusion This work reveals that HA-coated NLC could be used as a novel carrier to code-liver 5-FU and CDDP for gastric cancer therapy. HA-FU/C-NLC could be a promising targeted and combinational therapy in nanomedicine. PMID:26089667

  9. Participation of DNA repair in the response to 5-fluorouracil

    PubMed Central

    Wyatt, Michael D.; Wilson, David M.

    2008-01-01

    The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer. Intracellular metabolites of 5-FU can exert cytotoxic effects via inhibition of thymidylate synthetase, or through incorporation into RNA and DNA, events that ultimately activate apoptosis. In this review, we cover the current data implicating DNA repair processes in cellular responsiveness to 5-FU treatment. Evidence points to roles for base excision repair (BER) and mismatch repair (MMR). However, mechanistic details remain unexplained, and other pathways have not been exhaustively interrogated. Homologous recombination is of particular interest, because it resolves unrepaired DNA intermediates not properly dealt with by BER or MMR. Furthermore, crosstalk among DNA repair pathways and S-phase checkpoint signaling has not been examined. Ongoing efforts aim to design approaches and reagents that (i) approximate repair capacity and (ii) mediate strategic regulation of DNA repair in order to improve the efficacy of current anti-cancer treatments. PMID:18979208

  10. Downregulation of Rap1 promotes 5-fluorouracil-induced apoptosis in hepatocellular carcinoma cell line HepG2.

    PubMed

    Zha, Yong; Gan, Ping; Yao, Qian; Ran, Feng-Ming; Tan, Jing

    2014-04-01

    Recent studies have revealed that repressor/activator protein (Rap1) not only protects telomeres from sister chromatid exchange, but also functions in genomewide transcriptional regulation. Knockdown of Rap1 sensitizes breast cancer cells to adriamycin-induced apoptosis. However, little is known about the role of Rap1 in the progression of hepatocellular carcinoma (HCC). The present study aimed to investigate the functions of Rap1 in HCC progression and to determine whether targeting the Rap1 signaling pathway may be of therapeutic value against HCC. We found knockdown of Rap1 by microRNA (miRNA) interference enhanced significantly apoptosis and 5-fluorouracil (5-FU) chemosensitivity in HepG2 cell line. Rap1 miRNA downregulated nuclear factor-κB p65 (NF-κB p65) expression, and upregulated inhibitor of NF-κB (IκB) expression. In vivo, Rap1 miRNA combined with 5-FU treatment led to a significant reduction of tumor growth as compared with 5-FU alone. The results indicate that Rap1 miRNA can effectively enhance sensitivity of HepG2 cell line to 5-FU chemotherapy in vitro and in vivo. PMID:24549317

  11. Gelam honey and ginger potentiate the anti cancer effect of 5-FU against HCT 116 colorectal cancer cells.

    PubMed

    Hakim, Luqman; Alias, Ekram; Makpol, Suzana; Ngah, Wan Zurinah Wan; Morad, Nor Azian; Yusof, Yasmin Anum Mohd

    2014-01-01

    The development of chemopreventive approaches using a concoction of phytochemicals is potentially viable for combating many types of cancer including colon carcinogenesis. This study evaluated the anti-proliferative effects of ginger and Gelam honey and its efficacy in enhancing the anti-cancer effects of 5-FU (5-fluorouracil) against a colorectal cancer cell line, HCT 116. Cell viability was measured via MTS (3-(4,5-dimethylthiazol-2- yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium) assay showing ginger inhibiting the growth of HCT 116 cells more potently (IC50 of 3mg/mL) in comparison to Gelam honey (IC50 of 75 mg/mL). Combined treatment of the two compounds (3mg/mL ginger+75 mg/mL Gelam honey) synergistically lowered the IC50 of Gelam honey to 22 mg/mL. Combination with 35 mg/mL Gelam honey markedly enhanced 5-FU inhibiting effects on the growth of HCT 116 cells. Subsequent analysis on the induction of cellular apoptosis suggested that individual treatment of ginger and Gelam honey produced higher apoptosis than 5-FU alone. In addition, treatment with the combination of two natural compounds increased the apoptotic rate of HCT 116 cells dose- dependently while treatment of either ginger or Gelam honey combined with 5-FU only showed modest changes. Combination index analysis showed the combination effect of both natural compounds to be synergistic in their inhibitory action against HCT 116 colon cancer cells (CI 0.96 < 1). In conclusion, combined treatment of Gelam honey and ginger extract could potentially enhance the chemotherapeutic effect of 5-FU against colorectal cancer. PMID:24969899

  12. 5-Fluorouracil-lipid conjugate: potential candidate for drug delivery through encapsulation in hydrophobic polyester-based nanoparticles.

    PubMed

    Ashwanikumar, N; Kumar, Nisha Asok; Nair, S Asha; Kumar, G S Vinod

    2014-11-01

    The encapsulation of 5-fluorouracil (5-FU) in hydrophobic polymeric materials is made feasible by a lipid-based prodrug approach. A lipid-5-FU conjugate of 5-FU with palmitic acid was synthesized in two-step process. A synthesized dipalmitoyl derivative (5-FUDIPAL) was characterized using Fourier transform infrared spectroscopy and (1)H-nuclear magnetic resonance. The 5-FUDIPAL was encapsulated in polyester-based polymers by the double emulsion-solvent evaporation method. The nanoparticles were characterized by scanning electron microscopy, transmission electron microscopy and dynamic light scattering. The thermal stability was assessed by differential scanning calorimetry data. In vitro release kinetics measurements of the drug from nanoparticles showed the controlled release pattern over a period of time. Cytotoxicity measurements by MTT assay confirmed that dipalmitoyl derivative in nano formulation successfully inhibited the cell growth. Thus the combined physical and biological evaluation of the different polyester-based nanoparticle containing the modified drug showed a facile approach to delivering 5-FU to the tumour site with enhanced efficacy. PMID:25110286

  13. Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis.

    PubMed

    Dun, Jiening; Chen, Xueyan; Gao, Haixia; Zhang, Yan; Zhang, Huajun; Zhang, Yongjian

    2015-12-01

    Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (P < 0.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option. PMID:25736303

  14. Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck

    SciTech Connect

    Byfield, J.E.; Sharp, T.R.; Frankel, S.S.; Tang, S.G.; Callipari, F.B.

    1984-05-01

    Eighteen patients with advanced epithelial cancers of the head and neck region were studied for their tolerance and response to combined cycles of 120-hour infused 5-fluorouracil (5-FU) and external-beam radiation therapy. 5-FU infusions were given under conditions where radiosensitization would be expected at the higher infusion doses. Coincident radiation treatments were given as four sequential daily fractions of 250 rad each administered during days 1 through 4 of each five-day infusion cycle. The patients were rested for at least nine days after each cycle or longer until toxicity was resolved. The regimen was then repeated in each patient for a total of five treatment cycles. Thereafter therapy was consolidated, usually by boost radiation without drug. In sequential patient subsets the infusion load was progressively escalated in a phase I format. The complete response rate for stage IV patients was 75% with survival benefit compared to prior results. 5-FU dose-dependent combined modality loco-regional toxicity was demonstrated without significant enhancement of systemic toxicity of any form; 5-FU dose-dependent enhanced responsiveness and survival benefit is also suggested. Further scheduling and response studies of 5-FU under radiosensitizing conditions appear warranted.

  15. Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma.

    PubMed

    Harada, Koji; Ferdous, Tarannum; Harada, Toyoko; Ueyama, Yoshiya

    2016-07-01

    Cancer cells show enhanced glucose consumption and lactate production even in the presence of abundant oxygen, a phenomenon known as the Warburg effect, which is related to tumor proliferation, progression and drug-resistance in cancers. Hypoxia-inducible factor-1 (HIF-1) and several members of Phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway positively contribute to the Warburg effect, whereas AMP activated protein Kinase (AMPK) acts as a negative regulator. Targeting the regulator molecules of Warburg effect might be a useful strategy to effectively kill cancer cells. Metformin was reported to be effective against various cancers as it inhibits cell proliferation by activating AMPK, and inhibiting mTOR and HIF-1α. Several studies suggested the efficacy of metformin with 5-fluorouracil (5-FU) against esophageal and colon cancer. In this study, we evaluated the efficacy of metformin and 5-FU combined therapy against human oral squamous cell carcinoma (OSCC) in vitro and in vivo. MTT assay and TUNEL assay revealed that metformin (4 mg/ml) and 5-FU (2.5 µg/ml) combination treatment effectively inhibited cell growth and induced apoptosis in OSCC cell lines (HSC2, HSC3 and HSC4) compared to either agent alone. Lactate colorimetric assay detected decreased level of lactate in the supernatants of metformin and 5-FU treated cells compared to cells treated with metformin or 5-FU. Western blot analysis showed marked downregulation of HIF-1α and mTOR expression, and upregulation of AMPKα in cells treated with metformin and 5-FU combination treatment. Combination therapy with metformin (200 mg/kg, i.p.) and 5-FU (10 mg/kg, i.p.) for 4 weeks (5 days/week) effectively reduced HSC2 tumor growth (77.6%) compared to metformin (59.9%) or 5-FU (52%) alone in nude mice. These findings suggest that metformin and 5-FU combined therapy could exert strong antitumor effect against OSCC through the inhibition of

  16. Formulation and characterization of nanoliposomal 5-fluorouracil for cancer nanotherapy.

    PubMed

    Elmeshad, A N; Mortazavi, S M; Mozafari, M R

    2014-03-01

    A scalable and safe method was developed to prepare nanoliposome carriers for the entrapment and delivery of 5-fluorouracil (5-FU). The carrier systems were composed of endogenously occurring dipalmitoylphosphatidylcholine (DPPC), negatively charged dicetylphosphate (DCP), cholesterol (CHOL) and glycerol (3%, v/v). Nanoliposomes were prepared by the heating method in which no harmful chemical or procedure is involved. Results indicated fast and reproducible formation of non-toxic liposomes that possess high entrapment efficiency (up to 96.9%) and vesicle size range of ca. 530-620 nm. Transmission electron and optical micrographs of the 5-FU liposomes revealed that they were spherical and some were multilayered. There was an increase in the release rate of 5-FU from the liposomes prepared with a high ratio of drug:lipid. The release data showed that the highest release rates were obtained for nanoliposomes containing 5-FU with the drug concentration of 500 mM and that it followed the diffusion model. Nanoliposome preparation method introduced here has the potential of large-scale manufacture of safe and efficient carriers of 5-FU. PMID:23834067

  17. 5-Fluorouracil loaded Eudragit fibers prepared by electrospinning.

    PubMed

    Illangakoon, U Eranka; Yu, Deng-Guang; Ahmad, Bilal S; Chatterton, Nicholas P; Williams, Gareth R

    2015-11-30

    A series of 5-fluorouracil (5-FU) loaded core/shell electrospun fibers is reported. The fibers have shells made of Eudragit S100 (ES-100), and drug-loaded cores comprising poly(vinylpyrrolidone), ethyl cellulose, ES-100, or drug alone. Monolithic 5-FU loaded ES-100 fibers were also prepared for comparison. Electron microscopy showed all the fibers to have smooth cylindrical shapes, and clear core-shell structures were visible for all samples except the monolithic fibers. 5-FU was present in the amorphous physical form in all the materials prepared. Dissolution studies showed that the ES-100 shell was not able to prevent drug release at pH 1.0, even though the polymer is completely insoluble at this pH: around 30-80% of the maximum drug release was reached after 2h immersion at pH 1.0. These observations are ascribed to the low molecular weight of 5-FU permitting it to diffuse through pores in the ES-100 coating, and the relatively high acid solubility of the drug providing a thermodynamic impetus for this to happen. In addition, the fibers were observed to be broken or merged following 2h at pH 1.0, giving additional escape routes for the 5-FU. PMID:26410755

  18. [Improved Response to 5-FU Using Dose Adjustment and Elastomeric Pump Selection Based on Monitoring of the 5-FU Level--A Case Report].

    PubMed

    Muneoka, Katsuki; Shirai, Yoshio; Kanda, Junkichi; Sasaki, Masataka; Wakai, Toshifumi; Wakabayashi, Hiroyuki

    2015-10-01

    A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg・h/L)were 21 and 44 mg・h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg・h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit. PMID:26489552

  19. [A case of 5-fluorouracil-induced hyperammmonia after chemotherapy for metastatic colon cancer].

    PubMed

    Nakamura, Masamoto; Kobashikawa, Kasen; Tamura, Jiro; Takaki, Ryo; Ohshiro, Masaru; Matayoshi, Ryoji; Hirata, Tetsuo; Kinjyo, Fukunori; Fujita, Jiro

    2009-12-01

    A 79-year-old woman with colon cancer and multiple liver metastases was admitted to our hospital for systemic chemotherapy. She underwent first cycle of modified FOLFOX6 chemotherapy. She was confused on treatment day 5. Blood test revealed her serum ammonia level to be 121 microg/dl. We diagnosed 5-fluorouracil (5FU)-induced hyperammonemia. Conservative treatment resulted in improvement of metal status. The reason for hyperammonemia after administration of 5FU was the excess production of ammonium from metabolites of 5FU. PMID:19966516

  20. A 5-fluorouracil-loaded pH-responsive dendrimer nanocarrier for tumor targeting.

    PubMed

    Jin, Yiguang; Ren, Xia; Wang, Wei; Ke, Lijing; Ning, Erjuan; Du, Lina; Bradshaw, Jeremy

    2011-11-28

    A novel long-circulating and pH-responsive dendrimer nanocarrier was prepared for delivering 5-fluorouracil (5-FU) to tumors through the targeting of nanoparticles to the low pH environment of tumors. The nanocarrier, poly(2-(N,N-diethylamino)ethyl methacrylate) with methoxy-poly(ethylene glycol)-poly(amidoamine) (PPD), had a core-shell structure with 4.0 G poly(amidoamine) (PAMAM) as the core and parallel poly(2-(N,N-diethylamino)ethyl methacrylate) (PDEA) chains and methoxy-poly(ethylene glycol) (mPEG) chains as the shell. The PDEA chain was pH-responsive, and the PEG chains led to long circulation in blood vessels to achieve tumor targeting. The sizes, drug encapsulation and release of PPD nanocarriers showed high pH-dependency due to the PDEA chains, as they were hydrophilic at pH 6.5 and hydrophobic at pH 7.4. The encapsulation efficiency of 5-FU in PPD nanocarriers was as high as 92.5% through the pH transition. The release of 5-FU from PPD nanocarriers was much faster at pH 6.5 than at pH 7.4. The 5-FU-loaded nanocarrier had a long half-life after intravenous administration in mice and showed high tumor targeting. This nanocarrier composite also showed enhanced anticancer effects. PPD is a promising nanocarrier of anticancer drugs with high encapsulation, tumor targeting and pH-responsive release in tumors. PMID:21925254

  1. Synergistic anticancer effect of exogenous wild-type p53 gene combined with 5-FU in human colon cancer resistant to 5-FU in vivo

    PubMed Central

    Xie, Qi; Wu, Min-Yi; Zhang, Ding-Xuan; Yang, Yi-Ming; Wang, Bao-Shuai; Zhang, Jing; Xu, Jin; Zhong, Wei-De; Hu, Jia-Ni

    2016-01-01

    AIM To investigate the anticancer effect of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of rAd-p53 in reversal of 5-FU resistance. METHODS Nude mice bearing human colon cancer SW480/5-FU (5-FU resistant) were randomly assigned to four groups (n = 25 each): control group, 5-FU group, rAd-p53 group, and rAd-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C (PKC), permeability-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (Western blot) and apoptosis (TUNEL) were determined. RESULTS The area ratios of tumor cell apoptosis were larger in the rAd/p53 + 5-FU group than that in the control, 5-FU and rAd/p53 groups (P < 0.05), and were larger in the rAd/p53 group than that of the control group (P < 0.05) and the 5-FU group at more than 48 h (P < 0.05). The p53 expression was higher in the rAd/p53 and the rAd/p53 + 5-FU groups than that of the control and 5-FU groups (P < 0.05), and were higher in the rAd/p53 + 5-FU group than that of the rAd/p53 group (P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the rAd/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups (P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and rAd/p53 groups at more than 48 h (P < 0.05). In the rAd/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h (P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h (P < 0.05). CONCLUSION 5-FU combined with rAd-p53 has a synergistic anticancer effect in SW480/5-FU (5-FU resistance), which contributes to reversal of 5-FU

  2. FLOW CYTOMETRIC DETECTION OF ABNORMAL FETAL ERYTHROPOIESIS: APPLICATION TO 5-FLUOROURACIL-INDUCED ANEMIA

    EPA Science Inventory

    Previously, we observed that administration of 20-40 mg/kg 5-fluorouracil (5-FU) to pregnant rats on gestational day (GD) 14 produced fetal anemia on GD 16-17, as evidenced by dose-dependent decreases in the cell counts, hematocrit, and hemoglobin content of fetal blood obtained ...

  3. [Analysis of sensitivity of stromal stem cells (CFU-f) from rat bone marrow and fetal liver to 5-fluorouracil].

    PubMed

    Paiushina, O V; Damaratskaia, E I; Bueverova, E I; Nikonova, T M; Butorina, N N; Molchanova, E A; Starostin, V I

    2006-01-01

    The sensitivity of stromal stem cells (CFU-f) from rat bone marrow and fetal liver to the cytotoxic effect of 5-fluorouracil (5-FU) was compared in vivo and in vitro. Cells from both tissues demonstrated a similar resistance to 5-FU in vitro; however, stromal stem cells from fetal liver proved notably more sensitive to 5-FU compared to marrow CFU-f in vivo. Cells forming colonies of different size were identified in stem cell populations from both tissues. Cells giving rise to small colonies had a higher resistance to 5-FU both in vivo and in vitro. PMID:17168462

  4. Active hexose correlated compound potentiates the antitumor effects of low-dose 5-fluorouracil through modulation of immune function in hepatoma 22 tumor-bearing mice

    PubMed Central

    Cao, Zhiyun; Chen, Xuzheng; Lan, Lan; Zhang, Zhideng; Du, Jian

    2015-01-01

    BACKGROUND/OBJECTIVES A variety of immunomodulators can improve the efficacy of low-dose chemotherapeutics. Active hexose correlated compound (AHCC), a mushroom mycelia extract, has been shown to be a strong immunomodulator. Whether AHCC could enhance the antitumor effect of low-dose 5-fluorouracil (5-FU) via regulation of host immunity is unknown. MATERIALS/METHODS In the current study Hepatoma 22 (H22) tumor-bearing mice were treated with PBS, 5-FU (10 mg·kg-1·d-1, i.p), or AHCC (360 mg·kg-1·d-1, i.g) plus 5-FU, respectively, for 5 d. CD3+, CD4+, CD8+, and NK in peripheral blood were detected by flow cytometry. ALT, AST, BUN, and Cr levels were measured by biochemical assay. IL-2 and TNFα in serum were measured using the RIA kit and apoptosis of tumor was detected by TUNEL staining. Bax, Bcl-2, and TS protein levels were measured by immunohistochemical staining and mRNA level was evaluated by RT-PCR. RESULTS Diet consumption and body weight showed that AHCC had no apparent toxicity. AHCC could reverse liver injury and myelosuppression induced by 5-FU (P < 0.05). Compared to mice treated with 5-FU, mice treated with AHCC plus 5-FU had higher thymus index, percentages of CD3+, CD4+, and NK cells (P < 0.01), and ratio of CD4+/CD8+ (P < 0.01) in peripheral blood. Radioimmunoassay showed that mice treated with AHCC plus 5-FU had the highest serum levels of IL-2 and TNFα compared with the vehicle group and 5-FU group. More importantly, the combination of AHCC and 5-FU produced a more potent antitumor effect (P < 0.05) and caused more severe apoptosis in tumor tissue (P < 0.05) compared with the 5-FU group. In addition, the combination of AHCC and 5-FU further up-regulated the expression of Bcl-2 associated X protein (Bax) (P < 0.01), while it down-regulated the expression of B cell lymphoma 2 (Bcl-2) (P < 0.01). CONCLUSIONS These results support the claim that AHCC might be beneficial for cancer patients receiving chemotherapy. PMID:25861418

  5. Investigations on the Interactions of 5-Fluorouracil with Herring Sperm DNA: Steady State/Time Resolved and Molecular Modeling Studies

    NASA Astrophysics Data System (ADS)

    Chinnathambi, Shanmugavel; Karthikeyan, Subramani; Velmurugan, Devadasan; Hanagata, Nobutaka; Aruna, Prakasarao; Ganesan, Singaravelu

    2015-04-01

    In the present study, the interaction of 5-Fluorouracil with herring sperm DNA is reported using spectroscopic and molecular modeling techniques. This binding study of 5-FU with hs-DNA is of paramount importance in understanding chemico-biological interactions for drug design, pharmacy and biochemistry without altering the original structure. The challenge of the study was to find the exact binding mode of the drug 5-Fluorouracil with hs-DNA. From the absorption studies, a hyperchromic effect was observed for the herring sperm DNA in the presence of 5-Fluorouracil and a binding constant of 6.153 × 103 M-1 for 5-Fluorouracil reveals the existence of weak interaction between the 5-Fluorouracil and herring sperm DNA. Ethidium bromide loaded herring sperm DNA showed a quenching in the fluorescence intensity after the addition of 5-Fluorouracil. The binding constants for 5-Fluorouracil stranded DNA and competitive bindings of 5-FU interacting with DNA-EB systems were examined by fluorescence spectra. The Stern-Volmer plots and fluorescence lifetime results confirm the static quenching nature of the drug-DNA complex. The binding constant Kb was 2.5 × 104 L mol-1 and the number of binding sites are 1.17. The 5-FU on DNA system was calculated using double logarithmic plot. From the Forster nonradiative energy transfer study it has been found that the distance of 5-FU from DNA was 4.24 nm. In addition to the spectroscopic results, the molecular modeling studies also revealed the major groove binding as well as the partial intercalation mode of binding between the 5-Fluorouracil and herring sperm DNA. The binding energy and major groove binding as -6.04 kcal mol-1 and -6.31 kcal mol-1 were calculated from the modeling studies. All the testimonies manifested that binding modes between 5-Fluorouracil and DNA were evidenced to be groove binding and in partial intercalative mode.

  6. Anti-tumor effect of L-methionine-deprived total parenteral nutrition with 5-fluorouracil administration on Yoshida sarcoma-bearing rats.

    PubMed Central

    Goseki, N; Endo, M; Onodera, T; Kosaki, G

    1991-01-01

    L-methionine-deprived total parenteral nutrition (methionine-deprived TPN), infusing amino acid solution devoid of L-methionine and L-cysteine by the method of TPN as an only protein source, showed enhancement of the effect of several anti-cancer agents. In this study the combined effect of the methionine-deprived TPN with administration of 5-fluorouracil (5-FU) was examined in Yoshida Sarcoma (YS)-bearing rats, from aspects of effects on the tumor metastasis and the host animal's life span, in the following four groups treated with: methionine-deprived TPN with administration of 5-FU, methionine-deprived TPN without administration of 5-FU, L-methionine-contained TPN plus 5-FU, and L-methionine-contained TPN without 5-FU. In the first experiment, TPN was continued for 8 days in the four groups, and the anti-cancer effect of methionine-deprived TPN and administration of 5-FU based on both the growth of the primary tumor at the implanted site and the tumor metastasis was studied from the view point of pathologic findings of animals killed immediately after these treatments. In experiment 2 the survival period was examined after these treatments for 10 days with subsequent oral feeding until death. The results were as follows: proliferation of YS, transplanted subcutaneously, was markedly suppressed; particularly hematogenous metastasis, characteristic in YS, was prominently blunted then obtained an apparent longer survival period in rats treated with the methionine-deprived TPN with administration of 5-FU. PMID:1905913

  7. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting

    PubMed Central

    Nasr, Mohamed; Ghorab, Mohamed K.; Abdelazem, Ahmed

    2014-01-01

    The objective of this study was to prepare cubosomal nanoparticles containing a hydrophilic anticancer drug 5-fluorouracil (5-FU) for liver targeting. Cubosomal dispersions were prepared by disrupting a cubic gel phase of monoolein and water in the presence of Poloxamer 407 as a stabilizer. Cubosomes loaded with 5-FU were characterized in vitro and in vivo. In vitro, 5-FU-loaded cubosomes entrapped 31.21% drug and revealed nanometer-sized particles with a narrow particle size distribution. In vitro 5-FU release from cubosomes exhibited a phase of rapid release of about half of the entrapped drug during the first hour, followed by a relatively slower drug release as compared to 5-FU solution. In vivo biodistribution experiments indicated that the cubosomal formulation significantly (P<0.05) increased 5-FU liver concentration, a value approximately 5-fold greater than that observed with a 5-FU solution. However, serum serological results and histopathological findings revealed greater hepatocellular damage in rats treated with cubosomal formulation. These results demonstrate the successful development of cubosomal nanoparticles containing 5-FU for liver targeting. However, further studies are required to evaluate hepatotoxicity and in vivo antitumor activity of lower doses of 5-FU cubosomal formulation in treatment of liver cancer. PMID:26579429

  8. Formulation factors for preparing ocular biodegradable delivery system of 5-fluorouracil microparticles.

    PubMed

    Yeh, M K; Tung, S M; Lu, D W; Chen, J L; Chiang, C H

    2001-01-01

    Microparticles containing 5-fluorouracil (5-FU) were prepared using poly(DL-lactide-co-glycolide) with an oil-in-oil emulsion/solvent extraction technique. Particle characteristics including size distribution, 5-FU loading efficiencies, in vitro release and degradation were investigated. The dispersed phase was composed of PLG dissolved in dichloromethane, and the continuous phase was paraffin oil containing lecithin. 5-FU was successfully entrapped in the microparticles with trapping efficiencies up to 76%, loading level 10% w/v, and particle size 3 microm. Release profiles of 5-FU loaded microparticles were determined to follow a first-order-time relationship. An optimized preparation of 5-FU microparticles was achieved and was capable of controlling the release of 5-FU over 21 days with an in vitro delivery rate of 0.4 microg 5-FU/mg particles/day in the study. Preliminary animal studies indicated that the 5-FU loaded microparticles as an ocular delivery system showed no ocular toxicity and no significant inflammatory response in rabbits for 2 months. The 5-FU loaded microparticles approach, with PLG, might be a potential for the application of long-term delivery of hydrophilic drugs in the eye. PMID:11428679

  9. A study of purified montmorillonite intercalated with 5-fluorouracil as drug carrier.

    PubMed

    Lin, F H; Lee, Y H; Jian, C H; Wong, Jau-Min; Shieh, Ming-Jium; Wang, Cheng-Yi

    2002-05-01

    Since its introduction over 40 years ago, 5-fluorouracil (5-FU) has remained the only effective chemotherapy option available for the treatment of colorectal cancer (CRC). However, this cytotoxic anticancer drug often causes severe side effects because it does not act selectively on the tumor. It has been reported that the 5-FU showed considerable toxicity when administered by intravenous injections or via alimentary tract. Although, many materials have been developed for carrying 5-FU, there has been no clinically acceptable carrier for 5-FU till now. Montmorillonite, one of the clay minerals, consists of hydrated aluminum silicates with fine grains and large spaces between the layers. Isomorphous substitution of cations is common. In the study, we attempt to intercalate 5-FU into interlayers of montmorillonite through ion exchange. Montmorillonite was purified from crude clays of bentonite in Tai-dong, Taiwan by filtration and sedimentation. Solutions of 5-FU with different concentrations were prepared by dissolving various amounts of 5-FU into 10 ml NaOH solution. Purified montmorillonite powder was soaked in 5-FU solution for a period of time with different pH values and temperatures. In this study, we try to intercalate 5-FU into interlayers of montmorillonite to find out optimum conditions, such as soaking time, temperature, pH value, initial 5-FU concentration, etc., to prepare composites of 5-FU and montmorillonite (5-FU/mont). UV, SDT, FTIR, XRD are used to characterize the 5-FU/mont composite. From the results. 5-FU was successfully intercalated into the interlayer of montmorillonite both by free surface absorption and OH replacement. The optimum condition for 5-FU/mont preparations is 1.185 wt% of 5-FU as initial concentration under a pH value of 11.6 at a temperature of 80 degrees C and a soaking time of 2 h. The total amount of 5-FU in montmorillonite is about 87.5 mg for each gram of montmorillonite, which can be proved by thermal gravimetric analysis

  10. Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: Clinical and occupational implications

    PubMed Central

    LAMBERTI, MONICA; PORTO, STEFANIA; ZAPPAVIGNA, SILVIA; STIUSO, PAOLA; TIRINO, VIRGINIA; DESIDERIO, VINCENZO; MELE, LUIGI; CARAGLIA, MICHELE

    2015-01-01

    5-Fluorouracil (5-FU), often used in combination with levofolene (LF), can induce, as an important side effect, the hand-foot syndrome (HFS) due to toxicity on keratinocytes. This can also damage workers involved in its handling. In the present study, we investigated the mechanisms of the toxicity induced by 5-FU alone or together with LF on human keratinocytes in culture. We found that the two drugs, as expected, had potentiating activity on keratinocyte growth inhibition and that this effect was mediated by induction of apoptosis. In our experimental model, an increased autophagic vacuole accumulation was observed in keratinocytes treated with 5-FU as a significant increase of the monodansylcadaverine (MDC) labeling (marker of late autophagy vacuoles) was recorded. However, the synergism of 5-FU with LF on apoptotic occurrence was not paralleled by a similar increase in autophagic vacuoles at 72 h suggesting an antagonistic effect of LF on autophagy elicited by 5-FU. Differential effects on reactive oxygen species (ROS) elevation in cells treated with 5-FU alone or the combination between 5-FU and LF were also observed. 5-FU induced a time-dependent increase of both O2− and lipid peroxidation while the combination of 5-FU and LF caused a stronger intracellular O2− increase only at 24 h while at 48 and 72 h its effect was lower when compared with that one of 5-FU alone. On the other hand, the addition of LF to 5-FU caused a stronger increase of lipid peroxidation at 48 and 72 h, but its effects were significantly lower at 24 h. These results suggest for the first time that LF potentiates the cytotoxicity of 5-FU on keratinocytes likely through the antagonism on autophagy escape pathway and consequent apoptosis potentiation. PMID:25709090

  11. [Four cases of 5-fluorouracil-related hyperammonemia in patients with large intestinal cancer and multiple liver metastases, including a case of hyperammonemia treated using hemodialysis].

    PubMed

    Iida, Tomoya; Wagatsuma, Kohei; Tani, Motohiro; Sasaki, Hajime; Naganawa, Yumiko; Isshiki, Hiroyuki; Murakami, Kayo; Satoh, Shuji; Shimizu, Haruo; Kaneto, Hiroyuki

    2015-02-01

    Systemic chemotherapy based on 5-fluorouracil (5-FU) is a standard treatment for unresectable or recurrent large intestinal cancer. Although hyperammonemia is a known side effect of 5-FU that can cause serious pathological conditions, only a few cases have been reported. We describe 4 cases of 5-FU-related hyperammonemia with impairment of consciousness in patients who received 5-FU chemotherapy for large intestinal cancer with multiple liver metastases. Hemodialysis was effective in 1 severe case. There have been no detailed reports on the use of hemodialysis for hyperammonemia caused by 5-FU. Renal dysfunction is considered to be a risk factor for hyperammonemia caused by 5-FU and it is necessary to pay particular attention in patients with renal dysfunction who receive chemotherapy with 5-FU. Here we summarize our cases together with 16 previously reported cases of hyperammonemia caused by 5-FU in Japan. PMID:25748155

  12. Interactions of radiation and 5-fluorouracil, cyclophosphamide or methotrexate in intestinal crypt cells

    SciTech Connect

    von der Maase, H.

    1984-01-01

    The interactions of radiation and 5-fluorouracil (5-FU), cyclophosphamide (CTX), or methotrexate (MTX) in mouse jejunal crypt cells were studied using the microcolony survival assay. 5-FU given from 48 hr before to 24 hr after irradiation resulted in an almost constant, increased cell kill except at injection 6 hr after irradiation, which resulted in a more pronounced effect. CTX enhanced the radiation effect only when given simultaneously with or up to 3 hr after irradiation. The effect of MTX, extremely dependent on the sequence and interval between drug administration and irradiation, was most prominent when administered 1 hr before irradiation. At this drug-radiation interval, the D/sub 0/ surprisingly increased by a factor of 2.4, whereas MTX 15 min before irradiation displaced the survival curve to the left without changing the D/sub 0/. The influence of MTX on the radiation response disappeared when the drug was given either 96 hr before or 3 hr after irradiation.

  13. In vitro effect of 5-fluorouracil and paclitaxel on Echinococcus granulosus larvae and cells.

    PubMed

    Pensel, P E; Albani, C; Gamboa, G Ullio; Benoit, J P; Elissondo, M C

    2014-12-01

    Human cystic echinococcosis is a zoonosis caused by the metacestode stage of the tapeworm Echinococcus granulosus. Although benzimidazole compounds such as albendazole and mebendazole have been the cornerstone of chemotherapy for the disease, there is often no complete recovery after treatment. Hence, in searching for novel treatment options, we examined the in vitro efficacies of 5-fluorouracil (5-FU) and paclitaxel (PTX) against E. granulosus germinal cells, protoscoleces and cysts. 5-FU or PTX inhibited the growth of E. granulosus cells in a time dependent manner. Although both treatments had a protoscolicidal effect, 5-FU had a considerably stronger effect than PTX. 5-FU produced a dose- and time-dependent effect, provoking the complete loss of viability after 24 days of incubation. Moreover, cysts did not develop following the inoculation of treated protoscoleces into mice. The loss of viability was slower in PTX treated protoscoleces, reaching to approximately 60% after 30 days. The results of the in vitro treatment with 5-FU and PTX were similar in secondary murine cysts. The employment of SEM and TEM allowed us to examine, at an ultrastructural level, the effects induced by 5-FU and PTX on E. granulosus germinal cells, protoscoleces and murine cysts. In conclusion, the data obtained clearly demonstrated that 5-FU and PTX at clinically achievable concentrations inhibit the survival of larval cells, protoscoleces and metacestodes. In vivo studies to test the antiparasitic activities of 5-FU and PTX are currently being undertaken on the murine model of cystic echinococcosis. PMID:25088684

  14. Genetic evidence for involvement of membrane trafficking in the action of 5-fluorouracil.

    PubMed

    Hu, Lingling; Yao, Fan; Ma, Yan; Liu, Qiannan; Chen, Si; Hayafuji, Tsutomu; Kuno, Takayoshi; Fang, Yue

    2016-08-01

    To identify novel genes that mediate cellular sensitivity and resistance to 5-fluorouracil (5-FU), we performed a genome-wide genetic screening to identify altered susceptibility to 5-FU by Schizosaccharomyces pombe haploid nonessential gene deletion library containing 3004 deletion mutants. We identified 50 hypersensitive and 12 resistant mutants to this drug. Mutants sensitive or resistant to 5-FU were classified into various categories based on their putative functions. The largest group of the genes whose disruption renders cells altered susceptibility to 5-FU is involved in nucleic acid metabolism, but to our surprise, the second largest group is involved in membrane trafficking. In addition, several other membrane traffic mutants examined including gdi1-i11, ypt3-i5, Δryh1, Δric1, and Δaps1 exhibited hypersensitivity to 5-FU. Furthermore, we found that 5-FU in low concentration that generally do not affect cell growth altered the localization of Syb1, a secretory vesicle SNARE synaptobrevin which is cycled between the plasma membrane and the endocytic pathway. Notably, 5-FU at such low concentration also significantly inhibited the secretion of acid phosphatase. Altogether, our findings revealed the first evidence that 5-FU influences membrane trafficking as the potential underlying mechanism of the drug action. PMID:27255861

  15. Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats.

    PubMed

    Prisciandaro, Luca D; Geier, Mark S; Butler, Ross N; Cummins, Adrian G; Howarth, Gordon S

    2011-04-01

    Certain live bacteria have demonstrated preliminary indications of efficacy for the treatment of chemotherapy-induced intestinal mucositis. However, probiotic derived supernatants (SN) have yet to be investigated in the mucositis setting. We evaluated SN from Escherichia coli Nissle 1917 (EcN) and Lactobacillus fermentum BR11 (BR11) for their capacity to decrease 5-Fluorouracil (5-FU)-induced damage in vivo. Female Dark Agouti rats were gavaged with 1 mL of either SN or vehicle daily (days 0-8) and intraperitoneally injected with 5-FU (150 mg/kg) on day 5 to induce mucositis. On day 9, animals were culled and intestinal tissues collected. Significantly lower histological damage scores were apparent in the jejunum of 5-FU treated rats receiving SN compared to 5-FU controls. Myeloperoxidase levels in the jejunum of 5-FU treated rats were increased in vehicle and BR11 SN treatments compared to untreated controls, whereas no significant increase was observed after EcN SN treatment. 5-FU treatment significantly reduced villus height and crypt depth in the jejunum compared to normal controls; however no significant reduction in these parameters was observed in 5-FU treated rats receiving either SN. We conclude that bacterial SN, especially EcN, partially protect the intestine from 5-FU mucositis. Further studies are required to define specific mechanisms by which SN exert their beneficial effects. PMID:21307648

  16. Augmentation of antitumor activity of 5-fluorouracil by interferon alpha is associated with up-regulation of p27Kip1 in human hepatocellular carcinoma cells.

    PubMed

    Eguchi, H; Nagano, H; Yamamoto, H; Miyamoto, A; Kondo, M; Dono, K; Nakamori, S; Umeshita, K; Sakon, M; Monden, M

    2000-07-01

    Several clinical trials have demonstrated the effectiveness of combination therapy with 5-fluorouracil (5-FU) and IFN-alpha in colon cancer, hepatocellular carcinoma (HCC), and other malignancies. In our preliminary clinical studies, we have observed outstanding effects with this combination therapy in patients with advanced HCC. However, the underlying mechanism by which IFN-alpha modulates the effects of 5-FU is unknown. We, therefore, conducted a mechanistic study using two HCC cell lines, PLC/PRF/5 and HuH7. IFN-alpha significantly enhanced the growth inhibitory effect of 5-FU in PLC/PRF/5 cells but not in HuH7 cells, and the isobolographic analysis indicated that this effect was synergistic. Flow cytometric analysis showed a delay in the progression of G0-G1 to S phase in PLC/PRF/5, and a sustained, induction of the cyclin-dependent kinase inhibitor p27-Kip1 and down-regulation of cyclin D1 was observed. Moreover, increased expression of p27Kip1 was associated with reduced CDK-2-associated kinase activity. Another difference in the two cell types was that PLC/PRF/5 expressed abundant IFN receptors, but HuH7 did not. Apoptosis assays were not helpful in explaining the mechanism. Our results suggest that the synergistic effects of 5-FU and IFN-alpha may in part be attributable to alterations in cell cycle progression via up-regulation of p27Kip1. PMID:10914738

  17. Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines

    PubMed Central

    Zoli, Wainer; Ulivi, Paola; Tesei, Anna; Fabbri, Francesco; Rosetti, Marco; Maltoni, Roberta; Giunchi, Donata Casadei; Ricotti, Luca; Brigliadori, Giovanni; Vannini, Ivan; Amadori, Dino

    2005-01-01

    Introduction The aim of the study was to evaluate the activity of a combination of doxorubicin (Dox), paclitaxel (Pacl) and 5-fluorouracil (5-FU), to define the most effective schedule, and to investigate the mechanisms of action in human breast cancer cells. Methods The study was performed on MCF-7 and BRC-230 cell lines. The cytotoxic activity was evaluated by sulphorhodamine B assay and the type of drug interaction was assessed by the median effect principle. Cell cycle perturbation and apoptosis were evaluated by flow cytometry, and apoptosis-related marker (p53, bcl-2, bax, p21), caspase and thymidylate synthase (TS) expression were assessed by western blot. Results 5-FU, used as a single agent, exerted a low cytotoxic activity in both cell lines. The Dox→Pacl sequence produced a synergistic cytocidal effect and enhanced the efficacy of subsequent exposure to 5-FU in both cell lines. Specifically, the Dox→Pacl sequence blocked cells in the G2-M phase, and the addition of 5-FU forced the cells to progress through the cell cycle or killed them. Furthermore, Dox→Pacl pretreatment produced a significant reduction in basal TS expression in both cell lines, probably favoring the increase in 5-FU activity. The sequence Dox→Pacl→48-h washout→5-FU produced a synergistic and highly schedule-dependent interaction (combination index < 1), resulting in an induction of apoptosis in both experimental models regardless of hormonal, p53, bcl-2 or bax status. Apoptosis in MCF-7 cells was induced through caspase-9 activation and anti-apoptosis-inducing factor hyperexpression. In the BRC-230 cell line, the apoptotic process was triggered only by a caspase-dependent mechanism. In particular, at the end of the three-drug treatment, caspase-8 activation triggered downstream executioner caspase-3 and, to a lesser degree, caspase-7. Conclusion In our experimental models, characterized by different biomolecular profiles representing the different biology of human breast

  18. A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice

    PubMed Central

    Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

    2016-01-01

    5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion–evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0−t): 12.53±1.65 mg/L*h vs 7.80±0.83 and 5.82±0.83 mg/L*h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU. PMID:27042001

  19. A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice.

    PubMed

    Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

    2016-01-01

    5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion-evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0-t): 12.53±1.65 mg/L(*)h vs 7.80±0.83 and 5.82±0.83 mg/L(*)h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU. PMID:27042001

  20. Aqueous Extract of Solanum nigrum Leaves Induces Autophagy and Enhances Cytotoxicity of Cisplatin, Doxorubicin, Docetaxel, and 5-Fluorouracil in Human Colorectal Carcinoma Cells

    PubMed Central

    Tai, Chen-Jei; Tai, Cheng-Jeng; Lin, Yi-Feng; Jian, Jiun-Yu; Chang, Yu-Jia; Chang, Chun-Chao

    2013-01-01

    Colorectal cancer is a common cancer worldwide, and chemotherapy is a mainstream approach for advanced and recurrent cases. Development of effective complementary drugs could help improve tumor suppression efficiency and control adverse effects from chemotherapy. The aqueous extract of Solanum nigrum leaves (AE-SN) is an essential component in many traditional Chinese medicine formulas for treating cancer, but there is a lack of evidence verifying its tumor suppression efficacy in colorectal cancer. The purpose of this study is to evaluate the tumor suppression efficacy of AE-SN using DLD-1 and HT-29 human colorectal carcinoma cells and examine the combined drug effect when combined with the chemotherapeutic drugs cisplatin, doxorubicin, docetaxel, and 5-fluorouracil. The results indicated that AE-SN induced autophagy via microtubule-associated protein 1 light chain 3 A/B II accumulation but not caspase-3-dependent apoptosis in both cell lines. The IC50s after 48 hours of treatment were 0.541 and 0.948 mg/ml AE-SN in DLD-1 and HT-29, respectively. AE-SN also demonstrated a combined drug effect with all tested drugs by enhancing cytotoxicity in tumor cells. Our results suggest that AE-SN has potential in the development of complementary chemotherapy for colorectal cancer. PMID:23843876

  1. Aqueous Extract of Solanum nigrum Leaves Induces Autophagy and Enhances Cytotoxicity of Cisplatin, Doxorubicin, Docetaxel, and 5-Fluorouracil in Human Colorectal Carcinoma Cells.

    PubMed

    Tai, Chen-Jei; Wang, Chien-Kai; Tai, Cheng-Jeng; Lin, Yi-Feng; Lin, Chi-Shian; Jian, Jiun-Yu; Chang, Yu-Jia; Chang, Chun-Chao

    2013-01-01

    Colorectal cancer is a common cancer worldwide, and chemotherapy is a mainstream approach for advanced and recurrent cases. Development of effective complementary drugs could help improve tumor suppression efficiency and control adverse effects from chemotherapy. The aqueous extract of Solanum nigrum leaves (AE-SN) is an essential component in many traditional Chinese medicine formulas for treating cancer, but there is a lack of evidence verifying its tumor suppression efficacy in colorectal cancer. The purpose of this study is to evaluate the tumor suppression efficacy of AE-SN using DLD-1 and HT-29 human colorectal carcinoma cells and examine the combined drug effect when combined with the chemotherapeutic drugs cisplatin, doxorubicin, docetaxel, and 5-fluorouracil. The results indicated that AE-SN induced autophagy via microtubule-associated protein 1 light chain 3 A/B II accumulation but not caspase-3-dependent apoptosis in both cell lines. The IC50s after 48 hours of treatment were 0.541 and 0.948 mg/ml AE-SN in DLD-1 and HT-29, respectively. AE-SN also demonstrated a combined drug effect with all tested drugs by enhancing cytotoxicity in tumor cells. Our results suggest that AE-SN has potential in the development of complementary chemotherapy for colorectal cancer. PMID:23843876

  2. Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression

    SciTech Connect

    Choi, Seungho; Ku, Ja-Lok

    2011-08-26

    Highlights: {yields} MELK expression significantly increased when the cells are exposed to radiation or 5-FU. {yields} Suppression of MELK caused cell cycle changes and decrease in proliferation. {yields} Radiation or 5-FU treatment after MELK suppression by siRNA induced growth inhibition. -- Abstract: It was reported that the local recurrence would be caused by cancer stem cells acquiring chemo- and radio-resistance. Recently, one of the potential therapeutic targets for colorectal and other cancers has been identified, which is maternal embryonic leucine zipper kinase (MELK). MELK is known as an embryonic and neural stem cell marker, and associated with the cell survival, cell proliferation, and apoptosis. In this study, SNU-503, which is a rectal cancer cell line, was treated with radiation or 5-fluorouracil (5-FU), and elevation of the MELK expression level was observed. Furthermore, the cell line was pre-treated with small interfering RNA (siRNA) against MELK mRNA before treatment of radiation or 5-FU and its effects on cell cycle and proliferation were observed. We demonstrated that knockdown of MELK reduced the proliferation of cells with radiation or 5-FU treatment. In addition, MELK suppression caused changes in cell cycle. In conclusion, MELK could be associated with increased resistance of colorectal cancer cells against radiation and 5-FU.

  3. Tegafur Substitution for 5-Fu in Combination with Actinomycin D to Treat Gestational Trophoblastic Neoplasm.

    PubMed

    Peng, Mei; Ding, Yiling; Yu, Ling; Deng, Yali; Lai, Weisi; Hu, Yun; Zhang, Hongwen; Wu, Xianqing; Fan, Hong; Ding, Hui; Wu, Yilin; Tao, Guangshi

    2015-01-01

    Although 5-fluorouracil (5-Fu) combination chemotherapy provides a satisfactory therapeutic response in patients with gestational trophoblastic neoplasms (GTNs), it has severe side effects. The current study analyzed the therapeutic effects and side effects of tegafur plus actinomycin D (Act-D) vs. 5-Fu plus Act-D for the treatment of GTNs based on controlled historical records. A total of 427 GTN cases that received tegafur and Act-D combination chemotherapy at the Second Xiangya Hospital of XiangYa Medical School between August 2003 and July 2013 were analyzed based on historical data. A total of 393 GTN cases that received 5-Fu plus Act-D between August 1993 and July 2003 at the same hospital were also analyzed, which constituted the control group. The therapeutic effects, toxicity and side effects after chemotherapy were compared between the groups. The overall response rate was 90.63% in the tegafur+Act-D group (tegafur group) and 92.37% in the 5-Fu+Act-D group (5-Fu group); these rates were not significantly different (P > 0.05). However, the incidence rates of myelosuppression (white blood cell decline), gastrointestinal reactions (nausea, vomiting, dental ulcer, and diarrhea), skin lesions and phlebitis were lower in the tegafur group than in the 5-Fu group (P < 0.05). The results of this study may provide useful data for the clinical application of tegafur in GTN treatment. PMID:26599757

  4. Tegafur Substitution for 5-Fu in Combination with Actinomycin D to Treat Gestational Trophoblastic Neoplasm

    PubMed Central

    Peng, Mei; Ding, Yiling; Yu, Ling; Deng, Yali; Lai, Weisi; Hu, Yun; Zhang, Hongwen; Wu, Xianqing; Fan, Hong; Ding, Hui; Wu, Yilin; Tao, Guangshi

    2015-01-01

    Although 5-fluorouracil (5-Fu) combination chemotherapy provides a satisfactory therapeutic response in patients with gestational trophoblastic neoplasms (GTNs), it has severe side effects. The current study analyzed the therapeutic effects and side effects of tegafur plus actinomycin D (Act-D) vs. 5-Fu plus Act-D for the treatment of GTNs based on controlled historical records. A total of 427 GTN cases that received tegafur and Act-D combination chemotherapy at the Second Xiangya Hospital of XiangYa Medical School between August 2003 and July 2013 were analyzed based on historical data. A total of 393 GTN cases that received 5-Fu plus Act-D between August 1993 and July 2003 at the same hospital were also analyzed, which constituted the control group. The therapeutic effects, toxicity and side effects after chemotherapy were compared between the groups. The overall response rate was 90.63% in the tegafur+Act-D group (tegafur group) and 92.37% in the 5-Fu+Act-D group (5-Fu group); these rates were not significantly different (P > 0.05). However, the incidence rates of myelosuppression (white blood cell decline), gastrointestinal reactions (nausea, vomiting, dental ulcer, and diarrhea), skin lesions and phlebitis were lower in the tegafur group than in the 5-Fu group (P < 0.05). The results of this study may provide useful data for the clinical application of tegafur in GTN treatment. PMID:26599757

  5. 5-fluorouracil-induced leukoencephalopathy in patients with breast cancer.

    PubMed

    Choi, S M; Lee, S H; Yang, Y S; Kim, B C; Kim, M K; Cho, K H

    2001-06-01

    The purpose of this study is to determine the characteristic clinical features, radiologic findings, and precipitating and prognostic factors in the patients with breast cancer and with 5-Fluorouracil (5-FU)-induced leukoencephalopathy. We reviewed the medical records of six breast cancer patients who developed leukoencephalopathy after chemotherapy which included 5-FU and also evaluated thorough neurological examinations including mini-mental status examination, cerebrospinal fluid studies, brain images and brain biopsies. Six patients exhibited slowly progressing neurologic symptoms characterized by the impairment of cognitive function, abulia, ataxic gait, and/or akinetic mutism. None of the patients had any specific causes or etiologic factors for leukoencephalopathy. Brain MRI in all patients showed diffuse periventricular white matter changes in the T2-weighted MR image. Brain biopsy in Patient 1 showed fragmented axonal fiber and minimally deprived myelination with many scattered macrophages. Five patients who treated with steroids at the onset of neurological symptoms showed clinical improvement, regardless of their age, sex, the pathology and stage of breast cancer, or the total dosage of chemotherapeutic agents. We conclude that leukoencephalopathy in these cases could be attributable to 5-FU neurotoxicity and suggest that the administration of steroids might be the treatment of choice. PMID:11410695

  6. The aggravating factors of hyperammonemia related to 5-fluorouracil infusion--a report of two cases.

    PubMed

    Kikuta, Shu; Asakage, Takahiro; Nakao, Kazunari; Sugasawa, Masashi; Kubota, Akatsuki

    2008-06-01

    Hyperammonemia or hyperammonemic leukoencephalopathy sometimes occurs as an adverse event after 5-fluorouracil (5-FU) chemotherapy. The actual mechanism responsible for hyperammonemia by 5-FU administration is not known. Patient 1, a 48-year-old woman with cervical esophageal squamous cell carcinoma (SCC) presented with transient hyperammonemic leukoencephalopathy after undergoing combined chemotherapy (750mg/body/day of 5-FU for 5 days+100mg/body/day of cisplatin). Patient 2, a 58-year-old man with oropharyngeal and lower esophageal SCCs presented with hyperammonemia without leukoencephalopathy while undergoing combined chemotherapy (1200mg/body/day of 5-FU for 5 days+120mg/body/day of cisplatin). The neural symptoms of both patients improved after the termination of 5-FU administration and the early administration of fluid replacement. Ammonia can accumulate in the body when catabolism is insufficient because of an impairment in the urea cycle. The excess production of ammonium from 5-FU catabolites in addition to aggravating factors, e.g., renal dysfunction, constipation and body weight loss, may explain the transient hyperammonemia seen in the present two cases. The incidence of hyperammonemia by 5-FU administration will be one of the adverse events to need care in future and may be decreased by being aware of the presence of renal dysfunction, taking measures to prevent constipation, and nutritional management. PMID:17826933

  7. Folic Acid Supplementation Adversely Affects Chemosensitivity of Colon Cancer Cells to 5-fluorouracil.

    PubMed

    Ishiguro, Lisa; Yang, Michael; Sohn, Kyoung-Jin; Streutker, Catherine J; Grin, Andrea; Croxford, Ruth; Kim, Young-In

    2016-07-01

    Folic acid (FA) fortification and widespread supplemental use have significantly increased folate status in North America. Furthermore, >50% of colorectal cancer patients use FA supplement. The increased folate status may interfere with cancer chemotherapy. We investigated the effect of FA supplementation on chemosensitivity of human colon cancer cells to 5-fluorouracil (5-FU) using a xenograft model. Mice harboring human HCT116 colon cancer xenografts were randomized to receive the control, or 4× or 12.5× supplemental levels of FA. Within each diet group, mice were randomized to receive 5-FU+leucovorin or saline and xenograft growth and characteristics were determined. The expression of genes involved in folate metabolism and cancer treatment was determined. FA supplementation and 5-FU significantly interacted to influence xenograft growth (P < 0.007). At the control level, 5-FU significantly inhibited the growth of the xenografts (P < 0.0001). However, at the 4× supplemental level, 5-FU-treated xenografts grew faster than untreated xenografts (P = 0.048) while at the 12.5× supplemental level, 5-FU exhibited no effect. Cell proliferation, degree of necrosis, and expression of the selected genes did not significantly differ by the supplemental levels of FA. Our data suggest that FA supplementation may be detrimental to 5-FU chemotherapy of colon cancer and pose public health concern. PMID:27175995

  8. Inhibition of Transient Receptor Potential Channel 5 Reverses 5-Fluorouracil Resistance in Human Colorectal Cancer Cells*

    PubMed Central

    Wang, Teng; Chen, Zhen; Zhu, Yifei; Pan, Qiongxi; Liu, Yanjun; Qi, Xiaowei; Jin, Linfang; Jin, Jian; Ma, Xin; Hua, Dong

    2015-01-01

    5-Fluorouracil (5-Fu) is commonly used in the chemotherapy of colorectal cancer (CRC), but resistance to 5-Fu occurs in most cases, allowing cancer progression. Suppressing ABCB1 (ATP-binding cassette, subfamily B, member 1), which is a pump overproduced in cancer cells to export cytotoxic drugs, is an attractive strategy to overcome drug resistance. In the present study, transient receptor potential channel TrpC5 was found to be overproduced at the mRNA and protein levels together with ABCB1 in 5-Fu-resistant human CRC HCT-8 (HCT-8/5-Fu) and LoVo (LoVo/5-Fu) cells. More nuclear-stabilized β-catenin accumulation was found in HCT-8/5-Fu and LoVo/5-Fu cells than in HCT-8 and LoVo cells. Suppressing TrpC5 expression with TrpC5-specific siRNA inhibited the canonical Wnt/β-catenin signal pathway, reduced the induction of ABCB1, weakened the ABCB1 efflux pump, and caused a remarkable reversal of 5-Fu resistance in HCT-8/5-Fu and LoVo/5-Fu cells. On the contrary, enforcing TrpC5 expression resulted in an activated Wnt/β-catenin signal pathway and up-regulation of ABCB1. Taken together, we demonstrated an essential role of TrpC5 in ABCB1 induction and drug resistance in human CRC cells via promoting nuclear β-catenin accumulation. PMID:25404731

  9. Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss.

    PubMed

    Raghu Nadhanan, Rethi; Abimosleh, Suzanne M; Su, Yu-Wen; Scherer, Michaela A; Howarth, Gordon S; Xian, Cory J

    2012-06-01

    Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day(-1)·rat(-1)) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H(2)O + Sal, H(2)O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H(2)O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFα, osteoclast marker receptor activator of nuclear factor-κB, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss. PMID:22436700

  10. New chitosan nanospheres for the delivery of 5-fluorouracil: preparation, characterization and in vitro studies.

    PubMed

    Cavalli, Roberta; Leone, Federica; Minelli, Rosalba; Fantozzi, Roberto; Dianzani, Chiara

    2014-01-01

    The aim of this work was to develop new chitosan nanospheres for the delivery of 5-fluorouracil (5-FU). Drug loaded nanospheres were prepared using a technique derived from a combination of coacervation and emulsion droplet coalescence methods. The size and morphology of nanospheres were characterized by laser light scattering and transmission electron microscopy. The 5-FU interaction with chitosan nanospheres was investigated by DSC analysis and FT-IR spectroscopy. The in vitro release was studied by dialysis bag technique. Cytotoxicity of 5-FU loaded chitosan nanospheres was evaluated in vitro on HT29 and PC-3 cell lines. The effects of 5-FU loaded chitosan nanospheres on adhesion of tumor cells to human umbilical vein endothelial cells (HUVEC) were also investigated. 5-FU loaded chitosan nanospheres appeared with a spherical shape, with a mean diameter of about 200 nm and a negative zeta potential of about - 6.0 mV. The successful interaction between drug and chitosan nanosphere matrix was demonstrated by both DSC and FT-IR analyses. The quantitative determination of 5-FU was assayed by UV-Vis analysis. The encapsulation efficiency of 5-FU content was about 70%. A kinetic study of in vitro release demonstrated that the percentages of 5-FU delivered from nanospheres was approx. 10% after 3 hours. The in vitro studies showed that 5-FU loaded nanospheres were effective in reducing tumor cell proliferation in a time- and concentration-dependent manner. 5-FU nanospheres were also able to inhibit both HT29 and PC-3 adhesion to HUVEC after 48 hours of treatment. PMID:24499357

  11. 5-Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial.

    PubMed

    Tsavaris, N B; Tentas, K; Kosmidis, P; Mylonakis, N; Sakelaropoulos, N; Kosmas, C; Lisaios, B; Soumilas, A; Mandrekois, D; Tsetis, A; Klonaris, C

    1996-10-01

    Leucovorin (LV) enhances the activity of 5-fluorouracil (5FU). Based on these data, we performed a randomized trial with 5FU, epirubicin (EPI), mitomycin C(MMC) with/ without LV in advanced gastric cancer (AGC). The purpose of our study was to investigate if the addition of LV improved the response rate of the combination 5FU EPI, MMC (FEM) over FEM. From January 1988 until April 1994, 88 patients with recurrent or metastatic AGC were randomly received 5FU, EPI, MMC with (group A) or without (group B) LV. Between the two arms of the study no difference was noticed in sex, performance status, primary site of tumor, and lymph node metastases. Therapy included group A (5FU 600 mg/m2/day, i.v. bolus, on days 1, 8, 29, 36, and EPI 45 mg/m2/day, i.v. bolus, on days 1 and 29, MMC 10 mg/m2/day, i.v. bolus, on day 1) and group B (the same as group A plus LV 200 mg/m2/day by 2 h intravenous infusion with 5FU intravenous push at midinfusion). No significant difference in response rate was noticed between the two treatment arms; there were two (5%) patients with complete response in group A, and five (12%) in A and 11 (26%) partial responders in group B (p < 0.1). A significantly higher number of patients achieving stable disease was observed in group B; 19 (44%) in comparison to group A 10 (24%) (p < 0.048). There were more patients with progressive disease in group A 25 (59%) than in group B 12 (28%) (p < 0.003) (Table 2). No difference was noted in mean duration of response: group A, 15.8 (6-31) weeks; and group B, 17.6 (6-28) weeks. The mean time to progression was for group A [11.4 (6-35) weeks] and for group B [17.6 (8-33) weeks]. Mean survival was for group A [27.4 (12-59) weeks] and for group B [30.6 (17-53) weeks], for 50% of patients. Causes of death were, for group A, 40 patients from disease progression and two sudden deaths; for group B, causes of death were for 41 patients disease progression and two sudden deaths. There were two patients in group A and one in

  12. Double-blind randomised placebo-controlled phase III study of an E. coli extract plus 5-fluorouracil versus 5-fluorouracil in patients with advanced colorectal cancer.

    PubMed

    Unger, C; Häring, B; Kruse, A; Thumann, A; Schneider, B; Clemm, C; Weber, B; Clevert, H D; Hockertz, S; Kalousek, M B

    2001-01-01

    The primary aim of this study was to evaluate the toxicity (mucositis, diarrhea and leucopenia) of a therapy with 5-fluorouracil (CAS 51-21-8; 5-FU) plus an E. coli extract (LC-Extract, Laves coli extract, Colibiogen inject, cell-free soluble fraction from lysed E. coli, Laves strain) in comparison with 5-FU plus placebo. Secondary endpoints included general toxicity, response rate according to WHO, survival time and quality of life. 164 patients with advanced colorectal cancer were enrolled in this randomised, placebo-controlled, double-blind, multicenter phase III study. The treatment consisted of 0.167 ml/kg/d LC-Extract or placebo followed by 500-750 mg/m2/d 5-FU on five consecutive days, repeated every three weeks for up to six treatment cycles. 158 (77 verum, 81 placebo) patients were evaluable for toxicity, 144 (72 verum, 72 placebo) evaluable for response. The therapy with LC-Extract was well tolerated. Adverse events that occurred during the study were mainly judged as 5-FU- or tumor-related. Toxicity from treatment with 600 mg/m2/d 5-FU in both treatment groups was very low. After treatment with 750 mg/m2/d 5-FU patients in the placebo-group experienced a higher CTC toxicity than in the LC-Extract groups. Remission rate and survival time showed a slight trend in favour of LC-Extract. These results suggest a positive benefit-risk ratio of the additional application of LC-Extract to 5-FU in the treatment of advanced colorectal cancer especially for administration of high doses of 5-FU. PMID:11367875

  13. Pharmacokinetic, biodistribution and therapeutic efficacy of 5-fluorouracil-loaded pH-sensitive PEGylated liposomal nanoparticles in HCT-116 tumor bearing mouse

    PubMed Central

    Udofot, Ofonime; Affram, Kevin; Smith, Taylor; Tshabe, Bulumko; Krishnan, Sunil; Sachdeva, Mandip; Agyare, Edward

    2016-01-01

    The objective of the study was to investigate the pharmacokinetics and efficacy of 5-FU entrapped pH-sensitive liposomal nanoparticles with surface-modified anti-epidermal growth factor receptor (EGFR) antibody (pHLNps-5-FU) delivery system. Cytotoxicity of 5-FU and pHLNps-5-FU was determined in vitro against HCT-116 cells. The biodistribution and pharmacokinetic parameters of the administered 5-FU and pHLNps-5-FU as well as efficacy of 5-FU and pHLNps-5-FU were determined in HCT-116 subcutaneous mouse model. Mean size of pHLNp-5-FU was 164.3 ± 8.4 nm with entrapment efficiency (E.E) of 54.17%. While cytotoxicity of 5-FU and pHLNps-5-FU showed a strong dose-dependent, pHLNps-5-FU proved to be more effective (2–3 fold high) than that of 5-FU against HCT-116 cells. Pharmacokinetic study showed a prolonged plasma circulation of pHLNps-5-FU and a more significant body exposure while accumulation of pHLNps-5-FU in tumor was significantly higher than that of free 5-FU. Further, the efficacy of pHLNps-5-FU, was greater than free 5-FU at equivalent 5-FU dose. The study suggests that pHLNps may be an effective drug delivery system to enhance the anticancer activity of 5-FU against colorectal tumor growth. PMID:27200415

  14. Effect of intralesional 5 fluorouracil injection in primary pterygium

    PubMed Central

    Khan, Muhammad Saim; Malik, Sidra; Basit, Imran

    2016-01-01

    Objective: To determine mean change in visual acuity, corneal astigmatism and clinical appearance of pterygium after intralesional injection of 5-Fluorouracil. Methods: This was a Quasi experimental study conducted at Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan from June 2014 to May 2015. Total 68 eyes of 54 patients were included in the study. Patients were treated by injecting 0.1 ml of 5-FU (5mg) weekly injections for 04 weeks. All the patients underwent ophthalmic clinical examination that included Uncorrected distant visual acuity (UCVA), corrected distant visual acuity (CDVA), keratometery with Auto Ref-keratometer (RK-F1, Canon) and slit lamp examination before and 04 weeks after the last injection. Results: Total 68 eyes of 54 patients (18 females and 36 males) were treated with intralesional injection of 5 FU. Out of total, 30 were right eyes while 38 were left eyes. Age of patients ranged from 23 to 53 years with mean age of 39.2 ± 4.90 years. Mean UCVA and corneal astigmatism before treatment were 0.162 ± 0.167 and 2.12 ± 1.53 respectively while the same parameters 04 weeks after last injection of 5 FU were 0.166 ± 0.168 and 1.92±1.45 respectively. The magnitude of induced change in astigmatism was (0.235 ± 1.35). Ninety seven percent of the patients showed improvement in clinical appearance. Conclusion: Intralesional 5-FU injection results in significant clinical and cosmetic improvement of primary pterygium. PMID:27022360

  15. Thymoquinone subdues tumor growth and potentiates the chemopreventive effect of 5-fluorouracil on the early stages of colorectal carcinogenesis in rats

    PubMed Central

    Kensara, Osama Adnan; El-Shemi, Adel Galal; Mohamed, Amr Mohamed; Refaat, Bassem; Idris, Shakir; Ahmad, Jawwad

    2016-01-01

    Colorectal cancer (CRC) is one of the most prevalent cancers and has a high mortality rate. Insensitivity and the limited therapeutic efficacy of its standard chemotherapeutic drug, 5-fluorouracil (5-FU), represents an important challenge in CRC treatment. The robust antitumor properties of thymoquinone (TQ), the main bioactive constituent of Nigella sativa, have recently been demonstrated on different cancers. We investigated whether TQ could potentiate the chemopreventive effect of 5-FU to eradicate the early stages of CRC and elucidated its underlying mechanisms. An intermediate-term (15 weeks) model of colorectal tumorigenesis was induced in male Wistar rats by azoxymethane (AOM), and the animals were randomly and equally divided into five groups: control, AOM, AOM/5-FU, AOM/TQ, and AOM/5-FU/TQ. TQ (35 mg/kg/d; 3 d/wk) was given during the seventh and 15th weeks post-AOM injection, while 5-FU was given during the ninth and tenth weeks (12 mg/kg/d for 4 days; then 6 mg/kg every other day for another four doses). At week 15, the resected colons were subjected to macroscopic, histopathological, molecular, and immunohistochemical examinations. Interestingly, 5-FU/TQ combination therapy resulted in a more significant reduction on AOM-induced colorectal tumors and large aberrant crypts foci than treatment with the individual drugs. Mechanistically, 5-FU and TQ remarkably cooperated to repress the expression of procancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF, and TBRAS and upregulate the expression of anti-tumorigenesis DKK-1, CDNK-1A, TGF-β1, TGF-βRII, Smad4, and GPx. Overall, our findings present the first report describing the in vivo enhancement effect of combined TQ and 5-FU against early stages of CRC; however, further studies are required to determine the value of this combination therapy in an advanced long-term model of CRC and also to realize its clinical potential. PMID:27468227

  16. Galactosylated nanostructured lipid carriers for delivery of 5-FU to hepatocellular carcinoma.

    PubMed

    Varshosaz, Jaleh; Hassanzadeh, Farshid; Sadeghi, Hojjat; Khadem, Mostafa

    2012-09-01

    The aim of the present study was to design a targeted delivery system of 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). Lactobionic acid (LB) was conjugated to stearyl amine (SA) by a chemical reaction. The nanostructured lipid carriers (NLCs), containing LB conjugate, lecithin, glyceryl monostearate, oil [oleic acid (OA) or Labrafac 5 or 10%], and 5-FU, were dissolved in alcohol/acetone, the oil phase was added to the aqueous phase containing Tween 80 or Solutol(®) HS15 (0.25 or 0.5%), and NLCs were prepared by an emulsification-solvent diffusion method. Physical properties and drug release were studied in NLCs. The thiazolyl blue tetrazolium bromide assay was used to study the cytotoxicity of NLCs on HepG(2) cells, and the cellular uptake of NLCs was determined by flow cytometry. Fourier transform infrared spectroscopy and (1)H-NMR spectra confirmed the successful conjugation of LB and SA. The optimized NLCs consisted of 0.5% Solutol HS15 and 10% OA oil. The particle size of these nanoparticles was 139.2 nm, with a zeta potential of -18 mV, loading efficiency of 34.2%, release efficiency after 2 hours of the release test was 72.6%, and crystallinity was 0.63%. The galactosylated NLCs of 5-FU were cytotoxic on the HepG(2) cell line in a half concentration of 5-FU and seems promising in reducing 5-FU dose in HCC. PMID:22385296

  17. The influence of the structure and the composition of water/AOT-Tween 85/IPM microemulsion system on transdermal delivery of 5-fluorouracil.

    PubMed

    Yanyu, Xiao; Fang, Liu; Qineng, Ping; Hao, Cai

    2012-12-01

    The purpose of this study was to investigate the influence of the structure and the composition of water/Aerosol-OT (AOT)-Tween 85/isopropylmyristate (IPM) microemulsion system (WATI) on transdermal delivery of 5-fluorouracil (5-FU). The structure of WATI was characterized by measuring surface tension, density, viscosity, electric conductivity, and differential scanning calorimetry. The effect of the drug loading, water content, component compositions and the amount of mixed surfactant on permeation of 5-FU through mice skin was evaluated by using Franz-type diffusion cells. The results in vitro implied that WATI was W/O microemulsion when the water content was below 20 wt% at fixed 20 wt% of mixed surfactant at 25°C, then might be transformed to a bicontinuous structure, finally, formed O/W microemulsion with water content over 30 wt%. Increase of the drug loading can directly facilitate the penetration of the drug across the skin. Drug diffusion after 12 h from the bicontinuous microemulsion (795.1 ± 22.3 µg·cm(-2)) would be fastest compared to that from the W/O microemulsion (650.2 ± 11.7 µg·cm(-2)) and the O/W microemulsion (676.6 ± 14.8 µg·cm(-2)). The combination of AOT and IPM could bring about synergistic effect on the skin enhancement, however, Tween 85 in WATI decreased the cumulative permeation amount of 5-FU. The content of mixed surfactant had no effect on the permeation of 5-FU at fixed surfactant/cosurfactant ratio (K(m) = 2). Thus, the increased transdermal delivery the hydrophilic drug of 5-FU was found to be concerned with both of the structure and the composition of WATI. PMID:22324326

  18. The over-expression of FGFR4 could influence the features of gastric cancer cells and inhibit the efficacy of PD173074 and 5-fluorouracil towards gastric cancer.

    PubMed

    Li, Jingjing; Ye, Yanwei; Wang, Min; Lu, Lisha; Han, Chao; Zhou, Yubing; Zhang, Jingmin; Yu, Zujiang; Zhang, Xiefu; Zhao, Chunlin; Wen, Jianguo; Kan, Quancheng

    2016-05-01

    The aim was to investigate the function of fibroblast growth factor receptor 4 (FGFR4) in gastric cancer (GC) and explore the treatment value of agent targeted to FGFR4. Function assays in vitro and in vivo were performed to investigate the discrepancy of biological features among the GC cells with different expression of FGFR4. GC cells were treated with the single and combination of PD173074 (PD, an inhibitor of FGFR4) and 5-fluorouracil (5-Fu). The invasion ability were stronger, and the apoptosis rates were lower in MGC803 and BGC823 cells treated with FGFR4-LV5 (over-expression of FGFR4 protein) (P < 0.05). The proliferation ability of GC cells is reduced when treated by the single and combination of 5-Fu and PD while that of the FGFR4-LV5 group was less inhibited compared with control group (P < 0.05). The apoptosis rates are remarkably increased in GC cells treated with the single and combination of 5-Fu and PD (P < 0.05). However, the apoptosis rate obviously is reduced in GC cells treated with FGFR4-LV5 compared with control group (P < 0.05). The expression of PCNA and Bcl-XL is remarkably decreased, and the expression of Caspase-3 and cleaved Caspase-3 is obviously increased in GC cells treated with the single and combination of 5-Fu and PD. The tumor volumes of nude mice in FGFR4-LV5 group were much more increased (P < 0.05). The over-expression of FGFR4 enhanced the proliferation ability of GC in vitro and in vivo. The combination of 5-Fu and PD exerted synergetic effect in weakening the proliferation ability and promoting apoptosis in GC cells, while the over-expression of FGFR4 might inhibit the efficacy of two drugs. PMID:26662569

  19. Cooperative inhibitory effect of sinomenine combined with 5-fluorouracil on esophageal carcinoma

    PubMed Central

    Wang, Jing; Yang, Zi-Rong; Dong, Wei-Guo; Zhang, Ji-Xiang; Guo, Xu-Feng; Song, Jia; Qiu, Shi

    2013-01-01

    AIM: To investigate the inhibitory effects of sinomenine (SIN) combined with 5-fluorouracil (5-FU) on esophageal carcinoma in vitro and in vivo. METHODS: Esophageal carcinoma (Eca-109) cells were cultured in DMEM. The single or combined growth inhibition effects of SIN and 5-FU on the Eca-109 cells were examined by measuring the absorbance of CCK-8 dye in living cells. Hoechst 33258 staining and an Annexin V/PI apoptosis kit were used to detect the percentage of cells undergoing apoptosis. Western blotting was used to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis. SIN at 25 mg/kg and 5-FU at 12 mg/kg every 3 d, either combined or alone, was injected into nude mice and tumor growth inhibition and side effects of the drug treatment were observed. RESULTS: SIN and 5-FU, both in combination and individually, significantly inhibited the proliferation of Eca-109 cells and induced obvious apoptosis. Furthermore, the combined effects were greater than those of the individual agents (P < 0.05). Annexin V/PI staining and Hoechst 33258 staining both indicated that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone were significantly different from the control (P < 0.05). The up-regulation of Bax and down-regulation of Bcl-2 showed that the essential mechanism of apoptosis induced by SIN and 5-FU occurs via the mitochondrial pathway. SIN and 5-FU alone significantly inhibited the growth of tumor xenografts in vivo, and the combined inhibition rate was even higher (P < 0.05). During the course of chemotherapy, no obvious side effects were observed in the liver or kidneys. CONCLUSION: The combined effects of SIN and 5-FU on esophageal carcinoma were superior to those of the individual compounds, and the drug combination did not increase the side effects of chemotherapy. PMID:24363520

  20. Prolonged intraperitoneal infusion of 5-fluorouracil using a novel carrier solution.

    PubMed Central

    Kerr, D. J.; Young, A. M.; Neoptolemos, J. P.; Sherman, M.; Van-Geene, P.; Stanley, A.; Ferry, D.; Dobbie, J. W.; Vincke, B.; Gilbert, J.; el Eini, D.; Dombros, N.; Fountzilas, G.

    1996-01-01

    A novel peritoneal carrier solution, Icodextrin 20 (7.5%), has allowed exploration of prolonged, intraperitoneal (i.p.) infusion of the cytotoxic drug 5-fluorouracil (5-FU). A phase I and pharmacokinetic study was performed to determine the toxicities and maximum tolerated dose of prolonged and continuous intraperitoneal 5-FU in patients with peritoneal carcinomatosis. Seventeen patients were entered into this study. Each patient had a Tenckhoff catheter placed into the peritoneal cavity under general anaesthetic. After initial flushing and gradual increase in exchange volumes with Icodextrin 20, 5-FU was administered daily from Monday to Friday, 50% as a bolus in the exchange bag and 50% in an elastomeric infusor device delivering continuous 5-FU to the peritoneal cavity at 2 ml h-1. Treatment was continued for 12 weeks or until intolerable toxicity developed. Abdominal pain and infective peritonitis proved to be the main dose-limiting toxicities. Initial problems with infective peritonitis were overcome by redesign of the delivery system, and it proved possible to deliver 300 mg m-2 5-FU daily (5 days per week) for 12 weeks. Pharmacokinetic studies showed i.p. steady-state 5-FU concentrations (mean 47 500 ng ml-1) that were > 1000-fold higher than systemic venous levels (mean 30 ng ml-1). PMID:8980409

  1. Effect of laser phototherapy on enzymatic activity of salivary glands of hamsters treated with 5-Fluorouracil.

    PubMed

    Campos, Luana; Nicolau, José; Arana-Chavez, Victor E; Simões, Alyne

    2014-01-01

    The chemotherapeutic agent 5-Fluorouracil (5-FU) can induce salivary gland hypofunction (SGH); however, previous studies did not reach final conclusions on the influence of this drug on glandular tissue. Thus, the aim of this study was to investigate the effect of 5-FU on submandibular (SMs) and sublingual glands (SLs), as well as, the effect of laser phototherapy (LPT) on SGH induced by 5-FU. Eighty-five hamsters were divided into three groups: control (C), chemotherapy (CT) and laser (L), and the SGH was induced by two injections of 5-FU in groups CT and L. The irradiation was performed using a diode (λ780 nm/20 mW/5 J cm(-2)/0.2 J and 10 s per point/spot size of 0.04 cm(2)) and applied daily. On the euthanasia day, SMs and SLs were removed and biochemical analyses were carried out. The lactate dehydrogenase activity was increased in group CT when compared with group C for SLs and SMs (P < 0.05). In addition, the peroxidase and catalase activities were increased and superoxide dismutase was decreased by 5-FU (P < 0.05). However, LPT appears to be a protective mechanism against oxidative stress, tending to alter the activity of these antioxidant enzymes, suggesting LPT as a promising therapy to modulate the 5-FU harmful effect. PMID:24172058

  2. Combination therapy with methotrexate and 5-fluorouracil: a prospective randomized clinical trial of order of administration.

    PubMed

    Coates, A S; Tattersall, M H; Swanson, C; Hedley, D; Fox, R M; Raghavan, D

    1984-07-01

    Because of biochemical and tissue culture evidence casting doubt on the physiologic relevance of reported synergy afforded by sequential administration of methotrexate (MTX) followed by 5-fluorouracil (5-FU), a randomized controlled clinical trial was conducted in 108 patients with advanced cancer, including 70 with squamous cell carcinoma (SCC) of the head and neck, nine with SCC of other primary sites, 24 with colorectal, and five with gastric adenocarcinomas. Patients were randomized to receive weekly therapy consisting of MTX followed one hour later by 5-FU, or 5-FU followed one hour later by MTX. There was a trend to higher tumor response rates in patients treated with MTX before 5-FU (45% v 33% overall; 65% v 39% in patients with previously untreated head and neck cancer), but these differences were not significant, either by chi-square test or by multivariate stepwise logistic regression. The trend in survival favoring the reverse sequence of 5-FU before MTX was not significant in univariate analyses. Stepwise multivariate Cox model analysis showed that Eastern Cooperative Oncology Group performance status at study entry was the major prognostic factor for survival (P less than 0.001), but among the 70 patients with head and neck cancer, the sequence of drug administration was the only other significant prognostic factor for survival, and favored the sequence of 5-FU followed by MTX (P less than 0.025). PMID:6376719

  3. Topical Delivery of 5-Fluorouracil from Pheroid™ Formulations and the In Vitro Efficacy Against Human Melanoma.

    PubMed

    Chinembiri, Tawona N; Gerber, Minja; du Plessis, Lissinda; du Preez, Jan; du Plessis, Jeanetta

    2015-12-01

    Drug delivery vehicles can influence the topical delivery and the efficacy of an active pharmaceutical ingredient (API). In this study, the influence of Pheroid™ technology, which is a unique colloidal drug delivery system, on the skin permeation and antimelanoma efficacy of 5-fluorouracil were investigated. Lotions containing Pheroid™ with different concentrations of 5-fluorouracil were formulated then used in Franz cell skin diffusion studies and tape stripping. The in vitro efficacy of 5-fluorouracil against human melanoma cells (A375) was investigated using a flow cytometric apoptosis assay. Statistically significant concentrations of 5-fluorouracil diffused into and through the skin with Pheroid™ formulations resulting in an enhanced in vitro skin permeation from the 4.0% 5-fluorouracil lotion (p < 0.05). The stratum corneum-epidermis and epidermis-dermis retained 5-fluorouracil concentrations of 2.31 and 6.69 μg/ml, respectively, after a diffusion study with the 4.0% Pheroid™ lotion. Subsequent to the apoptosis assay, significant differences were observed between the effect of 13.33 μg/ml 5-fluorouracil in Pheroid™ lotion and the effects of the controls. The results obtained suggest that the Pheroid™ drug delivery system possibly enhances the flux and delivery of 5-fluorouracil into the skin. Therefore, using Pheroid™ could possibly be advantageous with respect to topical delivery of 5-fluorouracil. PMID:25956486

  4. MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4.

    PubMed

    Wei, Xueju; Wang, Weibin; Wang, Lanlan; Zhang, Yuanyuan; Zhang, Xian; Chen, Mingtai; Wang, Fang; Yu, Jia; Ma, Yanni; Sun, Guotao

    2016-04-01

    Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21. PMID:26864640

  5. Polymeric nanoparticles for oral delivery of 5-fluorouracil: Formulation optimization, cytotoxicity assay and pre-clinical pharmacokinetics study.

    PubMed

    Mattos, Ana Cristina de; Altmeyer, Clescila; Tominaga, Tania Toyomi; Khalil, Najeh Maissar; Mainardes, Rubiana Mara

    2016-03-10

    Poly(lactic acid) (PLA) or poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) blend nanoparticles were developed loading 5-fluorouracil (5-FU), an antitumor agent broadly used in therapy. A 2(3) factorial experimental design was conducted to indicate an optimal formulation and demonstrate the influence of the interactions of components on the mean particle size and drug encapsulation efficiency. Optimized PLA nanoparticles presented 294nm and 51% of 5-FU encapsulation efficiency and PLA-PEG blend nanoparticles presented 283nm and 55% of 5-FU encapsulation efficiency. In vitro release assay demonstrated after 320h about 50% of 5-FU was released from PLA and PLA-PEG blend nanoparticles. Release kinetics of 5-FU from nanoparticles followed second order and the release mechanism calculated by Korsmeyer-Peppas model was diffusion and erosion. In the assessment of cytotoxicity over Hep-2 tumor cells, PLA or PLA-PEG blend nanoparticles presented similar IC50 value than free 5-FU. Pharmacokinetic parameters after oral administration of 5-FU were improved by nanoencapsulation. Bioavailability, Cmax, Tmax, t1/2 and distribution volume were significantly improved, while clearance were decreased. PEG presence in nanoparticles didn't influence physicochemical and biological parameters evaluated. PLA and PLA-PEG nanoparticles can be potential carriers for oral delivery of 5-FU. PMID:26775869

  6. Optimized synthesis of glycyrrhetinic acid-modified chitosan 5-fluorouracil nanoparticles and their characteristics

    PubMed Central

    Cheng, Mingrong; Chen, Houxiang; Wang, Yong; Xu, Hongzhi; He, Bing; Han, Jiang; Zhang, Zhiping

    2014-01-01

    The nanoparticle drug delivery system, which uses natural or synthetic polymeric material as a carrier to deliver drugs to targeted tissues, has a broad prospect for clinical application for its targeting, slow-release, and biodegradable properties. Here, we used chitosan (CTS) and hepatoma cell-specific binding molecule glycyrrhetinic acid to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared (IR) spectra and hydrogen-1 nuclear magnetic resonance. The GA-CTS/5-fluorouracil (5-FU) nanoparticles were synthesized by combining GA-CTS and 5-FU and conjugating 5-FU onto the GA-CTS nanomaterial. The central composite design was performed to optimize the preparation process as CTS:tripolyphosphate sodium (TPP) weight ratio =5:1, 5-FU:CTS weight ratio =1:1, TPP concentration =0.05% (w/v), and cross-link time =50 minutes. GA-CTS/5-FU nanoparticles had a mean particle size of 193.7 nm, a polydispersity index of 0.003, a zeta potential of +27.4 mV, and a drug loading of 1.56%. The GA-CTS/5-FU nanoparticle had a protective effect on the drug against plasma degrading enzyme, and provided a sustained release system comprising three distinct phases of quick, steady, and slow release. Our study showed that the peak time, half-life time, mean residence time and area under the curve of GA-CTS/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (Cmax) was lower. We demonstrated that the nanoparticles accumulated in the liver and have significantly inhibited tumor growth in an orthotropic liver cancer mouse model. PMID:24493926

  7. Development of in situ gelling and bio adhesive 5-Fluorouracil enema.

    PubMed

    Wang, Lu-Lu; Zheng, Wen-Sheng; Chen, Shao-Hua; Fang, Xia-Qin

    2013-01-01

    In this study, a novel 5-Fluorouracil (5-FU) enema with good bio adhesion and temperature sensitivity was developed using in situ gelling technology. The preparation was formulated as a free-flowing liquid before use, while a layer of gel film was quickly formed when administered in the rectum, with a large contact surface area. It also demonstrated good biocompatibility, appropriate gel strength and bio adhesive force with excellent adhesion to rectal mucosa and prolonged action time, allowing more effective drug absorption and diffusion to surrounding tissues. Poloxamer 407 and poloxamer 188 were applied to adjust the gelling temperature. With the addition of carbopol and polycarbophil (bio adhesive substances), the solubility of 5-FU and gel strength increased, the temperature of gelation and the surface area of drug contact on mucous epithelium decreased. Decreased adhesive force between the preparation and the mucous membrane of the rectum was demonstrated with improving carbopol and polycarbophil's concentration. In vitro release demonstrated that 5-FU in situ gelling enema with different bases had a rapid and almost complete drug release. We used an optimized formulation of P407/P188/polycarbophil/5-FU (17/2.5/0.2/1.0) for animal experiments. The result showed that the drug evenly covered the surface of the rectum and there was no leakage in 6 hours. The in situ gelling enema showed significantly higher rectal tissue levels of 5-FU compared with suppository and intravenous administration, indicating that 5-FU could be well absorbed due to the enlarged releasing area, longer retention time and larger amount of dissolved active ingredients. Systemically, 5-FU levels in the enema group were similar to those in the suppository group and significantly lower than the intravenous group. The enema was not associated with morphological damage to rectal tissue. These results suggest that the bio adhesive and in situ gelling enema could be a more effective rectal

  8. Neoadjuvant Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Radiation for Rectal Cancer

    SciTech Connect

    Dipetrillo, Tom; Pricolo, Victor; Lagares-Garcia, Jorge; Vrees, Matt; Klipfel, Adam; Cataldo, Tom; Sikov, William; McNulty, Brendan; Shipley, Joshua; Anderson, Elliot; Khurshid, Humera; Oconnor, Brigid; Oldenburg, Nicklas B.E.; Radie-Keane, Kathy; Husain, Syed; Safran, Howard

    2012-01-01

    Purpose: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. Methods and Materials: Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m{sup 2}/week for 6 weeks), and continuous infusion 5-FU (200 mg/m{sup 2}/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m{sup 2}/week. Resection was performed 4-8 weeks after the completion of chemoradiation. Results: The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). Conclusions: Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.

  9. 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation

    PubMed Central

    Wang, Juan; Peng, Liang; Zhang, Ruihua; Zheng, Zihan; Chen, Chun; Cheung, Ka Lung; Cui, Miao; Bian, Guanglin; Xu, Feihong; Chiang, David; Hu, Yuan; Chen, Ye; Lu, Geming; Yang, Jianjun; Zhang, Hui; Yang, Jianfei; Zhu, Hongfa; Chen, Shu-hsia; Liu, Kebin; Zhou, Ming-Ming; Sikora, Andrew G.; Li, Liwu; Jiang, Bo; Xiong, Huabao

    2016-01-01

    While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without apparent effect on Treg, TH2, and significantly suppresses thymidylate synthase (TS) expression in TH17 and TH1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs TH17 and TH1 cell differentiation without affecting the differentiation of either Treg or TH2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing TH17 and TH1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing TH17 and TH1 immune responses. PMID:27027355

  10. Thymidylate synthase expression and activity: relation to S-phase parameters and 5-fluorouracil sensitivity.

    PubMed Central

    Mirjolet, J. F.; Barberi-Heyob, M.; Merlin, J. L.; Marchal, S.; Etienne, M. C.; Milano, G.; Bey, P.

    1998-01-01

    Six human cancer cell lines exhibiting a large range of sensitivity to 5-fluorouracil (5-FU) were evaluated for thymidylate synthase (TS) and p53 gene expression, TS and dihydropyrimidine dehydrogenase (DPD) activity, as well as cell cycle parameters, S-phase fraction (SPF), bromodeoxyuridine labelling index (LI) and S-phase duration (SPD). All these parameters were investigated for 7 days in asynchronously growing cell populations and compared with the cell sensitivity to 5-FU. No significant correlation was found between S-phase parameters and TS gene expression and/or activity. TS activity was higher in proliferating cells; however, it was not significantly higher in rapidly growing cell lines with short SPD. Neither TS gene expression nor activity was found to correlate with 5-FU sensitivity. On the another hand, a statistically significant correlation (P < 0.0001) was observed between LI and SPD and 5-FU sensitivity. The present results suggest that cell cycle parameters such as SPD and/or LI could be better parameters for 5-FU sensitivity prediction than TS gene expression and/or activity. This could be especially informative in cases of concomitant radio-chemotherapy as S-phase parameters are already proposed for hyperfractionated radiotherapy planning. PMID:9662252

  11. Heterochromatin Protein 1 Binding Protein 3 Expression as a Candidate Marker of Intrinsic 5-Fluorouracil Resistance

    PubMed Central

    HADAC, JAMIE N.; MILLER, DEVON D.; GRIMES, IAN C.; CLIPSON, LINDA; NEWTON, MICHAEL A.; SCHELMAN, WILLIAM R.; HALBERG, RICHARD B.

    2016-01-01

    Background Despite receiving post-operative 5-fluorouracil (5-FU)-based chemotherapy, approximately 50% of patients with stage IIIC colon cancer experience recurrence. Currently, no molecular signature can predict response to 5-FU. Materials and Methods Mouse models of colon cancer have been developed and characterized. Individual tumors in these mice can be longitudinally monitored and assessed to identify differences between those that are responsive and those that are resistant to therapy. Gene expression was analyzed in serial biopsies that were collected before and after treatment with 5-FU. Colon tumors had heterogeneous responses to treatment with 5-FU. Microarray analysis of pretreatment biopsies revealed that Hp1bp3, a gene encoding heterochromatin protein 1 binding protein 3, was differentially expressed between sensitive and resistant tumors. Conclusion Using mouse models of human colorectal cancer, Hp1bp3 was identified as a candidate marker of intrinsic 5-FU resistance and may represent a potential biomarker for patient stratification or a target of clinical importance. PMID:26976970

  12. Targeted delivery of 5-fluorouracil to cholangiocarcinoma cells using folic acid as a targeting agent.

    PubMed

    Ngernyuang, Nipaporn; Seubwai, Wunchana; Daduang, Sakda; Boonsiri, Patcharee; Limpaiboon, Temduang; Daduang, Jureerut

    2016-03-01

    There are limits to the standard treatment for cholangiocarcinoma (CCA) including drug resistance and side effects. The objective of this study was to develop a new technique for carrying drugs by conjugation with gold nanoparticles and using folic acid as a targeting agent in order to increase drug sensitivity. Gold nanoparticles (AuNPs) were functionalized with 5-fluorouracil (5FU) and folic acid (FA) using polyethylene glycol (PEG) shell as a linker (AuNPs-PEG-5FU-FA). Its cytotoxicity was tested in CCA cell lines (M139 and M213) which express folic acid receptor (FA receptor). The results showed that AuNPs-PEG-5FU-FA increased the cytotoxic effects in the M139 and M213 cells by 4.76% and 7.95%, respectively compared to those treated with free 5FU+FA. It is found that the cytotoxicity of the AuNPs-PEG-5FU-FA correlates with FA receptor expression suggested the use of FA as a targeted therapy. The mechanism of cytotoxicity was mediated via mitochondrial apoptotic pathway as determined by apoptosis array. In conclusion, our findings shed some light on the use of gold nanoparticles for conjugation with potential compounds and FA as targeted therapy which contribute to the improvement of anti-cancer drug efficacy. In vivo study should be warranted for its effectiveness of stability, biosafety and side effect reduction. PMID:26706547

  13. Quantitative, Qualitative and In Vitro Evaluation of Solid Lipid Nanoparticles Containing 5-Fluorouracil

    NASA Astrophysics Data System (ADS)

    Majrad, Mohamed Saleh

    The primary goal of this research work was to develop solid lipid nanoparticles (SLNs) containing 5-Flourouracil and to evaluate its effect on various cell lines. The solid lipid nanoparticles were prepared through a new temperature modulated solidification technique developed in our laboratory. Particle size analysis by dynamic light scattering (DLS) and morphology evaluation by transmission electron microscopy (TEM) demonstrated that the SLNs are nanoparticulates. Cytotoxic activity of SLN loaded 5-Fluorouracil showed a decrease in viability when compared to pure solution of 5-FU on PC-3 and Caco-2 cell line. Blank SLN showed no decrease in cell viability when the concentration increased. Biocompatibility studies of SLNs in human RBCs indicated that 5-FU SLN formulations are compatible. Bovine permeability study shows that apparent permeability for 5-FU SLN was 0.000348 cm/s and 1.339 cm/s for 5-FU solution. The preliminary results from various in vitro evaluations suggest that 5-FU loaded SLNs have the potential to be used as an anti-cancer drug delivery system.

  14. Photoreactivity of 5-fluorouracil under UVB light: photolysis and cytotoxicity studies.

    PubMed

    Miolo, Giorgia; Marzano, Christine; Gandin, Valentina; Palozzo, Angelo C; Dalzoppo, Daniele; Salvador, Alessia; Caffieri, Sergio

    2011-08-15

    The photodegradation of the chemotherapeutic agent 5-fluorouracil (5-FU) under UVB light was studied both in aqueous and methanol solutions and in systemic and topical formulations. As monitored by HPLC, photodegradation in solution takes place in a concentration dependent manner; thus, the solution for parenteral administration (10(-1) M) showed negligible loss of the active principle. On the contrary, the commercial cream containing 5% of 5-FU showed low stability under UVB exposure. When dissolved either in water or methanol, 5-FU yields two photoproducts which have been characterized as two isomers coming from the addition of the solvent to the 5,6 double bond of the drug. As a consequence, photomodified 5-FU loses its antiproliferative activity on HCT-15 and HeLa cells. MS analysis showed that photoaddition occurred with nucleophilic amino acids, such as cysteine and serine, while susceptible amino acids (cysteine and methionine) were oxidized. In fact, high production of the superoxide anion under UVB light as well as photooxidation of BSA suggests protein photodamage as a mechanism of photosensitization. Indeed, some phototoxicity was shown in experiments on NCTC keratinocytes and MCF-7 resistant cells irradiated with UVB light. The interactions with these biological targets may contribute to skin phototoxicity and photoallergy induced by 5-FU in vivo. PMID:21728355

  15. Synergetic Effect of SLN-Curcumin and LDH-5-Fu on SMMC-7721 Liver Cancer Cell Line

    PubMed Central

    Zhu, Rongrong; Wu, Xianzheng; Xiao, Yu; Gao, Bo; Xie, Qian

    2013-01-01

    Abstract Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5-Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%±2.5% and 16.7%±1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma. PMID:23808828

  16. Synergetic effect of SLN-curcumin and LDH-5-Fu on SMMC-7721 liver cancer cell line.

    PubMed

    Zhu, Rongrong; Wu, Xianzheng; Xiao, Yu; Gao, Bo; Xie, Qian; Liu, Hui; Wang, Shilong

    2013-10-01

    Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5-Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%±2.5% and 16.7%±1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma. PMID:23808828

  17. Hyaluronic acid embedded cellulose acetate phthlate core/shell nanoparticulate carrier of 5-fluorouracil.

    PubMed

    Garg, Ashish; Rai, Gopal; Lodhi, Santram; Jain, Alok Pal; Yadav, Awesh K

    2016-06-01

    Aim of this research was to prepare hyaluronic acid-modified-cellulose acetate phthalate (HAC) core shell nanoparticles (NPs) of 5-fluorouracil (5-FU). HAC copolymer was synthesized and confirmed by fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. HAC NPs with 5-FU were prepared using HAC copolymer and compared with 5-FU loaded cellulose acetate phthalate (CAP) NPs. NPs were characterized by atomic force microscopy (AFM), particle size, zeta potential, polydispersity index, entrapment efficiency, in-vitro release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). HAC NPs were found slower release (97.30% in 48h) than (99.25% in 8h) CAP NPs. In cytotoxicity studies, showed great cytotoxic potential of 5-FU loaded HAC NPs in A549, MDA-MD-435 and SK-OV-3 cancer cellline. HAC NPs showing least hemolytic than CAP NPs and 5-FU. Area under curve (AUC), maximum plasma concentration (Cmax), mean residence time (MRT) and time to reach maximum plasma concentration Tmax), were observed 4398.1±7.90μgh/mL, 145.45±2.25μg/L, 45.74±0.25h, 72±0.50h, respectively of HAC NPs and 119.92±1.78μgh/mL, 46.38±3.42μg/L, 1.2±0.25h, 0.5±0.02h were observed in plain 5-FU solution. In conclusion, HAC NPs is effective deliver carrier of 5-FU for lung cancer. PMID:26955748

  18. Intra-lesional 5 fluorouracil for the management of recurrent pterygium

    PubMed Central

    Said, D G; Faraj, L A; Elalfy, M S; Yeung, A; Miri, A; Fares, U; Otri, A M; Rahman, I; Maharajan, S; Dua, H S

    2013-01-01

    Aim Recurrence is the most common complication arising from pterygium surgery. The aim of this study was to investigate the effectiveness of 5 fluorouracil (5FU) in halting the recurrence of pterygium after surgical excision. Methods A retrospective review of patients treated for pterygium recurrence was carried out. Patients with recurrent (secondary) pterygium were treated with multiple weekly intra-lesional injections of 0.1–0.2 ml (2.5–5 mg) 5FU post-operatively depending on the size of the recurrence. The treatment was started within 1 month from the date of recurrence. The time from surgery to start of recurrence, previous treatment modalities, and number of recurrences were documented. The number of injections required to induce arrest of progression and/or regression of vascularity and fleshiness of the pterygium and any complications related to 5FU treatment were examined. Results Fifteen eyes from 14 patients with recurrent pterygium treated with intra-lesional 5FU injections were analysed. Three of the 15 eyes had undergone a secondary excision and 12 had undergone a primary excision. In all, 93.3% of patients showed regression of the fibrovascular tissue (thickness and vascularity) and arrest of progression following a dose of 0.1–0.2 ml (2.5–5 mg) 5FU. Twelve eyes required three injections or fewer, whereas one patient required eight injections. This beneficial effect was maintained over an average follow-up period of 17 months. No complications from 5FU were observed. Conclusion The use of weekly intra-lesional 5FU injections for the treatment of recurrent pterygium is safe and effective in limiting the progression and inducing the regression of recurrent pterygium. The number of injections can be tailored according to clinical need. PMID:23807385

  19. 5-Fluorouracil, folinic acid and cisplatin in advanced colorectal cancer: a pilot study.

    PubMed

    Tsavaris, N; Tentas, K; Bacoyiannis, C; Katsikas, M; Sakelaropoulos, N; Kosmas, C; Daliani, D; Kosmidis, P

    1995-08-01

    The combination of 5-fluorouracil (5-FU) and folinic acid (FA) has demonstrated activity in colorectal cancer (CC). Cisplatin is reported to have synergistic activity with 5-FU. We examined the combination FA + 5-FU + cisplatin in patients who had previously received chemotherapy with FA + 5-FU and relapsed. Two months after the last dose of FA + 5-FU and documentation of relapse, patients continued with the regimen consisting of cisplatin 20 mg/m2 in 15 min i.v. infusion followed by FA 500 mg/m2 in 1 h i.v. infusion, in the middle of which 5-FU 500 mg/m2 i.v. bolus was administered, with adequate post-hydration. This was repeated weekly for 4 weeks followed by a 2 week rest, for a maximum of six cycles. A total of 30 patients with CC that had relapsed to the combination of FA + 5-FU were treated; 23 had previous surgery and none had radiotherapy. Local recurrence was found in eight patients, metastases in the liver in 21, in lymph nodes in six, lung six and peritoneal metastases in seven. Seven patients responded partially. Toxicity requiring dose reduction or discontinuation of treatment included neutropenia 42% (grade 3:7%), mucositis 28% (grade 1:2), diarrhea 63% (Grade 3:10%), nausea-vomiting 55% (Grade 3:10%), increased creatinine value in three patients and peripheral neuropathy in two patients. We conclude that evaluation of this regimen shows substantial toxicity, with satisfactory response as a second line chemotherapy in these heavily pretreated patients. PMID:7579565

  20. A designed 5-fluorouracil-based bridged silsesquioxane as an autonomous acid-triggered drug-delivery system.

    PubMed

    Giret, Simon; Théron, Christophe; Gallud, Audrey; Maynadier, Marie; Gary-Bobo, Magali; Garcia, Marcel; Wong Chi Man, Michel; Carcel, Carole

    2013-09-16

    Two new prodrugs, bearing two and three 5-fluorouracil (5-FU) units, respectively, have been synthesized and were shown to efficiently treat human breast cancer cells. In addition to 5-FU, they were intended to form complexes through H-bonds to an organo-bridged silane prior to hydrolysis-condensation through sol-gel processes to construct acid-responsive bridged silsesquioxanes (BS). Whereas 5-FU itself and the prodrug bearing two 5-FU units completely leached out from the corresponding materials, the prodrug bearing three 5-FU units was successfully maintained in the resulting BS. Solid-state NMR ((29) Si and (13) C) spectroscopy show that the organic fragments of the organo-bridged silane are retained in the hybrid through covalent bonding and the (1) H NMR spectroscopic analysis provides evidence for the hydrogen-bonding interactions between the prodrug bearing three 5-FU units and the triazine-based hybrid matrix. The complex in the BS is not affected under neutral medium and operates under acidic conditions even under pH as high as 5 to deliver the drug as demonstrated by HPLC analysis and confirmed by FTIR and (13) C NMR spectroscopic studies. Such functional BS are promising materials as carriers to avoid the side effects of the anticancer drug 5-FU thanks to a controlled and targeted drug delivery. PMID:23929826

  1. Dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms and their association with 5-fluorouracil/leucovorin chemotherapy in colorectal cancer.

    PubMed

    Zhu, Andrew X; Puchalski, Thomas A; Stanton, Vincent P; Ryan, David P; Clark, Jeffrey W; Nesbitt, Steven; Charlat, Olga; Kelly, Patrick; Kreconus, Elaine; Chabner, Bruce A; Supko, Jeffrey G

    2004-02-01

    The causes of interpatient variation in severe toxicity resulting from treatment with weekly 5-fluorouracil (5-FU)/ leucovorin (LV) are poorly understood. This study was undertaken to examine the contribution of commonly occurring polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene to interpatient variability in 5-FU pharmacokinetics and toxicity. Patients with stage III/IV colorectal cancer were treated by bolus intravenous (I.V.) injection with 500 mg/m2 doses of 5-FU and LV once every week. The pharmacokinetics of 5-FU was determined on weeks 1 and 4. Genotyping assays were developed for 8 polymorphisms in the DPYD gene. A well-characterized functional polymorphism in the 5' untranslated region of the thymidylate synthase (TS) gene was also analyzed. A cohort of 22 patients (15 male, 7 female) with a median age of 61 years was evaluated. Although there was no relationship between the area under the plasma concentration time curve (AUC) for the first dose of 5-FU and worst-grade toxicity during the first cycle of therapy, 3 of the 4 patients in whom the AUC on week 4 was more than equal to 5 microgram/h/mL greater than the value for the first dose experienced grade 3/4 toxicity during subsequent treatment. Among the 8 polymorphisms in the DPYD gene, 7 were found to vary in the study population but none were significantly associated with the AUC of 5-FU. There was no relationship between the DPYD and TS genotypes examined and 5-FU toxicity. Extensive polymorphism in the DPYD gene was observed; however, no conclusive correlations existed between the DPYD and TS genotype and 5-FU pharmacokinetics or toxicity. Decreases in 5-FU clearance in certain patients may provide insight into the increased toxicity following repetitive cycles of treatment with weekly I.V. bolus 5-FU. The present study offers useful themes for undertaking larger prospective pharmacogenetic studies in the future. PMID:15025795

  2. The c-MYC-ABCB5 axis plays a pivotal role in 5-fluorouracil resistance in human colon cancer cells.

    PubMed

    Kugimiya, Naruji; Nishimoto, Arata; Hosoyama, Tohru; Ueno, Koji; Enoki, Tadahiko; Li, Tao-Sheng; Hamano, Kimikazu

    2015-07-01

    c-MYC overexpression is frequently observed in various cancers including colon cancer and regulates many biological activities such as aberrant cell proliferation, apoptosis, genomic instability, immortalization and drug resistance. However, the mechanism by which c-MYC confers drug resistance remains to be fully elucidated. In this study, we found that the c-MYC expression level in primary colorectal cancer tissues correlated with the recurrence rate following 5-fluorouracil (5-FU)-based adjuvant chemotherapy. Supporting this finding, overexpression of exogenous c-MYC increased the survival rate following 5-FU treatment in human colon cancer cells, and knockdown of endogenous c-MYC decreased it. Furthermore, c-MYC knockdown decreased the expression level of ABCB5, which is involved in 5-FU resistance. Using a chromatin immunoprecipitation assay, we found that c-MYC bound to the ABCB5 promoter region. c-MYC inhibitor (10058-F4) treatment inhibited c-MYC binding to the ABCB5 promoter, leading to a decrease in ABCB5 expression level. ABCB5 knockdown decreased the survival rate following 5-FU treatment as expected, and the ABCB5 expression level was increased in 5-FU-resistant human colon cancer cells. Finally, using a human colon cancer xenograft murine model, we found that the combined 5-FU and 10058-F4 treatment significantly decreased tumorigenicity in nude mice compared with 5-FU or 10058-F4 treatment alone. 10058-F4 treatment decreased the ABCB5 expression level in the presence or absence of 5-FU. In contrast, 5-FU treatment alone increased the ABCB5 expression level. Taken together, these results suggest that c-MYC confers resistance to 5-FU through regulating ABCB5 expression in human colon cancer cells. PMID:25689483

  3. Effects of 5-Fluorouracil on Morphology, Cell Cycle, Proliferation, Apoptosis, Autophagy and ROS Production in Endothelial Cells and Cardiomyocytes

    PubMed Central

    Focaccetti, Chiara; Bruno, Antonino; Magnani, Elena; Bartolini, Desirée; Principi, Elisa; Dallaglio, Katiuscia; Bucci, Eraldo O.; Finzi, Giovanna; Sessa, Fausto; Noonan, Douglas M.; Albini, Adriana

    2015-01-01

    Antimetabolites are a class of effective anticancer drugs interfering in essential biochemical processes. 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used in the treatment of several solid tumors (gastro-intestinal, gynecological, head and neck, breast carcinomas). Therapy with fluoropyrimidines is associated with a wide range of adverse effects, including diarrhea, dehydration, abdominal pain, nausea, stomatitis, and hand-foot syndrome. Among the 5-FU side effects, increasing attention is given to cardiovascular toxicities induced at different levels and intensities. Since the mechanisms related to 5-FU-induced cardiotoxicity are still unclear, we examined the effects of 5-FU on primary cell cultures of human cardiomyocytes and endothelial cells, which represent two key components of the cardiovascular system. We analyzed at the cellular and molecular level 5-FU effects on cell proliferation, cell cycle, survival and induction of apoptosis, in an experimental cardioncology approach. We observed autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes. Reactive oxygen species (ROS) elevation characterized the endothelial response. These responses were prevented by a ROS scavenger. We found induction of a senescent phenotype on both cell types treated with 5-FU. In vivo, in a xenograft model of colon cancer, we showed that 5-FU treatment induced ultrastructural changes in the endothelium of various organs. Taken together, our data suggest that 5-FU can affect, both at the cellular and molecular levels, two key cell types of the cardiovascular system, potentially explaining some manifestations of 5-FU-induced cardiovascular toxicity. PMID:25671635

  4. Cytotoxicity of 5-fluorouracil-loaded pH-sensitive liposomal nanoparticles in colorectal cancer cell lines

    PubMed Central

    Udofot, Ofonime; Affram, Kevin; Israel, Bridg'ette; Agyare, Edward

    2015-01-01

    5-Fluorouracil (5-FU) is widely used in cancer therapy, either alone or in combination with other anti-cancer drugs. However, poor membrane permeability and a short half-life (5-20 min) due to rapid metabolism in the body necessitate the continuous administration of high doses of 5-FU to maintain the minimum therapeutic serum concentration. This is associated with significant side effects and a possibility of severe toxic effects. This study aimed to formulate 5-FU-loaded pH-sensitive liposomal nanoparticles (pHLNps-5-FU) and evaluate 5-FU release characteristics and anti-cancer effect of pHLNps-5-FU. Particle size and zeta potential were determined using a particle size analyzer. The release patterns of pHLNps-5-FU formulations were evaluated at 37°C at pH 3, 5, 6.5, and 7.4, while drug release kinetics of 5-FU from a pHLNp3–5-FU formulation were determined at pH 3 and 7.4 at different time points (37°C). Cell viability and clonogenic studies were conducted to evaluate the effectiveness of pHLNps-5-FU against HCT-116 and HT-29 cell lines while cellular uptake of rhodamine-labeled pHLNps-5-FU was determined by flow cytometry and confocal imaging. The average sizes of the pHLNp1–5-FU, pHLNp2–5-FU and pHLNp3–5-FU liposomes were 200nm ± 9.8nm, 181.9 nm ± 9.1 nm, and 164.3 nm ± 8.4 nm respectively. In vitro drug release of 5-FU from different pHLNps-5-FU formulations was the highest at pH 3.8. Both cell lines treated with pHLNps-5-FU exhibited reduced viability, two- or three-fold lower than that of 5-FU-treated cells. Flow cytometry and confocal imaging confirmed high uptake of rhodamine-labeled pHLNps-5-FU in both cell lines. The drug release profile of the chosen pHLNp3-5-FU formulation was optimal at pH 3 and had the poorest release profile at pH 7.4. The release profile of pHLNp3-5-FU showed that 5-FU release was two-fold higher at pH 3 than that at pH 7.4. This study demonstrates that pHLNp3-5-FU may be a potential candidate for the treatment of

  5. Synthesis of liver-targeting dual-ligand modified GCGA/5-FU nanoparticles and their characteristics in vitro and in vivo

    PubMed Central

    Cheng, Mingrong; Gao, Xiaoyan; Wang, Yong; Chen, Houxiang; He, Bing; Li, Yingchun; Han, Jiang; Zhang, Zhiping

    2013-01-01

    Nanoparticle drug delivery systems using polymers hold promise for clinical applications. We synthesized dual-ligand modified chitosan (GCGA) nanoparticles using lactic acid, glycyrrhetinic acid, and chitosan to target the liver in our previous studies. We then synthesized the GCGA/5-FU nanoparticles by conjugating 5-fluorouracil (5-FU) onto the GCGA nanomaterial, which had a mean particle size of 239.9 nm, a polydispersity index of 0.040, a zeta potential of +21.2 mV, and a drug loading of 3.90%. GCGA/5-FU nanoparticles had good slow release properties, and the release process could be divided into five phases: small burst release, gentle release, second burst release, steady release, and slow release. Inhibitory effects of GCGA/5-FU on tumor cells targeted the liver, and were time and dose dependent. GCGA nanoparticles significantly prolonged the efficacy of 5-FU on tumor cells, and alleviated the resistance of tumor cells to 5-FU. GCGA/5-FU nanoparticles were mostly concentrated in the liver, indicating that the GCGA nanoparticles were liver targeting. GCGA/5-FU nanoparticles significantly suppressed tumor growth in orthotopic liver transplantation mouse model, and improved mouse survival. PMID:24232303

  6. Preventive effect of Daiokanzoto (TJ-84) on 5-fluorouracil-induced human gingival cell death through the inhibition of reactive oxygen species production.

    PubMed

    Yoshida, Kaya; Yoshioka, Masami; Okamura, Hirohiko; Moriyama, Satomi; Kawazoe, Kazuyoshi; Grenier, Daniel; Hinode, Daisuke

    2014-01-01

    Daiokanzoto (TJ-84) is a traditional Japanese herbal medicine (Kampo formulation). While many Kampo formulations have been reported to regulate inflammation and immune responses in oral mucosa, there is no evidence to show that TJ-84 has beneficial effects on oral mucositis, a disease resulting from increased cell death induced by chemotherapeutic agents such as 5-fluorouracil (5-FU). In order to develop effective new therapeutic strategies for treating oral mucositis, we investigated (i) the mechanisms by which 5-FU induces the death of human gingival cells and (ii) the effects of TJ-84 on biological events induced by 5-FU. 5-FU-induced lactate dehydrogenase (LDH) release and pore formation in gingival cells (Sa3 cell line) resulted in cell death. Incubating the cells with 5-FU increased the expression of nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) and caspase-1. The cleavage of caspase-1 was observed in 5-FU-treated cells, which was followed by an increased secretion of interleukin (IL)-1β. The inhibition of the NLRP3 pathway slightly decreased the effects of 5-FU on cell viability and LDH release, suggesting that NLRP3 may be in part involved in 5-FU-induced cell death. TJ-84 decreased 5-FU-induced LDH release and cell death and also significantly inhibited the depolarization of mitochondria and the up-regulation of 5-FU-induced reactive oxygen species (ROS) and nitric oxide (NO) production. The transcriptional factor, nuclear factor-κB (NF-κB) was not involved in the 5-FU-induced cell death in Sa3 cells. In conclusion, we provide evidence suggesting that the increase of ROS production in mitochondria, rather than NLRP3 activation, was considered to be associated with the cell death induced by 5-FU. The results also suggested that TJ-84 may attenuate 5-FU-induced cell death through the inhibition of mitochondrial ROS production. PMID:25389767

  7. Preventive Effect of Daiokanzoto (TJ-84) on 5-Fluorouracil-Induced Human Gingival Cell Death through the Inhibition of Reactive Oxygen Species Production

    PubMed Central

    Yoshida, Kaya; Yoshioka, Masami; Okamura, Hirohiko; Moriyama, Satomi; Kawazoe, Kazuyoshi; Grenier, Daniel; Hinode, Daisuke

    2014-01-01

    Daiokanzoto (TJ-84) is a traditional Japanese herbal medicine (Kampo formulation). While many Kampo formulations have been reported to regulate inflammation and immune responses in oral mucosa, there is no evidence to show that TJ-84 has beneficial effects on oral mucositis, a disease resulting from increased cell death induced by chemotherapeutic agents such as 5-fluorouracil (5-FU). In order to develop effective new therapeutic strategies for treating oral mucositis, we investigated (i) the mechanisms by which 5-FU induces the death of human gingival cells and (ii) the effects of TJ-84 on biological events induced by 5-FU. 5-FU-induced lactate dehydrogenase (LDH) release and pore formation in gingival cells (Sa3 cell line) resulted in cell death. Incubating the cells with 5-FU increased the expression of nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) and caspase-1. The cleavage of caspase-1 was observed in 5-FU-treated cells, which was followed by an increased secretion of interleukin (IL)-1β. The inhibition of the NLRP3 pathway slightly decreased the effects of 5-FU on cell viability and LDH release, suggesting that NLRP3 may be in part involved in 5-FU-induced cell death. TJ-84 decreased 5-FU-induced LDH release and cell death and also significantly inhibited the depolarization of mitochondria and the up-regulation of 5-FU-induced reactive oxygen species (ROS) and nitric oxide (NO) production. The transcriptional factor, nuclear factor-κB (NF-κB) was not involved in the 5-FU-induced cell death in Sa3 cells. In conclusion, we provide evidence suggesting that the increase of ROS production in mitochondria, rather than NLRP3 activation, was considered to be associated with the cell death induced by 5-FU. The results also suggested that TJ-84 may attenuate 5-FU-induced cell death through the inhibition of mitochondrial ROS production. PMID:25389767

  8. Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

    NASA Astrophysics Data System (ADS)

    Chen, Lijue; She, Xiaodong; Wang, Tao; He, Li; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

    2015-08-01

    Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The

  9. LncRNA—UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p

    PubMed Central

    Bian, Zehua; Jin, Liugen; Zhang, Jiwei; Yin, Yuan; Quan, Chao; Hu, Yaling; Feng, Yuyang; Liu, Heyong; Fei, Bojian; Mao, Yong; Zhou, Leyuan; Qi, Xiaowei; Huang, Shenlin; Hua, Dong; Xing, Chungen; Huang, Zhaohui

    2016-01-01

    Recent preliminary studies reported the in vitro tumor-promoting effects of long non-coding RNA urothelial carcinoma associated 1 (UCA1) in colorectal cancer (CRC). However, the in vivo functions and molecular mechanism of UCA1 in CRC remain unclear. Therefore, we investigated the detailed role and mechanism of UCA1 in CRC. We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Functional assays revealed the in vitro and in vivo growth-promoting function of UCA1 and revealed that UCA1 can decrease the sensitivity of CRC cells to 5-FU by attenuating apoptosis. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC. PMID:27046651

  10. MicroRNA-21-mediated regulation of Sprouty2 protein expression enhances the cytotoxic effect of 5-fluorouracil and metformin in colon cancer cells.

    PubMed

    Feng, Yin-Hsun; Wu, Chao-Liang; Shiau, Ai-Li; Lee, Jenq-Chang; Chang, Jan-Gowth; Lu, Pei-Jung; Tung, Chao-Ling; Feng, Li-Yia; Huang, Wen-Tsung; Tsao, Chao-Jung

    2012-05-01

    Sprouty2 (Spry2) was identified recently as a tumor suppressor gene in cancer cells which inhibits the activation of receptor tyrosine kinases (RTKs). The present study explored the effect of Spry2 in colon cancer cells in order to assess its potential use in the treatment of colon cancer. Expression of Spry2 inhibited the growth of a colon cancer cell line, HCT116, and induced sensitization to fluorouracil (5-FU) and metformin. Spry2 promoted apoptosis of cancer cells in association with activation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) pathway and the blockade of Ras-Raf-Erk signaling. Treatment of Spry2-HCT116 cells with metformin resulted in a more prominent effect on the inhibition of cell migration. Inhibition of microRNA-21 (mir‑21) induced upregulation of Spry2 and PTEN which underscores the importance of mir-21 in Spry2-associated tumorigenesis of the colon. These results point toward a potential strategy for colon cancer treatment worthy of further investigation. PMID:22322462

  11. Synergistic effects of beta-aescin and 5-fluorouracil in human hepatocellular carcinoma SMMC-7721 cells.

    PubMed

    Ming, Z J; Hu, Y; Qiu, Y H; Cao, L; Zhang, X G

    2010-07-01

    The effects and mechanisms of action of beta-aescin and 5-fluorouracil (5-FU), alone and in combination, were studied in human hepatocellular carcinoma SMMC-7721 cells. Growth inhibition, cell cycle distribution, apoptosis, Bcl-2 expression and caspase activity were assessed. The Isobole-method/interaction-index analysis was applied to evaluate the synergy, additivity or antagonism of these agents. The results indicate that mixtures of beta-aescin and 5-FU showed a synergistic effect on the 50% inhibitory effect when their ratio was 4:1 when compared with either agent alone. The mechanism of action could be through the synergistic arrest of the cell cycle, induction of apoptosis, activation of caspases-3, 8 and 9, and down-regulation Bcl-2 expression. The results suggest that mixtures of these two agents had a synergistic inhibitory effect on SMMC-7721 cells, an observation which might be useful for the further development of anti-cancer drugs. PMID:20106644

  12. Non-platinum-based chemotherapy for treatment of advanced gastric cancer: 5-fluorouracil, taxanes, and irinotecan.

    PubMed

    Kang, Byung Woog; Kim, Jong Gwang; Kwon, Oh-Kyoung; Chung, Ho Young; Yu, Wansik

    2014-05-14

    Despite numerous advances in treatment options, advanced gastric cancer (AGC) remains a major public health issue and the leading cause of cancer-related deaths. Cisplatin is one of the most effective broad-spectrum anticancer drugs for AGC and a doublet combination regimen of either cisplatin-based or 5-fluorouracil (5FU)-based chemotherapy is generally used for treatment of patients with AGC. However, there is still no consensus on the best regimen for treating AGC. Recently, various new chemotherapeutic agents, including oral 5FU, taxanes, and irinotecan, have been identified as improving the outcomes for AGC when used as a single agent or in combination with non-platinum chemotherapy. Nonetheless, it is still unclear whether non-platinum-based chemotherapy is a viable treatment option for patients with AGC. Accordingly, this review focuses on the efficacy and tolerability of non-platinum-based chemotherapy for patients with AGC. PMID:24833869

  13. Non-platinum-based chemotherapy for treatment of advanced gastric cancer: 5-fluorouracil, taxanes, and irinotecan

    PubMed Central

    Kang, Byung Woog; Kim, Jong Gwang; Kwon, Oh-Kyoung; Chung, Ho Young; Yu, Wansik

    2014-01-01

    Despite numerous advances in treatment options, advanced gastric cancer (AGC) remains a major public health issue and the leading cause of cancer-related deaths. Cisplatin is one of the most effective broad-spectrum anticancer drugs for AGC and a doublet combination regimen of either cisplatin-based or 5-fluorouracil (5FU)-based chemotherapy is generally used for treatment of patients with AGC. However, there is still no consensus on the best regimen for treating AGC. Recently, various new chemotherapeutic agents, including oral 5FU, taxanes, and irinotecan, have been identified as improving the outcomes for AGC when used as a single agent or in combination with non-platinum chemotherapy. Nonetheless, it is still unclear whether non-platinum-based chemotherapy is a viable treatment option for patients with AGC. Accordingly, this review focuses on the efficacy and tolerability of non-platinum-based chemotherapy for patients with AGC. PMID:24833869

  14. Transient hyperammonemia related to chemotherapy with continuous infusion of high-dose 5-fluorouracil.

    PubMed

    Liaw, C C; Liaw, S J; Wang, C H; Chiu, M C; Huang, J S

    1993-06-01

    Hyperammonemic encephalopathy has been reported in patients receiving chemotherapy (CT). It is characterized by abrupt alteration in mental status with markedly elevated plasma ammonium levels in the absence of obvious liver disease. This paper reports seven patients who developed transient hyperammonemia during chemotherapy. The regimens all included continuous infusion of high-dose 5-fluorouracil (5-FU). The onset of hyperammonemic encephalopathy was 1.5-4 days after the start of CT. Five cases had infection and six had prerenal azotemia at the time of hyperammonemia. After management, plasma ammonium levels all returned to the normal range within 2 days. Except for one persistent coma, status of consciousness cleared completely. The true mechanism of transient hyperammonemia is unclear. The excess production of ammonium due to metabolites of 5-FU added to precipitating factors such as infection, hypovolemia or constipation may be the explanation for transient hyperammonemia in our study. PMID:8358058

  15. 5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection.

    PubMed

    Iskandar, Muhammad Zaid; Quasem, Wahid; El-Omar, Magdi

    2015-01-01

    A 33-year-old man presented to hospital with acute shortness of breath and evolving ST segment changes on ECG 3 days following a cycle of 5-fluorouracil (5-FU) for colon cancer. Despite no cardiac history, subsequent echocardiogram showed severe left ventricular systolic dysfunction. The patient was initially treated with heart failure medications and his coronary angiogram was normal. Chemotherapy was stopped and he was started on nitrates and calcium channel blockers. A repeat echocardiogram and cardiac MRI a week later showed complete resolution of his left ventricular dysfunction and he was discharged home. This case report summarises 5-FU cardiotoxicity, and emphasises the importance of early recognition and correct treatment, as left ventricular systolic dysfunction in this context is potentially reversible. PMID:25935919

  16. The combination therapy of α-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice.

    PubMed

    Aketa, Hiroshi; Tatsumi, Tomohide; Kohga, Keisuke; Tsunematsu, Hinako; Aono, Satoshi; Shimizu, Satoshi; Kodama, Takahiro; Nawa, Takatoshi; Shigekawa, Minoru; Hikita, Hayato; Sakamori, Ryotaro; Hosui, Atsushi; Miyagi, Takuya; Hiramatsu, Naoki; Kanto, Tatsuya; Hayashi, Norio; Takehara, Tetsuo

    2013-09-01

    α-Galactosylceramide (α-GalCer) has been reported to be therapeutic against metastatic liver tumors in mice. However, little is known regarding the efficacy of combined chemo-immunotherapy using α-GalCer and anticancer drugs. In this study, we evaluated the antitumor effect of the combination therapy of α-GalCer and 5-fluorouracil (5-FU) against liver tumors of MC38 colon cancer cells. The liver weights of tumor-bearing mice treated with the combination were significantly lower than those of nontreated mice and of mice treated with 5-FU or α-GalCer alone. No toxic effects on the liver and renal functions were observed in any of the treatment groups. α-GalCer treatment induced significant activation of liver NK cells in vivo, but 5-FU treatment did not. 5-FU treatment resulted in a significant upregulation of NKG2D activating molecules (Rae-1 and H60) and DNAM-1 ligands (CD112 and CD155) on MC38 cells, but α-GalCer did not. The cytolytic activity of α-GalCer-activated liver mononuclear cells against 5-FU-treated MC38 cells was significantly higher than that against nontreated cells. The increase of the cytolytic activity induced by 5-FU partially depended on NKG2D-Rae-1 or H60 signals. Depletion of NK cells significantly inhibited the antitumor efficacy of 5-FU against MC38 liver tumors, which suggested that the antitumor effect of 5-FU partially depended on the cytolytic activity of NK cells. These results demonstrated that the combination therapy of α-GalCer and 5-FU produced synergistic antitumor effects against liver tumors by increasing the expression of NK activating molecules on cancer cells. This study suggests a promising new chemo-immunotherapy against metastatic liver cancer. PMID:23420533

  17. Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil.

    PubMed

    Asara, Yolande; Marchal, Juan A; Carrasco, Esther; Boulaiz, Houria; Solinas, Giuliana; Bandiera, Pasquale; Garcia, Maria A; Farace, Cristiano; Montella, Andrea; Madeddu, Roberto

    2013-01-01

    Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd. PMID:23941782

  18. Cadmium Modifies the Cell Cycle and Apoptotic Profiles of Human Breast Cancer Cells Treated with 5-Fluorouracil

    PubMed Central

    Asara, Yolande; Marchal, Juan A.; Carrasco, Esther; Boulaiz, Houria; Solinas, Giuliana; Bandiera, Pasquale; Garcia, Maria A.; Farace, Cristiano; Montella, Andrea; Madeddu, Roberto

    2013-01-01

    Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd. PMID:23941782

  19. Sequential treatment with betulinic acid followed by 5-fluorouracil shows synergistic cytotoxic activity in ovarian cancer cells

    PubMed Central

    Wang, Ying-Jian; Liu, Jun-Bao; Dou, Yu-Chang

    2015-01-01

    Betulinic acid selectively inhibits the growth of ovarian carcinoma cell lines without affecting the normal cells. In the present study, the effect of 5-fluorouracil (5-FU) and betulinic acid (BA) combination on ovarian carcinoma cells was studied. The results demonstrated that ovarian carcinoma cells on concurrent or 5-FU followed by BA treatment show increased Sub-G1 cell population, increased rate of cell apoptosis and morphological changes in mitochondrial membrane. In OVCAR 432 cells treatment with sequential combination of 5-FU and BA increased the Sub-G1 cell population to 51.3% and growth inhibition rate of > 72%. However, exposure to BA before 5-FU treatment caused a decrease in rate of inhibition to < 35%. Treatment with combination of 5 μM of 5-FU and 1 μM of BA for 48 h, led to an induction of apoptosis in 79.7% and induced morphological changes in OVCAR 432 cells. The Western blot results showed high concentration of cytochrome c in the cell cytosol after 24 h of 5-FU and BA combination treatment. Treatment of BA-responsive RMS-13 cells with 5-FU and BA combination resulted in inhibition of GLI1, GLI2, PTCH1, and IGF2 genes. In addition, we found a significant reduction in hedgehog activity of RMS-13 cells after 5-FU and BA combination treatment by means of a hedgehog-responsive reporter assay. Therefore, 5-FU and BA combination can be a promising regimen for the treatment of ovarian carcinoma. PMID:25755712

  20. Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer: Trends and Challenges

    PubMed Central

    Tang, Jia-Cheng; Feng, Yi-Li; Liang, Xiao; Cai, Xiu-Jun

    2016-01-01

    Objective: 5-Fluorouracil (5-FU)-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice. This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system. Data Sources: All articles published in English from 1996 to date those assess the synergistic effect of autophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed. The search terms were “autophagy” and “5-FU” and (“colorectal cancer” or “hepatocellular carcinoma” or “pancreatic adenocarcinoma” or “esophageal cancer” or “gallbladder carcinoma” or “gastric cancer”). Study Selection: Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency of autophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized. The exclusion criteria for the articles were as follows: (1) new materials (e.g., nanomaterial)-induced autophagy; (2) clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers; and (3) immunogenic cell death for anticancer chemotherapy. Results: Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death. Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce. The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials. Conclusion: Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in

  1. Carcinoembryonic Antigen Expression and Resistance to Radiation and 5-Fluorouracil-Induced Apoptosis and Autophagy.

    PubMed

    Eftekhar, Ebrahim; Jaberie, Hajar; Naghibalhossaini, Fakhraddin

    2016-01-01

    Understanding the mechanism of tumor resistance is critical for cancer therapy. In this study, we investigated the effect of carcinoembryonic antigen (CEA) overexpression on UV-and 5-fluorouracil (5-FU)-induced apoptosis and autophagy in colorectal cancer cells. We used histone deacetylase (HDAC) inhibitor, NaB and DNA demethylating agent, 5-azacytidine (5-AZA) to induce CEA expression in HT29/219 and SW742 colorectal cancer cell lines. MTT assay was used to measure IC50 value of the cells exposed to graded concentrations of 5- FU with either 0.1 mM NaB or 1 μM 5-AZA for 72 h . Using CHO- and SW742-CEA transfectants, we also investigated the effect of CEA expression on UV- and 5-FU-induced apoptosis and autophagy. Treatment of HT29/219 cell line with NaB and 5-AZA increased CEA expression by 29% and 31%, respectively. Compared with control cells, the IC50 value for 5-FU of NaB and 5-AZA-treated cells increased by 40% and 57%, respectively. Treatment of SW742 cells with NaB or 5-AZA increased neither CEA expression nor the IC50 value for 5-FU. In comparison to parental cells, CEA expression also significantly protected transfected cells against UV-induced apoptosis. Decreased proportions of autophagy and apoptosis were also observed in 5-FU treated SW742- and CHO-CEA transfectants. We conclude that CEA expression can effectively protect colorectal cancer cells against radiation and drug-induced apoptosis and autophagy. PMID:27478804

  2. Thymidylate synthase gene amplification in human colon cancer cell lines resistant to 5-fluorouracil.

    PubMed

    Copur, S; Aiba, K; Drake, J C; Allegra, C J; Chu, E

    1995-05-17

    A series of 5-fluorouracil (5-FU)-resistant human colon H630 cancer cell lines were established by continuous exposure of cells to 5-FU. The concentration of 5-FU required to inhibit cell proliferation by 50% (IC50) in the parent colon line (H630) was 5.5 microM. The 5-FU IC50 values for the resistant H630-R1, H630-R10, and H630-R cell lines were 11-, 29-, and 27-fold higher than that for the parent H630 cell line. Using both the radioenzymatic 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) binding and catalytic assays for measurement of thymidylate synthase (TS) enzyme activity, there was significantly increased TS activity in resistant H630-R1 (13- and 23-fold), H630-R10 (37- and 40-fold), and H630-R (24- and 34-fold) lines, for binding and catalytic assays, respectively, compared with the parent H630 line. The level of TS protein, as determined by western immunoblot analysis, was increased markedly in resistant H630-R1 (23-fold), H630-R10 (33-fold), and H630-R (26-fold) cells. Northern analysis revealed elevations in TS mRNA levels in H630-R1 (18-fold), H630-R10 (39-fold), and H630-R (36-fold) cells relative to parent H630 cells. Although no major rearrangements of the TS gene were noted by Southern analysis, there was significant amplification of the TS gene in 5-FU-resistant cells, which was confirmed by DNA slot blot analysis. These studies demonstrate that continuous exposure of human colon cancer cells to 5-FU leads to TS gene amplification and overexpression of TS protein with resultant development of fluoropyrimidine resistance. PMID:7763285

  3. The effects of 5-fluorouracil and interferon-alpha on early healing of experimental intestinal anastomoses.

    PubMed Central

    de Waard, J. W.; Wobbes, T.; de Man, B. M.; van der Linden, C. J.; Hendriks, T.

    1996-01-01

    The continuing search for effective adjuvant therapy after resection of intestinal malignancies has prompted a growing interest in both immediate post-operative regional chemotherapy and the combination of 5-fluorouracil (5-FU) and interferon-alpha as drugs of choice. We have compared the effects of both compounds, alone and together, on early healing of intestinal anastomoses. Four groups (n = 26 each) of rats underwent resection and anastomosis of both ileum and colon: a control group and three groups receiving intraperitoneal 5-FU, interferon-alpha or both on the day of surgery and the next 2 days. Animals were killed 3 or 7 days (n = 10 each) after operation in order to measure anastomotic strength and hydroxyproline content. The remaining six animals in each group were used to study anastomotic collagen synthetic capacity at day 3. Three days after operation, ileal anastomotic bursting pressure was lowered by 37% in the 5-FU/interferon-alpha group (P = 0.0104). At day 7, anastomotic breaking strength was reduced significantly in ileum (P = 0.0221) and colon (P = 0.0054) of the 5-FU/interferon-alpha group and in colon of the interferon-alpha group (P = 0.0221). Collagen synthetic capacity was strongly suppressed by 5-FU but not by interferon-alpha. However, no differences in anastomotic hydroxyproline content were observed between groups at both days 3 and 7. Thus, post-operative use of interferon-alpha, in particular in combination with 5-FU, may be detrimental to anastomotic repair in the intestine. PMID:8795572

  4. Moderate intensity static magnetic fields affect mitotic spindles and increase the antitumor efficacy of 5-FU and Taxol.

    PubMed

    Luo, Yan; Ji, Xinmiao; Liu, Juanjuan; Li, Zhiyuan; Wang, Wenchao; Chen, Wei; Wang, Junfeng; Liu, Qingsong; Zhang, Xin

    2016-06-01

    Microtubules are the fundamental components in mitotic spindle, which plays essential roles in cell division. It was well known that purified microtubules could be affected by static magnetic fields (SMFs) in vitro because of the diamagnetic anisotropy of tubulin. However, whether these effects lead to cell division defects was unknown. Here we find that 1T SMFs induce abnormal mitotic spindles and increase mitotic index. Synchronization experiments show that SMFs delay cell exit from mitosis and cause mitotic arrest. These mimic the cellular effects of a microtubule-targeting drug Paclitaxel (Taxol), which is frequently used in combination with 5-Fluorouracil (5-FU) and Cisplatin in cancer treatment. Using four different human cancer cell lines, HeLa, HCT116, CNE-2Z and MCF7, we find that SMFs increase the antitumor efficacy of 5-FU or 5-FU/Taxol, but not Cisplatin, which indicates that the SMF-induced combinational effects with chemodrugs are drug-specific. Our study not only reveals the effect of SMFs on microtubules to cause abnormal mitotic spindles and delay cells exit from mitosis, but also implies the potential applications of SMFs in combination with chemotherapy drugs 5-FU or 5-FU/Taxol, but not with Cisplatin in cancer treatment. PMID:26775206

  5. 5-Fluorouracil-induced vasculitic injury manifesting as a multiorgan dysfunction in a patient with esophageal carcinoma.

    PubMed

    Zahid, Mohammad Faizan; Masood, Nehal; Shabbir-Moosajee, Munira

    2015-01-01

    5-Fluorouracil (5-FU) is an active chemoetheraputic agent in many malignancies, used both in the curative and metastatic setting. Therefore, the side effect profile of 5-FU is well-described and recognized. Here, we present a case of a 28-year-old male, who received 5-FU and carboplatin concurrently, with radiation, for esophageal carcinoma. On Day 3 of his 5-FU infusion, he developed simultaneous cardiac arrhythmias, renal dysfunction, and aphasia. Magnetic resonance imaging (MRI) of his brain revealed acute demyelination of the white matter corresponding to diffusion restriction, pointing toward a small vessel injury. The 5-FU infusion was promptly discontinued and stress dose steroids were administered. The patient's symptoms resolved rapidly with no residual effects. We believe this is the first case of multisystem, small-vessel, vasculopathy secondary to 5-FU. Early recognition and prompt discontinuation of the offending drug is essential for resolution of symptoms. Steroids, with their anti-inflammatory effects can aid in rapid recovery. PMID:26458637

  6. 5-Fluorouracil Induces Diarrhea with Changes in the Expression of Inflammatory Cytokines and Aquaporins in Mouse Intestines

    PubMed Central

    Sagara, Atsunobu; Matsumoto, Kenjiro; Hasegawa, Satoshi; Sato, Ken; Nishizaki, Maiko; Shoji, Tetsuro; Horie, Syunji; Nakagawa, Takayuki; Tokuyama, Shogo

    2013-01-01

    Although the mechanisms of 5-fluorouracil (5-FU)-induced diarrhea remain unclear, accumulating evidence has indicated that changes in the mucosal immune system and aquaporins (AQPs) may play a role in its pathogenesis. Therefore, we investigated the possible changes in the gene expression of inflammatory cytokines and AQPs in the intestines of mice with 5-FU-induced diarrhea. In the present study, the expressions of mRNAs that encode inflammatory cytokines, TNF-α, IL-1β, IL-6, Il-17A and IL-22, were significantly increased throughout the entire colon of mice that exhibited diarrhea following 5-FU administration. In contrast, the gene expression of IFNγ was upregulated only in the distal colon. These increases were significantly reduced by the administration of etanercept. However, 5-FU-induced diarrhea was not recovered by etanercept. On the other hand, the genes for AQPs 4 and 8 were markedly present in the colon, and these expressions in the intestines were significantly decreased by treatment with 5-FU. These decreases were not reversed by etanercept. These findings suggest TNF-α neutralization had no effect on the acutely 5-FU-induced diarrhea and impaired AQPs but reduced dramatically several inflammatory cytokines. PMID:23382968

  7. Efficacy of cryosurgery and 5-fluorouracil cream 0.5% combination therapy for the treatment of actinic keratosis.

    PubMed

    Hoover, William D; Jorizzo, Joseph L; Clark, Adele R; Feldman, Steven R; Holbrook, Judy; Huang, Karen E

    2014-11-01

    Actinic keratoses (AKs) are on a continuum of progression to squamous cell carcinoma (SCC). The most common AK treatment modalities are lesion-directed cryosurgery and field-directed therapy with 5-fluorouracil (5-FU); however, side effects can affect patient compliance. This study was performed to determine the efficacy and perceived side effects of combination treatment with cryosurgery and a shortened course of 5-FU cream 0.5% for AK lesions. Sixty participants with AK lesions underwent cryosurgery and were then randomized to apply 5-FU cream 0.5% or comparator cream once daily to the study area for 1 week. Participants were evaluated at weeks 3, 4, 8, and 26. After 8 weeks, treatment with cryosurgery and 5-FU cream 0.5% was more likely to result in complete clearance versus cryosurgery alone; however, no statistical difference was found in the complete clearance of AK lesions in the treatment group compared to cryosurgery alone at 26 weeks, while side effects in the treatment group were decreased. This study demonstrated the benefit of combination treatment of cryosurgery with 1 week of 5-FU compared to cryosurgery alone in clearing AK lesions for 2 months. This study shows promise for future studies with larger sample sizes to illustrate increased efficacy and decreased side effects with combination treatment of AKs with cryosurgery and 5-FU. PMID:25474455

  8. Inhibition of Growth and Metastasis of Colon Cancer by Delivering 5-Fluorouracil-loaded Pluronic P85 Copolymer Micelles

    PubMed Central

    Zhu, Pengxi; Zhao, Naping; Sheng, Dandan; Hou, Jing; Hao, Chong; Yang, Xue; Zhu, Bing; Zhang, Shanshan; Han, Zhipeng; Wei, Lixin; Zhang, Li

    2016-01-01

    Hepatic metastasis is the leading cause of mortality of colon cancer, which is still lack of an effective therapy. A new delivery system, pluronic P85 block copolymers, conveying chemotherapeutic agent 5-fluorouracil (5-Fu) for inhibiting growth and metastasis of colon cancer was designed and developed. In this study, we demonstrated that 5-Fu produce strong pesticide effect at lower doses in the present of pluronic P85 compared with control groups. The migration and invasion of HCT116 cells and RKO cells were examined and the results showed that migration and invasion capacities of HCT116 cells and RKO cells were reduced by administering 5-Fu/P85 copolymer micelles in vitro and in vivo which indicating an effectively activity. Interestingly, the content of CD133 + CXCR4+ cells in HCT116 cancer cells and RKO cells treated by 5-Fu/P85 copolymer micelles was decreased. Importantly, the epithelial-mesenchymal transition (EMT) of CD133 + CXCR4+ cells, which was strongly associated with liver metastasis of colon cancer, was also suppressed by giving 5-Fu/P85 copolymer micelles. The results indicated that 5-Fu/P85 copolymer micelles could inhibit the growth and metastasis of colon cancer, which could be attributed to the decrease of the content of CD133 + CXCR4+ cells and suppression of EMT of CD133 + CXCR4+ cells. PMID:26864651

  9. Comparative Label-free LC-MS/MS Analysis of Colorectal Adenocarcinoma and Metastatic Cells Treated with 5-Fluorouracil

    PubMed Central

    Bauer, Kerry M.; Lambert, Paul A.; Hummon, Amanda B.

    2013-01-01

    A label-free mass spectrometric strategy was used to examine the effect of 5-fluorouracil (5-FU) on the primary and metastatic colon carcinoma cell lines, SW480 and SW620, with and without treatment. 5-FU is the most common chemotherapeutic treatment for colon cancer. Pooled biological replicates were analyzed by nanoLC-MS/MS and protein quantification was determined via spectral counting. Phenotypic and proteomic changes were evident and often similar in both cell lines. The SW620 cells were more resistant to 5-FU treatment, with an IC50 2.7-fold higher than that for SW480. In addition, both cell lines showed pronounced abundance changes in pathways relating to antioxidative stress response and cell adhesion remodeling due to 5-FU treatment. For example, the detoxification enzyme NQO1 was increasedwith treatment in both cell lines, while disparate members of the peroxiredoxin family, PRDX2 or PRDX5 and PRDX6, were elevated with 5-FU exposure in either SW480 or SW620, respectively. Cell adhesion associated proteins CTNNB1 and RhoA showed decreased expression with 5-FU treatment in both cell lines. The differential quantitative response in the proteomes of these patient-matched cell lines to drug treatment underscores the subtle molecular differences separating primary and metastatic cancer cells. PMID:22623418

  10. A phase II randomised trial of 5-fluorouracil with or without interferon alpha-2a in advanced colorectal cancer.

    PubMed Central

    Piga, A.; Cascinu, S.; Latini, L.; Marcellini, M.; Bavosi, M.; Acito, L.; Bascioni, R.; Giustini, L.; Francini, G.; Pancotti, A.; Rossi, G.; Del Papa, M.; Carle, F.; Cellerino, R.

    1996-01-01

    With the association of 5-fluorouracil (5-FU) and alpha-interferon (IFN), objective responses as high as 26 63% have been reported in untreated patients with advanced colorectal cancer. However, grade 3-4 toxicity has also been reported. We have conducted a prospective phase II randomised study comparing 5-FU to 5-FU + IFN, to investigate whether the addition of IFN to a weekly 5-FU regimen devoid of significant toxicity used at our institutions could improve the effectiveness of 5-FU while maintaining acceptable toxicity. Patients with histologically proven advanced colorectal carcinoma were randomised to receive 5-FU 500 mg m-2 intravenous (i.v.) bolus on days 1-5 followed by 5-FU 500 mg m-2 i.v. bolus weekly from day 15, with or without IFN alpha-2a intramuscularly (i.m.) 1.5 mU daily on days 6-12 and 3 mU i.m. daily thereafter. The treatment was administered on an outpatient basis. Response was evaluated every 3 months, and treatment continued until progression or after two consecutive judgements of stable disease. Response rate was the main end point of the study. Of 141 patients eligible, 72 were randomised to 5-FU alone (arm A) and 69 to 5-FU + IFN (arm B). Responses were 9/72 (12.5%) in arm A and 6/69 (8.7%) in arm B; complete responses were three in arm A and two in arm B. Progression-free survival (median 4 months) and survival (median 12 months) were identical in the two arms. Toxicity was almost absent in arm A and moderate in arm B, represented mainly by haematological toxicity (usually leucopenia). In conclusion, overall survival was good in both arms of treatment and toxicity was moderate. While the response rate with 5-FU alone was in accord with the literature data, response to 5-FU + IFN was lower than expected. At least at this dosage and schedule, the association of 5-FU and IFN is no better than 5-FU alone and is of no clinical interest. PMID:8826868

  11. Herb-Drug Pharmacokinetic Interaction of a Traditional Chinese Medicine Jia-Wei-Xiao-Yao-San with 5-Fluorouracil in the Blood and Brain of Rat Using Microdialysis

    PubMed Central

    Chiang, Meng-Hsuan; Chang, Li-Wen; Wang, Ju-Wen; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-01-01

    According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS. PMID:25861367

  12. Temperature and magnetism bi-responsive molecularly imprinted polymers: Preparation, adsorption mechanism and properties as drug delivery system for sustained release of 5-fluorouracil.

    PubMed

    Li, Longfei; Chen, Lin; Zhang, Huan; Yang, Yongzhen; Liu, Xuguang; Chen, Yongkang

    2016-04-01

    Temperature and magnetism bi-responsive molecularly imprinted polymers (TMMIPs) based on Fe3O4-encapsulating carbon nanospheres were prepared by free radical polymerization, and applied to selective adsorption and controlled release of 5-fluorouracil (5-FU) from an aqueous solution. Characterization results show that the as-synthesized TMMIPs have an average diameter of about 150 nm with a typical core-shell structure, and the thickness of the coating layer is approximately 50 nm. TMMIPs also displayed obvious magnetic properties and thermo-sensitivity. The adsorption results show that the prepared TMMIPs exhibit good adsorption capacity (up to 96.53 mg/g at 25 °C) and recognition towards 5-FU. The studies on 5-FU loading and release in vitro suggest that the release rate increases with increasing temperature. Meanwhile, adsorption mechanisms were explored by using a computational analysis to simulate the imprinted site towards 5-FU. The interaction energy between the imprinted site and 5-FU is -112.24 kJ/mol, originating from a hydrogen bond, Van der Waals forces and a hydrophobic interaction between functional groups located on 5-FU and a NIPAM monomer. The electrostatic potential charges and population analysis results suggest that the imprinted site of 5-FU can be introduced on the surface of TMMIPs, confirming their selective adsorption behavior for 5-FU. PMID:26838836

  13. Differential interference of vitamin D analogs PRI-1906, PRI-2191, and PRI-2205 with the renewal of human colon cancer cells refractory to treatment with 5-fluorouracil.

    PubMed

    Kotlarz, Agnieszka; Przybyszewska, Małgorzata; Swoboda, Paweł; Miłoszewska, Joanna; Grygorowicz, Monika Anna; Kutner, Andrzej; Markowicz, Sergiusz

    2016-04-01

    This study was aimed to determine whether hypocalcemic analogs of active forms of vitamins D modulate expression of genes related to stem-like phenotype in colon cancer cell lines HT-29 and HCT-116 undergoing renewal after the treatment with 5-fluorouracil (5-FU). Both lines express vitamin D receptor, but differ in differentiation stage and vitamin D sensitivity. Cells that resisted the 5-FU exposure were treated with synthetic analog of 1,25-dihydroxyvitamin D2 (PRI-1906) and analogs of 1,25-dihydroxyvitamin D3 (PRI-2191 and PRI-2205). Proliferative activity was more profoundly affected by vitamin D analogs in HT-29/5-FU than in HCT-116/5-FU cells. In HT-29/5-FU cells, analogs PRI-1906 and PRI-2191 downregulated the expression of genes related to survival, re-growth, and invasiveness during renewal, while PRI-2205 increased expression of genes related to differentiation only. In HCT-116/5-FU cells, PRI-2191 decreased the expression of stemness- and angiogenesis-related genes, whereas PRI-1906 augmented their expression. The effects in HCT-116/5-FU cells were observed at higher concentrations of the analogs than those used for HT-29/5-FU cells. Out of the series of analogs studied, PRI-2191 might be used to counteract the renewal of both moderately and poorly differentiated cancer cells following conventional treatment. PMID:26511971

  14. MicroRNA-320a promotes 5-FU resistance in human pancreatic cancer cells

    PubMed Central

    Wang, Weibin; Zhao, Lijun; Wei, Xueju; Wang, Lanlan; Liu, Siqi; Yang, Yu; Wang, Fang; Sun, Guotao; Zhang, Junwu; Ma, Yanni; Zhao, Yupei; Yu, Jia

    2016-01-01

    The drug-resistance of pancreatic cancer cells results in poor therapeutic effect. To predict the therapeutic effect of the chemotherapy drugs to specific patients and to reverse the resistance of pancreatic cancer cells are critical for chemotherapy of pancreatic cancer. MicroRNAs (miRNAs) have been reported to play important roles in the genesis of drug-resistance of various cancer types. There are also many advantages of miRNAs in diagnosis and therapy of disease. Although several miRNAs regulating 5-Fluorouracil (5-FU) resistance in human pancreatic cancer have been reported, the detailed molecular mechanism remains to be determined. In this study, we found that miR-320a was significantly up-regulated in 5-FU resistant pancreatic cancer cells. Over-expression of miR-320a strongly contributed to pathogenesis of pancreatic cancer, which was represented by the increased proliferation, invasion, metastasis, drug-resistance characteristics and the epithelial-to-mesenchymal transition. Furthermore, we demonstrated that miR-320a was able to bind to 3′UTR of PDCD4 mRNA, and mediated its down-regulation in 5-FU resistance of human pancreatic cancer cells. Whereas restoration of PDCD4 expression could partially attenuate the function of miR-320a in pancreatic cancer. Taken together, our study demonstrated that miR-320a played important role in regulating 5-FU resistance by targeting PDCD4 and might be developed as new therapeutic target for pancreatic cancer. PMID:27279541

  15. MicroRNA-320a promotes 5-FU resistance in human pancreatic cancer cells.

    PubMed

    Wang, Weibin; Zhao, Lijun; Wei, Xueju; Wang, Lanlan; Liu, Siqi; Yang, Yu; Wang, Fang; Sun, Guotao; Zhang, Junwu; Ma, Yanni; Zhao, Yupei; Yu, Jia

    2016-01-01

    The drug-resistance of pancreatic cancer cells results in poor therapeutic effect. To predict the therapeutic effect of the chemotherapy drugs to specific patients and to reverse the resistance of pancreatic cancer cells are critical for chemotherapy of pancreatic cancer. MicroRNAs (miRNAs) have been reported to play important roles in the genesis of drug-resistance of various cancer types. There are also many advantages of miRNAs in diagnosis and therapy of disease. Although several miRNAs regulating 5-Fluorouracil (5-FU) resistance in human pancreatic cancer have been reported, the detailed molecular mechanism remains to be determined. In this study, we found that miR-320a was significantly up-regulated in 5-FU resistant pancreatic cancer cells. Over-expression of miR-320a strongly contributed to pathogenesis of pancreatic cancer, which was represented by the increased proliferation, invasion, metastasis, drug-resistance characteristics and the epithelial-to-mesenchymal transition. Furthermore, we demonstrated that miR-320a was able to bind to 3'UTR of PDCD4 mRNA, and mediated its down-regulation in 5-FU resistance of human pancreatic cancer cells. Whereas restoration of PDCD4 expression could partially attenuate the function of miR-320a in pancreatic cancer. Taken together, our study demonstrated that miR-320a played important role in regulating 5-FU resistance by targeting PDCD4 and might be developed as new therapeutic target for pancreatic cancer. PMID:27279541

  16. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats.

    PubMed

    Shirasaka, T; Shimamoto, Y; Fukushima, M

    1993-09-01

    The possibility of decreasing the gastrointestinal (GI) toxic effects of 5-fluorouracil (5-FU) on the digestive tract such as its injury of cells and induction of diarrhea, without reducing its antitumor activity, was investigated in rats. Oxonic acid was found to inhibit the phosphorylation of 5-FU to 5-fluorouridine-5'-monophosphate catalyzed by pyrimidine phosphoribosyl-transferase in a different manner from allopurinol in cell-free extracts and intact cells in vitro. On p.o. administration of 5-FU (2 mg/kg) and a potent inhibitor of 5-FU degradation to Yoshida sarcoma-bearing rats, oxonic acid (10 mg/kg) was found to inhibit the formation of 5-fluorouridine-5'-monophosphate from 5-FU and its subsequent incorporation into the RNA fractions of small and large intestine but not of tumor and bone marrow tissues. This selective inhibition of 5-FU phosphorylation in the GI tract was due to the much higher concentrations of oxonic acid in GI tissues than in other tissues and the blood. On p.o. administration with the 5-FU derivative, UFT, which is a combined form of 1 M tegafur and 4 M uracil and usually administered p.o. to cancer patients in Japan, oxonic acid (10-50 mg/kg) markedly reduced injury of GI tissues and/or severe diarrhea without influencing the antitumor effect of UFT. These findings suggest that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats. PMID:7689420

  17. A 12-gene signature to distinguish colon cancer patients with better clinical outcome following treatment with 5-fluorouracil or FOLFIRI.

    PubMed

    Paquet, Eric R; Cui, Jing; Davidson, David; Pietrosemoli, Natalia; Hassan, Houssein Hajj; Tsofack, Serges P; Maltais, Annie; Hallett, Michael T; Delorenzi, Mauro; Batist, Gerald; Aloyz, Raquel; Lebel, Michel

    2015-07-01

    Currently, there is no marker in use in the clinical management of colon cancer to predict which patients will respond efficiently to 5-fluorouracil (5-FU), a common component of all cytotoxic therapies. Our aim was to develop and validate a multigene signature associated with clinical outcome from 5-FU therapy and to determine if it could be used to identify patients who might respond better to alternate treatments. Using a panel of 5-FU resistant and sensitive colon cancer cell lines, we identified 103 differentially expressed genes providing us with a 5-FU response signature. We refined this signature using a clinically relevant DNA microarray-based dataset of 359 formalin-fixed and paraffin-embedded (FFPE) colon cancer samples. We then validated the final signature in an external independent DNA microarray-based dataset of 316 stage III FFPE samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial. Finally, using a drug sensitivity database of 658 cell lines, we generated a list of drugs that could sensitize 5-FU resistant patients using our signature. We confirmed using the PETACC-3 dataset that the overall survival of subjects responding well to 5-FU did not improve with the addition of irinotecan (FOLFIRI; two-sided log-rank test p = 0.795). Conversely, patients who responded poorly to 5-FU based on our 12-gene signature were associated with better survival on FOLFIRI therapy (one-sided log-rank test p = 0.039). This new multigene signature is readily applicable to FFPE samples and provides a new tool to help manage treatment in stage III colon cancer. It also provides the first evidence that a subgroup of colon cancer patients can respond better to FOLFIRI than 5-FU treatment alone. PMID:27499901

  18. Cell Line Derived 5-FU and Irinotecan Drug-Sensitivity Profiles Evaluated in Adjuvant Colon Cancer Trial Data

    PubMed Central

    Delorenzi, Mauro; Jensen, Thomas; Jensen, Peter Buhl; Bosman, Fred; Tejpar, Sabine; Roth, Arnaud; Brunner, Nils; Hansen, Anker; Knudsen, Steen

    2016-01-01

    Purpose This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. Methods To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy. Results There was no statistically significant association between the irinotecan or SN-38 profiles and benefit from irinotecan. The 5-FU sensitivity profile showed a statistically significant association with relapse free survival (RFS) (hazard ratio (HR) = 0.54 (0.41–0.71), p<1e-05) and overall survival (HR = 0.47 (0.34–0.63), p<1e-06) in the PETACC-3 subpopulation. The effect of the 5-FU profile remained significant in a multivariable Cox Proportional Hazards model, adjusting for several relevant clinicopathological parameters. No statistically significant effect of the 5-FU profile was observed in the untreated cohort of 359 patients (relapse free survival, p = 0.671). Conclusion The irinotecan predictor had no predictive value. The 5-FU predictor was prognostic in stage III patients in PETACC-3 but not in stage II patients with no adjuvant therapy. This suggests a potential predictive ability of the 5-FU sensitivity profile to identify colon cancer patients who may benefit from 5-FU, however, any biomarker predicting benefit for adjuvant 5-FU must be rigorously evaluated in independent cohorts. Given differences

  19. Cost-effectiveness of adjuvant FOLFOX and 5FU/LV chemotherapy for patients with stage II colon cancer

    PubMed Central

    Ayvaci, Mehmet U.S.; Shi, Jinghua; Alagoz, Oguzhan; Lubner, Sam

    2014-01-01

    Purpose We evaluated the cost-effectiveness of adjuvant chemotherapy using 5-fluorouracil, leucovorin (5FU/LV), and oxaliplatin (FOLFOX) compared with 5FU/LV alone and 5FU/LV compared with observation alone for patients who had resected stage II colon cancer. Methods We developed two Markov models to represent the adjuvant chemotherapy and follow-up periods and a single Markov model to represent the observation group. We used calibration to estimate the transition probabilities among different toxicity levels. The base-case considered 60-year-old patients who had undergone an uncomplicated hemicolectomy for stage II colon cancer and was medically fit to receive 6 months of adjuvant chemotherapy. We measured health outcomes in quality-adjusted life-years (QALYs) and estimated costs using 2007 US$. Results In the base-case, adjuvant chemotherapy of FOLFOX regimen had an incremental cost-effectiveness ratio (ICER) of $54,359/QALY compared with the 5FU/LV regimen and the 5FU/LV regimen had an ICER of $14,584/QALY compared with the observation group from the third-party payer perspective. The ICER values were most sensitive to 5-year relapse probability, cost of adjuvant chemotherapy, and the discount rate for the FOLFOX arm, whereas the ICER value of 5FU/LV was most sensitive to the 5-year relapse probability, 5-year survival probability, and the relapse cost. The probabilistic sensitivity analysis indicate that the ICER of 5FU/LV is less than $50,000/QALY with a probability of 99.62% and the ICER of FOLFOX as compared to 5FU/LV is less than $50,000/QALY and $100,000/QALY with a probability of 44.48% and 97.24%, respectively. Conclusion While adjuvant chemotherapy with 5FU/LV is cost-effective at all ages for patients who had undergone an uncomplicated hemicolectomy for stage II colon cancer, FOLFOX is not likely to be cost-effective as compared to 5FU/LV. PMID:23313932

  20. Impact of Rhenium-188, Gemcitabine, and 5-Fluorouracil on Cholangiocellular Carcinoma Cells: An In Vitro Study

    SciTech Connect

    Wiesinger, Benjamin Farkas, Emese; Kehlbach, Rainer; Bantleon, Ruediger; Werner, Matthias; Wiskirchen, Jakub

    2009-07-15

    The purpose of this study was to compare the beneficial effects of radioactive stents and radioactive stents plus additional chemotherapy in the palliative treatment of cholangiocellular carcinomas. Cholangiocellular carcinoma cells (TFK-1 cells) were treated either with 8 Gy (RTB group) or 16 Gy (RTA group) {sup 188}Re or with {sup 188}Re irradiation (8 Gy) combined with either gemcitabine (8 Gy/Gem) or 5-fluorouracil (8 Gy/5-FU) at a dosage of 20 {mu}g/ml medium for 4 days and subsequently compared with an untreated control group. Proliferation kinetics were assessed on days 4, 7, 11, 18, 25, and 32. Colony formation assays were performed on days 7, 18, and 32 and cell cycle distribution was examined on days 4, 7, 11, 15, 25, and 39. Cell proliferation kinetics showed the lowest cell numbers in the 8 Gy/5-FU group (control, 15,390,000; RTA group, 8,394,000; RTB group, 5,609,000; 8 Gy/Gem group, 423,000; and 8 Gy/5-FU group, 297,667). In contrast, clonogenic activity on day 32 was lower in the 8 Gy/Gem group (control, 29.3 colonies; RTB group, 23.1 colonies; 8 Gy/5-FU group, 21.5 colonies; 8 Gy/Gem, 3.3 colonies; and even augmented in the RTA group, with 37.7 colonies). Cell cycle distribution showed similar curves for all groups on slightly different levels except for the 8 Gy/5-FU group, which showed a relatively augmented percentage of cells on day 7 in the G2 M cycle phase and on day 4 in the S phase. In conclusion, irradiation (8 Gy) with {sup 188}Re administered, e.g., via coated stents, combined with Gem could be a valid option for the treatment of CCCs.

  1. Inhibition of adriamycin cardiotoxicity by 5-fluorouracil: a potential free oxygen radical scavenger.

    PubMed

    Stathopoulos, G P; Malamos, N A; Dontas, I; Deliconstantinos, G; Perrea-Kotsareli, D; Karayannacos, P E

    1998-01-01

    Adriamycin (ADR), a broad spectrum anticancer agent, has a limit to total dose used, due to cumulative cardiotoxicity. This side effect has been tested in the present study in combined administration with 5-fluorouracil a cytotoxic drug that often is applied together with ADR in cancer treatment. The study was performed on Wistar rats, and the experiment consisted of weekly administration for 12 weeks of adriamycin alone, of 5-fluorouracil alone, a combination of both, and a control group (normal saline) in separate groups comprising 42 animals each. The histology of the cardiac muscle, large vessels and liver, biochemistry of serum cholesterol, triglycerides and HDL-C and oxygen free radical production were examined. It was found that addition of 5-FU to the ADR administration reduced significantly the cardiac lesions, delayed and reduced the increase of serum lipids, produced by ADR alone and oxygen free radical production was also reduced, indicating that 5-fluorouracil is acting as a scavenger of free radicals. PMID:9891497

  2. Development and Characterization of Novel Site Specific Hollow Floating Microspheres Bearing 5-Fu for Stomach Targeting

    PubMed Central

    Bhardwaj, Peeyush; Singh, Ranjit; Swarup, Anoop

    2014-01-01

    Multiple-unit-type oral floating hollow microspheres of 5-fluorouracil (5-Fu) were developed using modified solvent evaporation technique to prolong gastric residence time, to target stomach cancer, and to increase drug bioavailability. The prepared microspheres were characterized for micromeritic properties, floating behavior, entrapment efficiency, and scanning electron microscopy (SEM). The in vitro drug release and floating behavior were studied in simulated gastric fluid (SGF) at pH 1.2. The yield of microspheres was obtained up to 84.46 ± 6.47%. Microspheres showed passable flow properties. Based on optical microscopy, particle size was found to be ranging from 158.65 ± 12.02 to 198.67 ± 17.45 μm. SEM confirmed spherical size, perforated smooth surface, and a hollow cavity inside the microspheres. Different kinetic models for drug release were also applied on selected batches. PMID:25383377

  3. Effects of atmospheric pressure cold plasma on human hepatocarcinoma cell and its 5-fluorouracil resistant cell line

    NASA Astrophysics Data System (ADS)

    Yang, H.; Lu, R.; Xian, Y.; Gan, L.; Lu, X.; Yang, X.

    2015-12-01

    Atmospheric pressure cold plasma showed selective killing efficiency on cancer cells in vitro and in vivo, which makes plasma a potential option for cancer therapy. However, the plasma effects on chemotherapeutic drugs-resistant cells are rarely to be found. In this paper, the effects of plasma on human hepatocellular carcinoma Bel7402 cells and 5-fluorouracil (5-FU) resistant Bel7402/5FU cells were intensively investigated. The results showed that plasma induced superior toxicity to Bel7402 cells compared with Bel7402/5FU cells. Incubation with plasma-treated medium for 20 s induced more than 85% death rate in Bel7402 cells, while the same death ratio was achieved when Bel7402/5FU cells were treated for as long as 300 s. The hydrogen peroxide in the medium played a leading role in the cytotoxicity effects. Further studies implicated that when the treatment time was shorter than 60 s, the depolarization of mitochondrial membrane potential and apoptosis occurred through the intracellular reactive oxygen species accumulation in Bel7402 cells. Molecular analysis showed an increase in the transcription factor activity for AP-1, NF-кB, and p53 in Bel7402 cells. No obvious damage could be detected in plasma-treated Bel7402/5FU cells due to the strong intracellular reactive oxygen stress scavenger system.

  4. The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells

    PubMed Central

    Romano, Gabriele; Santi, Ludovica; Bianco, Maria Rosaria; Giuffrè, Maria Rita; Pettinato, Mariateresa; Bugarin, Cristina; Garanzini, Cristina; Savarese, Leonilde; Leoni, Silvia; Cerrito, Maria Grazia; Leone, Biagio Eugenio; Gaipa, Giuseppe; Grassilli, Emanuela; Papa, Michele; Lavitrano, Marialuisa; Giovannoni, Roberto

    2016-01-01

    TGF-β pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-β in cancer drug resistance. In this work, we show a specific activation of the TGF-β pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-βRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-β molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-β pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients. PMID:26956045

  5. Effects of atmospheric pressure cold plasma on human hepatocarcinoma cell and its 5-fluorouracil resistant cell line

    SciTech Connect

    Yang, H.; Gan, L.; Yang, X. E-mail: yangxl@mail.hust.edu.cn; Lu, R.; Xian, Y.; Lu, X. E-mail: yangxl@mail.hust.edu.cn

    2015-12-15

    Atmospheric pressure cold plasma showed selective killing efficiency on cancer cells in vitro and in vivo, which makes plasma a potential option for cancer therapy. However, the plasma effects on chemotherapeutic drugs-resistant cells are rarely to be found. In this paper, the effects of plasma on human hepatocellular carcinoma Bel7402 cells and 5-fluorouracil (5-FU) resistant Bel7402/5FU cells were intensively investigated. The results showed that plasma induced superior toxicity to Bel7402 cells compared with Bel7402/5FU cells. Incubation with plasma-treated medium for 20 s induced more than 85% death rate in Bel7402 cells, while the same death ratio was achieved when Bel7402/5FU cells were treated for as long as 300 s. The hydrogen peroxide in the medium played a leading role in the cytotoxicity effects. Further studies implicated that when the treatment time was shorter than 60 s, the depolarization of mitochondrial membrane potential and apoptosis occurred through the intracellular reactive oxygen species accumulation in Bel7402 cells. Molecular analysis showed an increase in the transcription factor activity for AP-1, NF-kB, and p53 in Bel7402 cells. No obvious damage could be detected in plasma-treated Bel7402/5FU cells due to the strong intracellular reactive oxygen stress scavenger system.

  6. Innovative bola-surfactant niosomes as topical delivery systems of 5-fluorouracil for the treatment of skin cancer.

    PubMed

    Paolino, Donatella; Cosco, Donato; Muzzalupo, Rita; Trapasso, Elena; Picci, Nevio; Fresta, Massimo

    2008-04-01

    An innovative niosomal system made up of alpha,omega-hexadecyl-bis-(1-aza-18-crown-6) (Bola), Span 80 and cholesterol (2:5:2 molar ratio) was proposed as a topical delivery system for 5-fluorouracil (5-FU), largely used in the treatment of different forms of skin cancers. Bola-niosomes showed a mean size of approximately 400 nm, which were reduced to approximately 200 nm by a sonication procedure with a polydispersion index value of 0.1. Bola-niosomes showed a loading capacity of approximately 40% with respect to the amount of 5-FU added during the preparation. 5-FU-loaded bola-niosomes were tested on SKMEL-28 (human melanoma) and HaCaT (non-melanoma skin cancer with a specific mutations in the p53 tumor suppressor gene) to assess the cytotoxic activity with respect to the free drug. 5-FU-loaded bola-niosomes showed an improvement of the cytotoxic effect with respect to the free drug. Confocal laser scanning microscopy studies were carried out to evaluate both the extent and the time-dependent bola-niosome-cell interaction. The percutaneous permeation of 5-FU-loaded niosomes was evaluated by using human stratum corneum and epidermis membranes. Bola-niosomes provided an increase of the drug penetration of 8- and 4-folds with respect to a drug aqueous solution and to a mixture of empty bola-niosomes with a drug aqueous solution. PMID:18191509

  7. Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma.

    PubMed

    Yamashita, Tomomi; Kato, Keizo; Long, Nguyen Khanh; Makita, Hiroki; Yonemoto, Kazuhiro; Iida, Kazuki; Tamaoki, Naritaka; Hatakeyama, Daijiro; Shibata, Toshiyuki

    2014-05-01

    Lifestyle, particularly smoking and alcohol consumption, may induce and/or inhibit drug metabolism. In order to reveal the effects of smoking and alcohol consumption on the 5-fluorouracil (5-FU)-related metabolic enzymes, namely thymidylate synthase, dihydropyrimidine dehydrogenase (DPD; a sole catabolic enzyme of 5-FU), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase, in oral squamous cell carcinomas, the mRNA expression of these enzymes was investigated in 29 surgical specimens and compared by the Brinkman index and drinking years. The surgical specimens were divided into normal and tumor regions and were independently analyzed using quantitative reverse transcription-polymerase chain reaction. There was a significantly positive correlation between DPD mRNA expression in these tissues and Brinkman index/drinking years, with OPRT mRNA expression being significantly correlated to the Brinkman index in tumor tissues. These results revealed that lifestyle habits, including smoking and alcohol consumption, may vary the activity of the 5-FU-related metabolic enzymes. DPD is the initial and rate-limiting enzyme in the catabolic pathway of 5-FU. Therefore, smoking and alcohol consumption may reduce the anticancer activity of 5-FU, possibly through the induction of DPD activity. PMID:24772313

  8. Is early post-operative treatment with 5-fluorouracil possible without affecting anastomotic strength in the intestine?

    PubMed Central

    van der Kolk, B M; de Man, B M; Wobbes, T; Hendriks, T

    1999-01-01

    Early post-operative local or systemic administration of 5-fluorouracil (5-FU) is under investigation as a means to improve outcome after resection of intestinal malignancies. It is therefore quite important to delineate accurately its potentially negative effects on anastomotic repair. Five groups (n = 24) of rats underwent resection and anastomosis of both ileum and colon: a control group and four experimental groups receiving daily 5-FU, starting immediately after operation or after 1, 2 or 3 days. Within each group, the drug (or saline) was delivered either intraperitoneally (n = 12) or intravenously (n = 12). Animals were killed 7 days after operation and healing was assessed by measurement of anastomotic bursting pressure, breaking strength and hydroxyproline content. In all cases, 5-FU treatment from the day of operation or from day 1 significantly (P < 0.025) and severely suppressed wound strength; concomitantly, the anastomotic hydroxyproline content was reduced. Depending on the location of the anastomosis and the route of 5-FU administration, even a period of 3 days between operation and first dosage seemed insufficient to prevent weakening of the anastomosis. The effects of intravenous administration, though qualitatively similar, were quantitatively less dramatic than those observed after intraperitoneal delivery. Post-operative treatment with 5-FU, if started within the first 3 days after operation, is detrimental to anastomotic strength and may compromise anastomotic integrity. © 1999 Cancer Research Campaign PMID:10027328

  9. Thymidylate Synthase Gene Polymorphism Affects the Response to Preoperative 5-Fluorouracil Chemoradiation Therapy in Patients With Rectal Cancer

    SciTech Connect

    Hur, Hyuk; Kang, Jeonghyun; Kim, Nam Kyu; Min, Byung Soh; Lee, Kang Young; Shin, Sang Joon; Keum, Ki Chang; Choi, Junjeong; Kim, Hoguen; Choi, Sung Ho; Lee, Mi-Young

    2011-11-01

    Purpose: This study aims to correlate thymidylate synthase (TS) gene polymorphisms with the tumor response to preoperative 5-fluorouracil (5-FU)-based chemoradiation therapy (CRT) in patients with rectal cancer. Methods and Materials: Forty-four patients with rectal cancer treated with 5-FU-based preoperative CRT were prospectively enrolled in this study. Thymidylate synthase expression and TS gene polymorphisms were evaluated in tumor obtained before preoperative CRT and were correlated with the pathologic response, as assessed by histopathologic staging (pTNM) and tumor regression grade. Results: Patients exhibited 2R/3R and 3R/3R tandem repeat polymorphisms in the TS gene. With regard to TS expression in these genotypes, 2R/3RC and 3RC/3RC were defined as the low-expression group and 2R/3RG, 3RC/3RG, and 3RG/3RG as the high-expression group. There was no significant correlation between TS expression and tumor response. There was no significant difference in the tumor response between patients homozygous for 3R/3R and patients heterozygous for 2R/3R. However, 13 of 14 patients in the low-expression group with a G>C single-nucleotide polymorphism (SNP) (2R/3RC [n = 5] or 3RC/3RC [n = 9]) exhibited a significantly greater tumor downstaging rate, as compared with only 12 of 30 patients in the high-expression group without the SNP (2R/3RG [n = 10], 3RC/3RG [n = 9], or 3RG/3RG [n = 11]) (p = 0.001). The nodal downstaging rate was also significantly greater in this low-expression group, as compared with the high-expression group (12 of 14 vs. 14 of 30, p = 0.014). However, there was no significant difference in the tumor regression grade between these groups. Conclusions: This study suggests that SNPs within the TS enhancer region affect the tumor response to preoperative 5-FU-based CRT in rectal cancer.

  10. Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours.

    PubMed Central

    Shibamoto, Y.; Murata, R.; Miyauchi, S.; Hirohashi, M.; Takagi, T.; Sasai, K.; Shibata, T.; Oya, N.; Takahashi, M.

    1996-01-01

    We investigated the combined effect of radiation and clinically relevant doses of emitefur (BOF-A2), a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation, in two types of murine tumours. In preliminary pharmacokinetic studies, the area under the curve for 5-FU in plasma, after administration of 12.5 mg kg-1 and 25 mg kg-1 emitefur in mice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 400-600 mg day-1 in humans. These doses (12.5 and 25 mg kg-1) of emitefur were evaluated either alone or in combination with single (15 Gy), five-fraction (4 Gy each) or ten-fraction (2.8 Gy each) irradiation using a tumour growth delay assay for SCCVII tumours and in combination with four-fraction (5 Gy each) irradiation using an in vivo-in vitro assay for EMT6 tumours. The anti-tumour and radiation-enhancing effects of 12.5 mg kg-1 emitefur were not significant in any except the ten-fraction experiment. On the other hand, multiple doses of 25 mg kg-1 emitefur given either alone or in combination with radiation produced marked effects. The mean tumour growth delay time (the time to double in volume for treated tumours minus that for untreated tumours) was 8.1 days for five administrations of 25 mg kg-1 emitefur. 10.4 days for five fractions of 4 Gy and 22.1 days for five treatments with the combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractions of 5 Gy with 25 mg kg-1 emitefur in EMT6 tumours was lower than that of four fractions of 7.5 Gy, but the effect of five fractions of 4 Gy with this dose of emitefur in SCCVII tumours was similar to the effect of five fractions of 6 Gy, and the effect of ten fractions of 2.8 Gy with 25 mg kg-1 emitefur was much higher than that of ten fractions of 4.2 Gy. In conclusion, emitefur given either alone

  11. [5-fluorouracil, high dose folinic acid and mitomycin C in the treatment of advanced digestive cancers].

    PubMed

    Seitz, J F; Diaw, A; Giovannini, M; Perrier, H; Gouvernet, J

    1994-02-01

    Thirty five patients presenting with advanced unresectable digestive tract cancers were treated with high-dose folinic acid (200 mg/m2/d, i.v. bolus) followed by 5-fluorouracil (400 mg/m2 i.v. bolus) on day 2 of uneven courses (day 2, day 58, day 114...). There were 20 colorectal cancers, nine gastric cancers, two oesophageal cancers, two cholangiocarcinomas, one islet cell pancreatic carcinoma and one adenocarcinoma of unknown origin. An objective response was noted in 11/27 evaluable patients (40.7 +/- 19%): four complete and seven partial responses including three of the seven patients who previously failed to respond to 5FU-containing regimen, and eight of the 20 patients who received no prior chemotherapy. Objective responses were encountered in three of the five gastric cancers, five of the 17 colorectal cancers, one oesophageal cancer, one islet cell pancreatic carcinoma and one cholangiocarcinoma. The median duration of response was 6 months and overall median survival was 12 months (range: 1-48). There was one toxic death (non reversible medullar aplasia after the 1st course). This study confirms that this combination is an active regimen both for patients previously resistant to 5FU or untreated patients. It warrants further evaluation (perhaps with continuous 5FU infusions). PMID:7894119

  12. Capecitabine or infusional 5-fluorouracil for gastroesophageal cancer: a cost–consequence analysis

    PubMed Central

    Horgan, A.M.; Knox, J.J.; Liu, G.; Sahi, C.; Bradbury, P.A.; Leighl, N.B.

    2011-01-01

    Background In patients with advanced gastroesophageal cancer, the phase iii Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (real-2) trial demonstrated equivalent clinical efficacy when capecitabine (x) was substituted for 5-fluorouracil (5fu) in the epirubicin–cisplatin–5fu (ecf) regimen. The present analysis compares the direct medical costs associated with both regimens. Methods This cost–consequence analysis of direct medical costs took resource utilization data from the real-2 trial where available. Direct medical costs were derived from the perspective of the Canadian public health care system in 2008 Canadian dollars. Mean cost per patient on each treatment arm was calculated. Results Drug costs from start of treatment until first progression, including pre- and post-chemotherapy medications and administration costs, totalled $5,344 for ecx as compared with $3,187 for ecf. Costs for treatment of adverse events were estimated at $2,621 for ecx as compared with $3,397 for ecf. An additional cost of $873 was associated with insertion of an implanted venous access. Total incremental cost of ecx over ecf was $508. Conclusions In advanced gastroesophageal cancer, capecitabine is an attractive alternative to 5fu. Although the drug cost per se is greater, use of capecitabine is associated with decreased consumption of hospital resources. Not only does capecitabine fit with patient preference for oral therapy, it also avoids the inconvenience and complications of central venous access. PMID:21505591

  13. 5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Comprehensive Review of the Literature.

    PubMed

    Shah, Vidhi V; Aldahan, Adam S; Mlacker, Stephanie; Alsaidan, Mohammed; Samarkandy, Sahal; Nouri, Keyvan

    2016-06-01

    Hypertrophic (HTSs) and keloid scars are common dermatological complaints produced by disruption of the normal wound-healing process. Despite a wide array of therapeutic options available to treat these lesions, HTSs and keloids continue to pose a significant challenge to clinicians in everyday practice. The chemotherapeutic drug 5-fluorouracil (5-FU) is a well-known treatment option reserved for recalcitrant HTSs and keloid lesions. We present clinicians with a comprehensive review of the published data concerning the use of 5-FU in the treatment of HTSs and keloids. The current evidence suggests that 5-FU is a safe and practical alternative for the treatment of HTSs and keloids as it may substantially improve the appearance of proliferative scars and reduce the chance of recurrence. This therapeutic option is most effective in conjunction with adjuvant therapy such as corticosteroids. Additional randomized controlled clinical trials with large sample sizes should be conducted to corroborate the existing efficacy and safety data in patients with HTSs and keloids. PMID:27105629

  14. Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

    PubMed Central

    LING, SUNBIN; TIAN, YU; ZHANG, HAIQUAN; JIA, KAIQI; FENG, TINGTING; SUN, DEGUANG; GAO, ZHENMING; XU, FEI; HOU, ZHAOYUAN; LI, YAN; WANG, LIMING

    2014-01-01

    Metformin exhibits anti-proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel-7402/5-fluorouracil (5-Fu; Bel/Fu) cells. The synergistic anti-proliferative effect of metformin combined with 5-Fu was evaluated using a Cell Counting kit-8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription-polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti-proliferative effect with 5-Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia-inducible factor-1α (HIF-1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF-1α/P-gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma. PMID:25310259

  15. Fatal immune haemolysis due to antibodies to individual metabolites of 5-fluorouracil.

    PubMed

    Yürek, S; Riess, H; Kreher, S; Dörken, B; Salama, A

    2010-08-01

    Confusion still exists in the diagnosis of drug-induced immune haemolysis (DIH). The aim of this study was to demonstrate antibodies specific to 5-fluorouracil (5-FU) in a patient with fatal immune haemolysis (IH). The case of a patient who died due to protracted IH is described. A 57-year-old female underwent treatment with oxaliplatin, 5-FU and folinic acid due to cholangiocarcinoma. Following drug administration, she was transfused because of a mild non-haemolytic anaemia and died following haemolysis. Serological testing including antibody screening, direct antiglobulin test and detection of drug-dependent antibodies was performed using standard techniques. The patient's serum was observed to be red in colour due to the presence of free haemoglobin prior to and following blood transfusion, and contained antibodies reactive with RBCs only in the presence of urine from several patients treated with 5-FU (ex vivo antigens). Drug-induced immune haemolysis (DIH) and metabolite-dependent antibodies should always be taken into consideration when a patient being administered any type of drug develops haemolysis. PMID:20456688

  16. Preparation of magnetite-chitosan/methylcellulose nanospheres by entrapment and adsorption techniques for targeting the anti-cancer drug 5-fluorouracil.

    PubMed

    Şanlı, Oya; Kahraman, Aslı; Kondolot Solak, Ebru; Olukman, Merve

    2016-05-01

    In this work, we have formulated novel nanospheres that could be used in the controlled release of the anticancer drug, 5-fluorouracil (5-FU). The nanospheres are composed of magnetite, containing chitosan (CS) and methylcellulose (MC). The drug entrapment was achieved through the encapsulation and adsorption processes. The effects of the preparation conditions, such as magnetite content, CS/MC ratio, crosslinking concentration, exposure time to glutaraldehyde (GA), and the drug/polymer ratio were investigated for both processes. The 5-FU release was found to follow the Fickian mechanism, and the Langmuir isotherm for the nanospheres was achieved through encapsulation and adsorption processes, respectively. PMID:25677468

  17. Kinetics and efficiency of a methyl-carboxylated 5-Fluorouracil-bovine serum albumin adduct for targeted delivery.

    PubMed

    Koziol, Michael J; Sievers, Torsten K; Smuda, Kathrin; Xiong, Yu; Müller, Angelika; Wojcik, Felix; Steffen, Axel; Dathe, Margitta; Georgieva, Radostina; Bäumler, Hans

    2014-03-01

    5-Fluorouracil (5-FU) is a clinically well-established anti-cancer drug effectively applied in chemotherapy, mainly for the treatment of breast and colorectal cancer. Substantial disadvantages are adverse effects, arising from serious damage of healthy tissues, and shortcoming pharmacokinetics due to its low molecular weight. A promising approach for improvement of such drugs is their coupling to suitable carriers. Here, a 5-FU adduct, 5-fluorouracil acetate (FUAc) is synthesized and covalently coupled to bovine serum albumin (BSA) as model carrier molecule. On average, 12 molecules FUAc are bound to one BSA. Circular dichriosm (CD)-spectra of BSA and FUAc-BSA are identical, suggesting no significant conformational differences. FUAc-BSA is tested on T-47D and MDA-MB-231 breast cancer cells. Proliferation inhibition of membrane albumin-binding protein (mABP)-expressing T-47D cells by FUAc-BSA is similar to that of 5-FU and only moderate for MDA-MB-231 cells that lack such expression. Therefore, a crucial role of mABP expression in effective cell growth inhibition by FUAc-BSA is assumed. PMID:24821671

  18. Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice.

    PubMed

    Araújo, C V; Lazzarotto, C R; Aquino, C C; Figueiredo, I L; Costa, T B; Alves, L A de Oliveira; Ribeiro, R A; Bertolini, L R; Lima, A A M; Brito, G A C; Oriá, R B

    2015-06-01

    Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/- -challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge. PMID:25945744

  19. Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

    PubMed Central

    Araújo, C.V.; Lazzarotto, C.R.; Aquino, C.C.; Figueiredo, I.L.; Costa, T.B.; de Oliveira Alves, L.A.; Ribeiro, R.A.; Bertolini, L.R.; Lima, A.A.M.; Brito, G.A.C.; Oriá, R.B.

    2015-01-01

    Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/--challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge. PMID:25945744

  20. Intravital imaging of the effects of 5-fluorouracil on the murine liver microenvironment using 2-photon laser scanning microscopy

    PubMed Central

    OKIGAMI, MASATO; TANAKA, KOJI; INOUE, YASUHIRO; SAIGUSA, SUSUMU; OKUGAWA, YOSHINAGA; TOIYAMA, YUJI; MOHRI, YASUHIKO; KUSUNOKI, MASATO

    2016-01-01

    5-fluorouracil (5FU) is often used in the treatment of colorectal cancer. 5FU improves the median overall and disease-free survival rates and reduces recurrence rates in patients who have undergone curative surgical resection. However, in the adjuvant setting, whether 5FU eradicates clinically undetectable micrometastases in target organs such as the liver, or whether 5-FU inhibits the adhesion of circulating tumor cells has not yet been established. In the present study, 5FU was administered following the inoculation of red fluorescent protein-expressing HT29 cells into green fluorescent protein (GFP)-transgenic nude mice to examine its inhibitory effect. 2-photon laser scanning microscopy was performed at selected time points for time-series imaging of liver metastasis of GFP-transgenic mice. The cell number in vessels was quantified to evaluate the response of the tumor microenvironment to chemotherapy. HT29 cells were visualized in hepatic sinusoids at the single-cell level. A total of 2 hours after the injection (early stage), time-series imaging revealed that the number of caught tumor cells gradually reduced over time. In the 5FU treatment group, no significant difference was observed in the cell number in the early stage. One week after the injection (late stage), a difference in morphology was observed. The results of the present study indicated that 5FU eradicated clinically undetectable micrometastases in liver tissues by acting as a cytotoxic agent opposed to preventing adhesion. The present study indicated that time-series intravital 2-photon laser scanning microscopic imaging of metastatic tumor xenografts may facilitate the screening and evaluation of novel chemotherapeutic agents with less interindividual variability. PMID:27073493

  1. Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer

    PubMed Central

    Hamaya, Yasushi; Guarinos, Carla; Tseng-Rogenski, Stephanie S.; Iwaizumi, Moriya; Das, Ritabrata; Jover, Rodrigo; Castells, Antoni; Llor, Xavier; Andreu, Montserrat; Carethers, John M.

    2015-01-01

    Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone. We tested if patients with EMAST CRCs (hMutSβ defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings. We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk. We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P<0.05). We observed no difference in survival between patients with stage II/III EMAST and non-EMAST cancers (P = 0.36). There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status. The loss of contribution of hMSH3 for 5-FU cytotoxicity may not adversely affect patient outcome, contrasting patients whose tumors completely lack DNA MMR function (MSI-H). PMID:25996601

  2. Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase: a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy

    PubMed Central

    Martino-Echarri, Estefania

    2014-01-01

    5-fluorouracil (5-FU) is the first line component used in colorectal cancer (CRC) therapy however even in combination with other chemotherapeutic drugs recurrence is common. Mutations of the adenomatous polyposis coli (APC) gene are considered as the initiating step of transformation in familial and sporadic CRCs. We have previously shown that APC regulates the cellular response to DNA replication stress and recently hypothesized that APC mutations might therefore influence 5-FU resistance. To test this, we compared CRC cell lines and show that those expressing truncated APC exhibit a limited response to 5-FU and arrest in G1/S-phase without undergoing lethal damage, unlike cells expressing wild-type APC. In SW480 APC-mutant CRC cells, 5-FU-dependent apoptosis was restored after transient expression of full length APC, indicating a direct link between APC and drug response. Furthermore, we could increase sensitivity of APC truncated cells to 5-FU by inactivating the Chk1 kinase using drug treatment or siRNA-mediated knockdown. Our findings identify mutant APC as a potential tumor biomarker of resistance to 5-FU, and importantly we show that APC-mutant CRC cells can be made more sensitive to 5-FU by use of Chk1 inhibitors. PMID:25301724

  3. The c-MYC-ABCB5 axis plays a pivotal role in 5-fluorouracil resistance in human colon cancer cells

    PubMed Central

    Kugimiya, Naruji; Nishimoto, Arata; Hosoyama, Tohru; Ueno, Koji; Enoki, Tadahiko; Li, Tao-Sheng; Hamano, Kimikazu

    2015-01-01

    c-MYC overexpression is frequently observed in various cancers including colon cancer and regulates many biological activities such as aberrant cell proliferation, apoptosis, genomic instability, immortalization and drug resistance. However, the mechanism by which c-MYC confers drug resistance remains to be fully elucidated. In this study, we found that the c-MYC expression level in primary colorectal cancer tissues correlated with the recurrence rate following 5-fluorouracil (5-FU)-based adjuvant chemotherapy. Supporting this finding, overexpression of exogenous c-MYC increased the survival rate following 5-FU treatment in human colon cancer cells, and knockdown of endogenous c-MYC decreased it. Furthermore, c-MYC knockdown decreased the expression level of ABCB5, which is involved in 5-FU resistance. Using a chromatin immunoprecipitation assay, we found that c-MYC bound to the ABCB5 promoter region. c-MYC inhibitor (10058-F4) treatment inhibited c-MYC binding to the ABCB5 promoter, leading to a decrease in ABCB5 expression level. ABCB5 knockdown decreased the survival rate following 5-FU treatment as expected, and the ABCB5 expression level was increased in 5-FU-resistant human colon cancer cells. Finally, using a human colon cancer xenograft murine model, we found that the combined 5-FU and 10058-F4 treatment significantly decreased tumorigenicity in nude mice compared with 5-FU or 10058-F4 treatment alone. 10058-F4 treatment decreased the ABCB5 expression level in the presence or absence of 5-FU. In contrast, 5-FU treatment alone increased the ABCB5 expression level. Taken together, these results suggest that c-MYC confers resistance to 5-FU through regulating ABCB5 expression in human colon cancer cells. PMID:25689483

  4. Skin cancer treatment by albumin/5-Fu loaded magnetic nanocomposite spheres in a mouse model.

    PubMed

    Misak, H; Zacharias, N; Song, Z; Hwang, S; Man, K-P; Asmatulu, R; Yang, S-Y

    2013-03-10

    Albumin/drug loaded magnetic nanocomposite spheres were fabricated using an oil-in-oil emulsion/solvent evaporation method, and tested on a mouse model (experimental squamous cell carcinoma) to determine the efficacy of the drug delivery system (DDS) on skin cancer. This novel DDS consists of human serum albumin, poly(lactic-co-glycolic acid) (PLGA), 5-fluorouracil (5-Fu), magnetic nanoparticles (10 nm) and fluorescent labeling molecule (diphenylhexatriene). One of the major purposes of using albumin is that it likely provides internal binding to and retention by the inflammatory tissues to reduce the amount of magnetic nanoparticles needed in the drug loaded microspheres (750–1100 nm). This study is aimed at reducing many negative side effects of conventionally used chemotherapy drugs by localizing the chemotherapy drug, controlling the release of the therapeutic agent and encouraging uptake of the DDS into cancerous cells. A group of mice treated with (1) the magnetic targeted DDS were compared to the other three groups, including, (2) DDS without a magnet, (3) 5-Fu local injection, and (4) untreated groups. The fluorescent tracer was ubiquitously identified inside the tumor tissue, and the DDS/tumor tissue boundary presented a leaky interface. The test results clearly showed that the magnetic targeted DDS exhibited significantly superior therapeutic effects in treating the skin cancer, with the increased efficacy to halt the tumor growth. PMID:23395619

  5. Characterization of a 5-fluorouracil-enriched osteoprogenitor population of the murine bone marrow.

    PubMed

    Falla, N; Van Vlasselaer; Bierkens, J; Borremans, B; Schoeters, G; Van Gorp, U

    1993-12-15

    In the presence of beta-glycerophosphate and vitamin C, cultures of normal mouse bone marrow cells form three-dimensional structures that stain positive with the Von Kossa technique and express alkaline phosphatase (ALP), collagen type I, and osteocalcin. Little is known about the characteristics and frequency of the cells that contribute to this phenomenon. Most likely, mature osteoblastic cells do not contribute to the nodule formation because no osteocalcin expressing cells are detected in the flushed marrow by in situ hybridization. Limiting dilution analysis shows that, in normal bone marrow, 1 of 2.2 x 10(5) cells has the potency to form a bone nodule and to express ALP, collagen, and osteocalcin in a temporal fashion. Upon in vivo treatment with 5-fluorouracil (5-FU), this frequency increases 12-fold, eg, 1 in 1.75 x 10(4) cells shows osteogenic activity. In comparison, fibroblast colony forming cells occur at a frequency of 1 of 2.5 x 10(4) or 1 of 5 x 10(3) plated cells in normal or 5-FU-treated marrow, respectively. Using density centrifugation, the majority of the osteoprogenitor cells in 5-FU marrow are found in the low-density (1.066 to 1.067 g/mL) fractions. In addition, these cells bind to nylon wool but not to plastic and aggregate in the presence of wheat germ agglutinin and soybean agglutinin. Scanning and transmission electron microscopy shows that the bone nodules in 5-FU marrow cultures are composed of fibroblastoid cells embedded in a mineralized collagen matrix. In conclusion, our results show that a quiescent cell population in the murine bone marrow with fibroblastoid characteristics contributes to the formation of bone-like nodules in vitro. PMID:8260697

  6. Preoperative Capecitabine and Pelvic Radiation in Locally Advanced Rectal Cancer-Is it Equivalent to 5-FU Infusion Plus Leucovorin and Radiotherapy?

    SciTech Connect

    Chan, Alexander K.; Wong, Alfred O.; Jenken, Daryl A.

    2010-04-15

    Purpose: The aim of this retrospective case-matching study was to compare the treatment outcomes and acute toxicity of preoperative radiotherapy (RT) with capecitabine vs. preoperative RT with intermittent 5-fluorouracil (5-FU) infusion, leucovorin, and mitomycin C in rectal cancer. Methods and Materials: We matched 34 patients who were treated with preoperative concurrent capecitabine and 50 Gy of RT by their clinical T stage (T3 or T4) and the tumor location (<=7 cm or >7 cm from the anal verge) with another 68 patients who were treated with preoperative intermittent 5-FU infusion, leucovorin, mitomycin C, and 50 Gy of RT for a comparison of the pathologic tumor response, local control, distant failure, and survival rates. Results: The pathologic complete response rate was 21% with capecitabine and 18% with 5-FU and leucovorin (p = 0.72). The rate of T downstaging after chemoradiation was 59% for both groups. The rate of sphincter-sparing resection was 38% after capecitabine plus RT and 43% after 5-FU plus RT (p = 0.67). At 3 years, there was no significant difference in the local control rate (93% for capecitabine and 92% for 5-FU and leucovorin), relapse-free rate (74% for capecitabine and 73% for 5-FU and leucovorin), or disease-specific survival rate (86% for capecitabine and 77% for 5-FU and leucovorin). The acute toxicity profile was comparable, with little Grade 3 and 4 toxicity. Conclusions: When administered with concurrent preoperative RT, both capecitabine and intermittent 5-FU infusion with leucovorin modulation provided comparable pathologic tumor response, local control, relapse-free survival, and disease-specific survival rates in rectal cancer.

  7. Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

    PubMed Central

    Cassidy, J; Douillard, J-Y; Twelves, C; McKendrick, J J; Scheithauer, W; Bustová, I; Johnston, P G; Lesniewski-Kmak, K; Jelic, S; Fountzilas, G; Coxon, F; Díaz-Rubio, E; Maughan, T S; Malzyner, A; Bertetto, O; Beham, A; Figer, A; Dufour, P; Patel, K K; Cowell, W; Garrison, L P

    2006-01-01

    Oral capecitabine (Xeloda®) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK. PMID:16622438

  8. Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

    PubMed

    Fernandez-Rozadilla, C; Cazier, J B; Moreno, V; Crous-Bou, M; Guinó, E; Durán, G; Lamas, M J; López, R; Candamio, S; Gallardo, E; Paré, L; Baiget, M; Páez, D; López-Fernández, L A; Cortejoso, L; García, M I; Bujanda, L; González, D; Gonzalo, V; Rodrigo, L; Reñé, J M; Jover, R; Brea-Fernández, A; Andreu, M; Bessa, X; Llor, X; Xicola, R; Palles, C; Tomlinson, I; Castellví-Bel, S; Castells, A; Ruiz-Ponte, C; Carracedo, A

    2013-06-01

    The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale. PMID:22310351

  9. Clinical experience with chronomodulated infusional 5-fluorouracil chemoradiotherapy for pancreatic adenocarcinoma

    SciTech Connect

    Keene, Kimberly S. . E-mail: Kimberlykeene@earthlink.net; Rich, Tyvin A.; Penberthy, David R.; Shepard, Robert C.; Adams, Reid; Jones, R. Scott

    2005-05-01

    Purpose: To evaluate retrospectively the efficacy and chronic toxicities of concurrent radiotherapy and chronomodulated infusion 5-fluorouracil (5-FU) in patients with pancreatic adenocarcinoma. Methods and Materials: Twenty-eight patients with pancreatic adenocarcinoma were treated between January 1997 and May 2000 with 5-FU chronomodulated chemoradiotherapy. Chronomodulated delivery of chemotherapy was chosen on the basis of a lower toxicity profile in the treatment of GI malignancies. The median age was 64 years. Of the 28 patients, 12 were men and 16 were women. Eight patients had unresectable disease and 20 were treated after pancreatic resection. The median radiation dose was 50.4 Gy given in 28 fractions. The median field length and width was 10.6 cm and 10.9 cm, respectively. Concurrent chemotherapy with 5-FU was administered 5 d/wk, with a median total dose of 8.4 g/m{sup 2} (300 mg/m{sup 2}/d). Chronomodulated 5-FU delivery consisted of a low basal infusion for 16 h followed by an 8-h escalating-deescalating infusion peaking at 10 PM. Survival and recurrence data were evaluated using Kaplan-Meier actuarial analysis. Toxicities were recorded using the Radiation Therapy Oncology Group grading system. Results: The median follow-up for all patients was 26 months (range, 4-68 months). The median overall survival for the 20 patients treated postoperatively was 34 months, with a 3- and 5-year actuarial survival rate of 40% and 21%, respectively. If the 3 patients with carcinoma of the ampulla were removed from the data set, the mean overall survival in the resected patients was 34 months, with a 3-year and 5-year actuarial survival rate of 40% and 17%, respectively. The 8 unresectable patients had a median overall survival of 14 months, and none lived past 2 years. No patient experienced Grade 3 or 4 hematologic toxicity or weight loss. Five patients had nausea and dehydration requiring i.v. fluids; only one (4%) was hospitalized. Four patients required a dose

  10. Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer

    PubMed Central

    Wu, D-W; Huang, C-C; Chang, S-W; Chen, T-H; Lee, H

    2015-01-01

    5-Fluorouracil (5-FU) is chemotherapeutic agent widely used for the treatment of colorectal cancer. Unfortunately, advanced colorectal cancer is often resistance to such chemotherapy and poor outcome. An adaptor protein paxillin (PXN) is phosphorylated at Y31/Y118 (pPXN-Y31/Y118) by Src contributes to cell mobility and Ser (S)272 of PXN in LD4 domain is important to the interaction between PXN and Bcl-2. We thus hypothesized that pPXN-Y31/Y118 may be required for Bcl-2 protein stability via PXN interacting with Bcl-2 to confer 5-FU resistance in colorectal cancer. Mechanistically, pPXN-S272 is phosphorylated through pPXN-Y31/Y118-mediated p21 protein-activated kinase 1 (PAK1) activation and pPXN-S272 is required for PXN to interact with Bcl-2. The interaction between PXN and Bcl-2 is essential for Bcl-2 protein stability through phosphorylation of Bcl-2 at S87 (pBcl-2-S87) by pPXN-Y31/Y118-mediated ERK activation. An increase in Bcl-2 expression by PXN is responsible for resistance to 5-FU. The resistance to 5-FU can be abolished by inhibitor of Src and PAK1 or Bcl-2 antagonist in cell and animal models. Among patients, Bcl-2 expression is positively correlated with expression of PXN and pPXN-S272, respectively. Patients with high PXN/high Bcl-2 or high pPXN-S272/high Bcl-2 tumors are commonly to have an unfavorable response to 5-FU-based chemotherapy, compared with patients who have high PXN, high pPXN-S272 or high Bcl-2 tumors alone. Therefore, we suggest that Src, PAK1 or Bcl-2 inhibitor may potentially overcome the resistance of 5-FU-based chemotherapy and consequently to improve outcomes in patients with PXN/Bcl-2 and pPXN-S272/Bcl-2-positive tumors. PMID:25323586

  11. Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways

    SciTech Connect

    Hwang, Jin-Taek; Ha, Joohun; Park, Ock Jin . E-mail: ojpark@hannam.ac.kr

    2005-07-01

    5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers, but its chemo-resistance remains as a major obstacle in clinical settings. In the present study, HT-29 colon cancer cells were markedly sensitized to apoptosis by both 5-FU and genistein compared to the 5-FU treatment alone. There is an emerging evidence that genistein, soy-derived phytoestrogen, may have potential as a chemotherapeutic agent capable of inducing apoptosis or suppressing tumor promoting proteins such as cyclooxygenase-2 (COX-2). However, the precise mechanism of cellular cytotoxicity of genistein is not known. The present study focused on the correlation of AMPK and COX-2 in combined cytotoxicity of 5-FU and genistein, since AMPK is known as a primary cellular homeostasis regulator and a possible target molecule of cancer treatment, and COX-2 as cell proliferation and anti-apoptotic molecule. Our results demonstrated that the combination of 5-FU and genistein abolished the up-regulated state of COX-2 and prostaglandin secretion caused by 5-FU treatment in HT-29 colon cancer cells. These appear to be followed by the specific activation of AMPK and the up-regulation of p53, p21, and Bax by genistein. Under same conditions, the induction of Glut-1 by 5-FU was diminished by the combination treatment with 5-FU and genistein. Furthermore, the reactive oxygen species (ROS) was found as an upstream signal for AMPK activation by genistein. These results suggested that the combination of 5-FU and genistein exert a novel chemotherapeutic effect in colon cancers, and AMPK may be a novel regulatory molecule of COX-2 expression, further implying its involvement in cytotoxicity caused by genistein.

  12. Dual role of macrophages in the response of C26 colon carcinoma cells to 5-fluorouracil administration

    PubMed Central

    Patras, Laura; Sesarman, Alina; Licarete, Emilia; Luca, Lavinia; Alupei, Marius Costel; Rakosy-Tican, Elena; Banciu, Manuela

    2016-01-01

    Previous studies have demonstrated that tumor-associated macrophages (TAMs) are pivotal players in tumor progression via modulation of tumor angiogenesis, inflammation, metastasis and oxidative stress, as well as of the response of cancer cells to cytotoxic drugs. Nevertheless, the role of TAMs in the prognosis of colorectal cancer remains controversial. Therefore, the present study aimed to investigate how TAMs mediate the response of C26 colon carcinoma cells to the cytotoxic drug 5-fluorouracil (5-FU), upon TAM co-cultivation with these cancer cells in vitro. In this respect, 5-FU cytotoxicity was assessed in C26 cells in standard culture and in a co-culture with peritoneal macrophages, the production of NF-κB was determined by western blot analysis, and the production of angiogenic/inflammatory proteins in each experimental model was evaluated by protein array analysis. To gain further evidence of the effect of TAMs on oxidative stress, malondialdehyde was measured through high-performance liquid chromatography, and the total nonenzymatic antioxidant levels and the production of nitrites were measured through colorimetric assays. The results demonstrated that TAMs exerted a dual role in the response of C26 cells to 5-FU administration in the co-culture model. Thus, on one side, TAMs sensitized C26 cells to 5-FU administration through inhibition of the production of inflammatory and angiogenic proteins in these cancer cells; however, they also protected cancer cells against 5-FU-induced oxidative stress. Collectively, the present findings suggest that the combined administration of 5-FU with pharmacological agents that prevent TAMs to maintain the physiological range of tumor cell oxidative stress may highly improve the therapeutic potential of this drug. PMID:27446416

  13. Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis.

    PubMed

    Fang, Luo; Xin, Wenxiu; Ding, Haiying; Zhang, Yiwen; Zhong, Like; Luo, Hong; Li, Jingjing; Yang, Yunshan; Huang, Ping

    2016-01-01

    Precision medicine characterizes a new era of cancer care and provides each patient with the right drug at the right dose and time. However, the practice of precision dosing is hampered by a lack of smart dosing algorithms. A pharmacokinetically guided (PKG) dosing algorithm is considered to be the leading strategy for precision chemotherapy, although the effects of PKG dosing are not completely confirmed. Hence, we conducted a meta-analysis to evaluate the effects of the PKG algorithm of 5-fluorouracil (5-FU) dosing on patients with solid tumors. A comprehensive retrieval was performed to identify all of the prospective controlled studies that compared the body surface area (BSA)-based algorithm with the PKG algorithm of 5-FU in patients with solid tumors. Overall, four studies with 504 patients were included. The PKG algorithm significantly improved the objective response rate of 5-FU-based chemotherapy compared with the BSA-based algorithm. Furthermore, PKG dosing markedly decreased the risk of total grade 3/4 adverse drug reactions, especially those related to hematological toxicity. Overall, the PKG algorithm may serve as a reliable strategy for individualized dosing of 5-FU. PMID:27229175

  14. Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis

    PubMed Central

    Fang, Luo; Xin, Wenxiu; Ding, Haiying; Zhang, Yiwen; Zhong, Like; Luo, Hong; Li, Jingjing; Yang, Yunshan; Huang, Ping

    2016-01-01

    Precision medicine characterizes a new era of cancer care and provides each patient with the right drug at the right dose and time. However, the practice of precision dosing is hampered by a lack of smart dosing algorithms. A pharmacokinetically guided (PKG) dosing algorithm is considered to be the leading strategy for precision chemotherapy, although the effects of PKG dosing are not completely confirmed. Hence, we conducted a meta-analysis to evaluate the effects of the PKG algorithm of 5-fluorouracil (5-FU) dosing on patients with solid tumors. A comprehensive retrieval was performed to identify all of the prospective controlled studies that compared the body surface area (BSA)-based algorithm with the PKG algorithm of 5-FU in patients with solid tumors. Overall, four studies with 504 patients were included. The PKG algorithm significantly improved the objective response rate of 5-FU-based chemotherapy compared with the BSA-based algorithm. Furthermore, PKG dosing markedly decreased the risk of total grade 3/4 adverse drug reactions, especially those related to hematological toxicity. Overall, the PKG algorithm may serve as a reliable strategy for individualized dosing of 5-FU. PMID:27229175

  15. In Vivo Chemoprotective Activity of Bovine Dialyzable Leukocyte Extract in Mouse Bone Marrow Cells against Damage Induced by 5-Fluorouracil

    PubMed Central

    Coronado-Cerda, Erika Evangelina; Franco-Molina, Moisés Armides; Mendoza-Gamboa, Edgar; Prado-García, Heriberto; Rivera-Morales, Lydia Guadalupe; Zapata-Benavides, Pablo; Rodríguez-Salazar, María del Carmen; Caballero-Hernandez, Diana; Tamez-Guerra, Reyes Silvestre; Rodríguez-Padilla, Cristina

    2016-01-01

    Chemotherapy treatments induce a number of side effects, such as leukopenia neutropenia, peripheral erythropenia, and thrombocytopenia, affecting the quality of life for cancer patients. 5-Fluorouracil (5-FU) is wieldy used as myeloablative model in mice. The bovine dialyzable leukocyte extract (bDLE) or IMMUNEPOTENT CRP® (ICRP) is an immunomodulatory compound that has antioxidants and anti-inflammatory effects. In order to investigate the chemoprotection effect of ICRP on bone marrow cells in 5-FU treated mice, total bone marrow (BM) cell count, bone marrow colony forming units-granulocyte/macrophage (CFU-GM), cell cycle, immunophenotypification, ROS/superoxide and Nrf2 by flow cytometry, and histological and hematological analyses were performed. Our results demonstrated that ICRP increased BM cell count and CFU-GM number, arrested BM cells in G0/G1 phase, increased the percentage of leukocyte, granulocytic, and erythroid populations, reduced ROS/superoxide formation and Nrf2 activation, and also improved hematological levels and weight gain in 5-FU treated mice. These results suggest that ICRP has a chemoprotective effect against 5-FU in BM cells that can be used in cancer patients. PMID:27191003

  16. Nanogels fabricated by lysozyme and sodium carboxymethyl cellulose for 5-fluorouracil controlled release.

    PubMed

    Zhu, Kunkun; Ye, Ting; Liu, Jinjin; Peng, Zheng; Xu, Shasha; Lei, Jieqiong; Deng, Hongbing; Li, Bin

    2013-01-30

    Lysozyme (Ly) and sodium carboxymethyl cellulose (CMC) were used to fabricate nanogels by a convenient method without using any chemical treatment except simple heating to achieve the denaturation temperature of Ly. The prepared nanogels were characterized by dynamic laser scattering (DLS), rheological analysis, transmission electron microscopy (TEM), field emission scanning electron microscope (FE-SEM) and X-ray photoelectron spectroscopy (XPS). The nanogels are of spherical shape with average hydrodynamic diameter of 241 nm and the swelling ratio of nanogels is about 5. Then 5-fluorouracil was used as a model drug to investigate the entrapment efficiency and release ability in nanogels. It turned out to be that the release in simulated gastric fluid (SGF) was more slowly compared with that in simulated intestinal fluid (SIF), which could protect the 5-Fu in stomach and ensure it released in intestines. PMID:23089579

  17. Unravelling the potential of a new uracil phosphoribosyltransferase (UPRT) from Arabidopsis thaliana in sensitizing HeLa cells towards 5-fluorouracil.

    PubMed

    Narayanan, Sharmila; Sanpui, Pallab; Sahoo, Lingaraj; Ghosh, Siddhartha Sankar

    2016-10-01

    In silico studies with uracil phosphoribosyltransferase from Arabidopsis thaliana (AtUPRT) revealed its lower binding energies for uracil and 5-fluorouracil (5-FU) as compared to those of bacterial UPRT indicating the prospective of AtUPRT in gene therapy implications. Hence, AtUPRT was cloned and stably expressed in cervical cancer cells (HeLa) to investigate the effect of prodrug 5-FU on these transfected cancer cells. The treatment of AtUPRT-expressing HeLa (HeLa-UPP) cells with 5-FU for 72h resulted in significant decrease in cell viability. Moreover, 5-FU was observed to induce apoptosis and perturb mitochondrial membrane potential in HeLa-UPP cells. While cell cycle analysis revealed significant S-phase arrest as a result of 5-FU treatment in HeLa-UPP cells, quantitative gene expression analysis demonstrated simultaneous upregulation of important cell cycle related genes, cyclin D1 and p21. The survival fractions of non-transfected, vector-transfected and AtUPRT-transfected HeLa cells, following 5-FU treatment, were calculated to be 0.425, 0.366 and 0.227, respectively. PMID:27180296

  18. Density functional theory based-study of 5-fluorouracil adsorption on β-cristobalite (1 1 1) hydroxylated surface: The importance of H-bonding interactions

    NASA Astrophysics Data System (ADS)

    Simonetti, S.; Compañy, A. Díaz; Pronsato, E.; Juan, A.; Brizuela, G.; Lam, A.

    2015-12-01

    Silica-based mesoporous materials have been recently proposed as an efficient support for the controlled release of a popular anticancer drug, 5-fluorouracil (5-FU). Although the relevance of this topic, the atomistic details about the specific surface-drug interactions and the energy of adsorption are almost unknown. In this work, theoretical calculations using the Vienna Ab-initio Simulation Package (VASP) applying Grimme's-D2 correction were performed to elucidate the drug-silica interactions and the host properties that control 5-FU drug adsorption on β-cristobalite (1 1 1) hydroxylated surface. This study shows that hydrogen bonding, electron exchange, and dispersion forces are mainly involved to perform the 5-FU adsorption onto silica. This phenomenon, revealed by favorable energies, results in optimum four adsorption geometries that can be adopted for 5-FU on the hydroxylated silica surface. Silanols are weakening in response to the molecule approach and establish H-bonds with polar groups of 5-FU drug. The final geometry of 5-FU adopted on hydroxylated silica surface is the results of H-bonding interactions which stabilize and fix the molecule to the surface and dispersion forces which approach it toward silica (1 1 1) plane. The level of hydroxylation of the SiO2 (1 1 1) surface is reflected by the elevated number of hydrogen bonds that play a significant role in the adsorption mechanisms.

  19. PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy

    PubMed Central

    Yan, Dongwang; Cui, Feifei; Wang, Xiaoliang; Yu, Fudong; Xue, Yingming; Feng, Xiaodong; Wang, Jingtao; Wang, Xiao; Jiang, Tao; Zhang, Meng; Zhao, Senlin; Yu, Yang; Tang, Huamei; Peng, Zhihai

    2015-01-01

    p21-Activated kinase 6 (PAK6) has been implicated in radiotherapy and docetaxel resistance. We have further evaluated PAK6 as a predictor of 5-fluorouracil (5-FU) treatment response in colon cancer. Here we report that in colon cancer PAK6 promotes tumor progression and chemoresistance both in vitro and in vivo. In the clinical analysis, PAK6 was overexpressed in 104 of 147 (70.75%) stage II and III patients who received 5-FU based chemotherapy after surgery. Multivariate Cox regression analysis indicated that PAK6 was an independent prognostic factor for overall survival (P < 0.001) and disease-free survival (P < 0.001). Colon cancer cell lines showed increased PAK6 expression upon 5-FU treatment. In PAK6-knockdown cells treated with 5-FU, cell viability and phosphorylation of BAD decreased, and the number of apoptotic cells, levels of cleaved caspase 3 and PARP increased compared to control cells. The opposite was observed in PAK6 overexpressing cells. Short hairpin RNA knockdown of PAK6 blocked cells in G2-M phase. Furthermore, Animal experiments results in vivo are consistent with outcomes in vitro. This study demonstrates that PAK6 is an independent prognostic factor for adjuvant 5-FU-based chemotherapy in patients with stage II and stage III colon cancer. PMID:25426562

  20. [Label-free monitoring 5-FU induced SW 620 cells apoptosis using FTIR microspectroscopy].

    PubMed

    Liu, Dong; Sun, Xue-Jun; Zhang, Chao; He, Sai; Du, Jun-Kai; Huo, Xiong-Wei; Zheng, Jian-Bao; Zhang, Shi-Yun; Zhang, Yuan-Fuz; Xu, Yi-Zhuang; Wu, Jin-Guang

    2013-12-01

    The aim of the present study was to evaluate Fourier transform infrared spectroscopy (FTIR) monitoring of biochemical changes in apoptosis cells. Different concentrations of 5-fluorouracil (5-FU) treated colon cancer cell lines SW620 were used to determine the optimum concentration of 5-FU IC50 by means of MTT assay. Cell starvation and 5-Fu synergistic cell cycle arrest was in G1 and S phase. FTIR combined with flow cytometry was applied to analysis of SW 620 cells and SW620 cells treated with 5-FU for 12h, 24h (early apoptosis) and 48 h (late apoptosis) respectively. The peak position and the intensity of all bands were measured and comparison was made between the SW620 and apoptotic SW620 cells. Apoptosis cells have following characteristics compared with SW620 cells (1) The band at 1 740 cm-1 is an C=O stretching vibration. Changes in these bands can reflect lipid changes, and relative peak intensity ratio 11740/11460 significantly increased (p<0. 05), indicating that the relative contents of lipid in apoptosis cells increased. (2) The band at the 1 410 cm-1 peak represents that C-H stretching related was increased to amino acid residues and shifted to higher wave numbers compared to other groups. I1410o/I 460 at early and late death phase was significantly increased, which suggests that the relative contents of amino acid residues in apoptosis cells increased (p <0. 05). New vibrational bands at 1 120 cm-1 appeared at 24 h and increased at 48 h compared with other groups. The 1 120 cm-1 absorption band is mainly due to ser, serine and threonine C-O(H) stretching vibration, and I1120/I 1460 significantly increased (p<0. 05), indicating that the relative quantity of amino acid residues in apoptosis cells increased due to that DNA unwinds the double helix. (3) 1 240 cm-1 is mainly due to the asymmetric stretching modes of phosphodiester groups shifting to higher wave number, illustrating that nucleic acid conformation was changed in apoptosis cells. (4) The band

  1. Clinical outcomes of amniotic membrane loaded with 5-FU PLGA nanoparticles in experimental trabeculectomy

    PubMed Central

    Hu, Fang; Zeng, Xiang-Yun; Xie, Zhao-Lian; Liu, Lin-Lin; Huang, Liang

    2015-01-01

    AIM To evaluate the effect of amniotic membrane loaded with 5-fluorouracil poly (lactic-co-glycolic acid) (PLGA) nanoparticles (5-FU-NPs) in the surgical outcomes of experimental trabeculectomy in rabbits. METHODS Thirty-two New Zealand white rabbits were randomly categorized into four groups with 8 rabbits in each group. Group 1, the control group, performed traditional trabeculectomy without adjuvant treatment. While the experimental groups performed compound trabeculectomy with different implantations including amniotic membrane (group 2), 5-FU-NPs (group 3) and amniotic membrane loaded with 5-FU-NPs (group 4). Clinical evaluations including IOP measurement and filtration bleb analysis were performed in all groups postoperatively. RESULTS There is no significant difference of mean IOP in all groups at first 7d after surgery. While at P14, mean IOPs of experimental group 2 (9.8±2.1 mm Hg), groups 3 (8.9±2.8 mm Hg) and group 4 (7.6±2.3 mm Hg) were significantly reduced compared to control group (12.4±2.6 mm Hg; n=8, P<0.05). At P21, mean IOPs of groups 3 (11.7±3.2 mm Hg) and group 4 (9.9±1.6 mm Hg) were significantly decreased compare to control group (17.9±1.6 mm Hg) and group 2 (16.6±2.8 mm Hg; n=8, P<0.05). At P28, mean IOPs of groups 3 (13.8±3.3 mm Hg) and group 4 (10.6±2.0 mm Hg) were also significantly reduced compare to control group (19.4±2.3 mm Hg) and group 2 (18.5±2.4 mm Hg; n=8, P<0.05). Meanwhile mean IOP of group 4 is significantly decreased compared to group 3 at P28 (n=8, P<0.05). Survival analysis of functional filtration blub in all groups revealed the longest survival time in group 4 (24.9±5.1d) compared to that in group 3 (20.6±4.3d), group 2 (15.0±5.2d) and control group (10.1±5.7d). CONCLUSION Amniotic membrane loaded with 5-Fu-NPs may function as an effective anti-scarring implant and provides improved long-term surgical outcomes for experimental trabeculectomy in rabbits. PMID:25709903

  2. Absence of large intragenic rearrangements in the DPYD gene in a large cohort of colorectal cancer patients treated with 5-FU-based chemotherapy.

    PubMed

    Paré, Laia; Paez, David; Salazar, Juliana; Del Rio, Elisabeth; Tizzano, Eduardo; Marcuello, Eugenio; Baiget, Montserrat

    2010-08-01

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Dihydropyrimidine dehydrogenase (DPD) is the enzyme responsible for the elimination of approximately 80% of the administered dose of 5-fluorouracil (5-FU). * Mutations in the DPD-coding gene have been shown to increase the risk of severe toxicity in 5-FU treated patients. * The IVS14+1G>A is the most common DPYD mutation. WHAT THIS STUDY ADDS * The intragenic rearrangements of DPYD using multiplex ligation-dependent probe amplification (MLPA) were studied for the first time in a large series of 234 colorectal cancer patients treated with 5-FU-containing chemotherapy. * No deletions or duplications of one or more DPYD exons were detected. The presence of the IVS14+1G>A mutation was also excluded. * These data show that neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation are responsible for the serious toxicity associated with a 5-FU containing regimen in this cohort of Spanish patients. AIMS To study the relationship between the toxicity associated with a 5-FU-based therapy and the presence of (i) the large intragenic rearrangements in the DPYD gene and (ii) the IVS14+1G>A mutation. METHODS We used the multiplex ligation-dependent probe amplification technique (MLPA) to study genomic DNA from 234 colorectal cancer patients treated with 5-FU-based chemotherapy. RESULTS We did not detect any deletion/duplication in the DPYD gene. The presence of the IVS14+1G>A mutation was also excluded. CONCLUSIONS Neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation play a significant role in the development of serious toxicity associated with a 5-FU containing regimen. PMID:20653680

  3. Polysaccharide-based nanocomplexes for co-encapsulation and controlled release of 5-Fluorouracil and Temozolomide.

    PubMed

    Di Martino, Antonio; Pavelkova, Alena; Maciulyte, Sandra; Budriene, Saulute; Sedlarik, Vladimir

    2016-09-20

    Polysaccharide-based nanocomplexes, intended for simultaneous encapsulation and controlled release of 5-Fluorouracil (5-FU) and Temozolomide (TMZ) were developed via the complexation method using chitosan, alginic and polygalacturonic acid. Investigation focused on the influence of polysaccharides on the properties of the system and amelioration of the stability of the drugs, in particular TMZ. The dimensions of particles and their ζ-potential were found to range between 100 and 200nm and -25 to +40mV, respectively. Encapsulation efficiency varied from 16% to over 70%, depending on the given system. The influence of pH on the release and co-release of TMZ and 5-FU was evaluated under different pH conditions. The stability of the loaded drug, in particular TMZ, after release was evaluated and confirmed by LC-MS analysis. Results suggested that the amount of loaded drug(s) and the release rate is connected with the weight ratio of polysaccharides and the pH of the media. One-way ANOVA analysis on the obtained data revealed no interference between the drugs during the encapsulation and release process, and in particular no hydrolysis of TMZ occurred suggesting that CS-ALG and CS-PGA would represent interesting carriers for multi-drug controlled release and drugs protection. PMID:27154260

  4. Porous clay heterostructures: A new inorganic host for 5-fluorouracil encapsulation.

    PubMed

    Gârea, S A; Mihai, A I; Ghebaur, A; Nistor, C; Sârbu, A

    2015-08-01

    This study proposed a new inorganic host for drug encapsulation. Porous clay heterostructure (PCH), synthesized using modified montmorillonite with hexadecyltrimethylammonium bromide, was used as host material and 5-fluorouracil (5-FU) as guest drug. Drug encapsulation within PCH in different conditions (soaking time, temperature and pH value) was investigated. Possible interactions of 5-FU with PCH were pointed out using different characterization methods like spectroscopic techniques (FT-IR, UV-vis, XPS), thermogravimetrical and BET analysis. The obtained results suggested that PCH host exhibits a high drug encapsulation efficiency which was influenced by factors like soaking time and pH value. PCH zeta potential value was strongly influenced by pH value. The PCH zeta potential significantly varies at acid pH, while a pH value higher than 7 provides a less variation. UV-vis analysis showed that after 30 min PCH host registered a maximum encapsulation efficiency value (44%) at room temperature using an incubation solution with a pH of 11. The soaking temperature does not substantially affect the loading of drug in PCH host. Thermogravimetrical analysis highlighted that drug encapsulation efficiency of PCH was mainly influenced by pH values. BET results confirmed the PCH synthesis and drug loading capacity. PMID:26022890

  5. Research on the development of bioadhesive vaginal tablets containing 5-fluorouracil.

    PubMed

    Cojocaru, Ileana; Palade, Laura; Popovici, Iuliana; Georgescu, Gabriela; Bîrsan, Magdalena

    2013-01-01

    Biomucoadhesive vaginal tablets are modern formulations used in current therapy to achieve controlled release of the active substance at the application site by maintaining the pharmaceutical preparation at that level. This can be achieved by using mucoadhesive substances with different mechanical and physical-chemical properties. Two cellulose derivatives of different viscosity, Metolose 90 SH 4000 and Metolose 90 SH 100000, and two types of polyacrylates with different cross linking degrees, Carbopol 71, low degree of cross linking, and Carbopol 974, high degree of cross linking were used. In a previous study twelve original formulations of bioadhesive vaginal tablets containing 100 mg 5-fluorouracil (5-FU)/tablet (F1-F12) were formulated, prepared and analyzed. The pharmacotechnical characterization of the bioadhesive vaginal tablets containing 5-FU was performed by determining their specific quality characteristics. For the optimization of formulations, the influence of formulation factors on some quality characteristics (mechanical strength, friability, disintegration time) which may be influenced by the nature and amount of auxiliary substances used was studied by SPSS statistical software and statistical analysis ANOVA tests. The results are in favor of formulations F1, F2 containing 20-30% Carbopol 71 and of 37-47% Microcelac. PMID:24505926

  6. Eudragit-coated dextran microspheres of 5-fluorouracil for site-specific delivery to colon.

    PubMed

    Rai, Gopal; Yadav, Awesh K; Jain, Narendra K; Agrawal, Govind P

    2016-01-01

    Objective of the present investigation was to prepare and evaluate the potential of enteric coated dextran microspheres for colon targeting of 5-fluorouracil (5-FU). Dextran microspheres were prepared by emulsification-crosslinking method and the formulation variables studied included different molecular weights of dextran, drug:polymer ratio, volume of crosslinking agent, stirring speed and time. Enteric coating (Eudragit S-100) of dextran microspheres was performed by oil-in-oil solvent evaporation method using different coat:core ratios (4:1 or 8:1). Uncoated and coated dextran microspheres were characterized by particle size, surface morphology, entrapment efficiency, DSC, in vitro drug release in the presence of dextranase and 2% rat cecal contents. The release study of 5-FU from coated dextran microspheres was pH dependent. No release was observed at acidic pH; however, the drug was released quickly where Eudragit starts solublizing there was continuous release of drug from the microspheres. Organ distribution study was suggested that coated dextran microspheres retard the release of drug in gastric and intestinal pH environment and released of drug from microspheres in colon due to the degradation of dextran by colonic enzymes. PMID:24845476

  7. Biocompatible drug delivery system for photo-triggered controlled release of 5-Fluorouracil.

    PubMed

    Jin, Qiao; Mitschang, Fabian; Agarwal, Seema

    2011-10-10

    The synthesis of a photo-triggered biocompatible drug delivery system on the basis of coumarin-functionalized block copolymers is reported. The coumarin-functionalized block copolymers poly(ethylene oxide)-b-poly(n-butyl methacrylate-co-4-methyl-[7-(methacryloyl)oxyethyloxy]coumarin)) (PEO-b-P(BMA- co-CMA)) were synthesized via atom transfer radical polymerization (ATRP). The micelle-drug conjugates were made by covalent bonding of anticancer drug 5-fluorouracil (5-FU) to the coumarin under UV irradiation at wavelength >310 nm. These micelle-drug conjugates possessed spherical morphology with diameters of 70 nm from TEM images. In vitro drug release experiments showed the controlled release of anticancer drug 5-FU from the micelle-drug conjugates under UV irradiation (254 nm). These micelle-drug conjugates also showed excellent biocompatibility by the in vitro cytotoxicity experiments. The results suggest that these micelle-drug conjugates could be a promising candidate for the delivery of anticancer agents with low side effects on normal cells and excellent therapeutic efficacy to cancer cells. PMID:21863834

  8. S-Nitrosoglutathione Accelerates Recovery from 5-Fluorouracil-Induced Oral Mucositis

    PubMed Central

    Skeff, Maria Adriana; Brito, Gerly A. C.; de Oliveira, Marcelo G.; Braga, Cintia M.; Cavalcante, Matheus M.; Baldim, Victor; Holanda-Afonso, Rosenilde C.; Silva-Boghossian, Carina M.; Colombo, Ana Paula; Ribeiro, Ronaldo A.; Moura-Neto, Vivaldo; Leitão, Renata F. C.

    2014-01-01

    Introduction Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy. Aim To evaluate the effect of the topical application of S-nitrosoglutathione (GSNO), a nitric oxide donor, on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters. Materials and Methods Oral mucositis was induced in male hamsters by two intraperitoneal administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day. Animals received saline, HPMC or HPMC/GSNO (0.1, 0.5 or 2.0 mM) 1 h prior to the 5-FU injection and twice a day for 10 or 14 days. Samples of cheek pouches were harvested for: histopathological analysis, TNF-α and IL-1β levels, immunohistochemical staining for iNOS, TNF-α, IL-1β, Ki67 and TGF-β RII and a TUNEL assay. The presence and levels of 39 bacterial taxa were analyzed using the Checkerboard DNA-DNA hybridization method. The profiles of NO released from the HPMC/GSNO formulations were characterized using chemiluminescence. Results The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h. Treatment with HPMC/GSNO (0.5 mM) significantly reduced mucosal damage, inflammatory alterations and cell death associated with 5-FU-induced oral mucositis on day 14 but not on day 10. HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14. In addition, we observed that the chemotherapy significantly increased the levels and/or prevalence of several bacterial species. Conclusion Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers. PMID:25478918

  9. Combination of interferon-alpha and 5-fluorouracil inhibits endothelial cell growth directly and by regulation of angiogenic factors released by tumor cells

    PubMed Central

    2009-01-01

    Background The combination therapy of interferon (IFN)-alpha and 5-fluorouracil (5-FU) improved the prognosis of the patients with hepatocellular carcinoma (HCC). To determine the molecular mechanisms of the anti-tumor and anti-angiogenic effects, we examined the direct anti-proliferative effects on human umbilical vein endothelial cells (HUVEC) and indirect effects by regulating secretion of angiogenic factors from HCC cells. Methods The direct effects on HUVEC were examined by TUNEL, Annexin-V assays and cell cycles analysis. For analysis of the indirect effects, the apoptosis induced by the conditioned medium from HCC cell treated by IFN-alpha/5-FU and expression of angiogenic factors was examined. Results IFN-alpha and 5-FU alone had anti-proliferative properties on HUVEC and their combination significantly inhibited the growth (compared with control, 5-FU or IFN alone). TUNEL and Annexin-V assays showed no apoptosis. Cell cycle analysis revealed that IFN-alpha and 5-FU delayed cell cycle progression in HUVEC with S-phase accumulation. The conditioned medium from HuH-7 cells after treatment with IFN/5-FU significantly inhibited HUVEC growth and induced apoptosis, and contained high levels of angiopoietin (Ang)-1 and low levels of vascular endothelial growth factor (VEGF) and Ang-2. Knockdown of Ang-1 in HuH-7 cells abrogated the anti-proliferative effects on HUVEC while knockdown of Ang-2 partially rescue the cells. Conclusion These results suggested that IFN-alpha and 5-FU had direct growth inhibitory effects on endothelial cells, as well as anti-angiogenic effects through regulation of angiogenic factors released from HCC cells. Modulation of VEGF and Angs secretion by IFN-alpha and 5-FU may contribute to their anti-angiogenic and anti-tumor effects on HCC. PMID:19821965

  10. Effect of combination therapy of siRNA targeting growth hormone receptor and 5-fluorouracil in hepatic metastasis of colon cancer

    PubMed Central

    ZHOU, DONG; ZHANG, YI; LIANG, DAOMING; YUAN, YONG; ZENG, DEMIAO; CHEN, JIAYONG; YANG, JIE

    2015-01-01

    The aim of this study was to investigate the effects of small interfering RNA (siRNA) targeting human growth hormone receptor (hGHR) combined with 5-fluorouracil (5-FU) on the hepatic metastasis of colon cancer. The animal model of liver metastases using human SW480 colon cancer cells was established on BALB/c mice and the siRNA interfering plasmid targeting hGHR gene was constructed. The tumor-bearing mice were randomly divided into the saline control, plasmid, growth hormone (GH), 5-FU, 5-FU+plasmid and 5-FU+plasmid+GH groups. The liver metastasis in each group was observed. All the animals showed liver metastases and using siRNA-interfering plasmid treatment the incidence of liver metastases was significantly reduced in the tumor groups compared to the saline or GH group. The combined treatment of interfering plasmid and 5-FU slightly decreased the incidence of liver metastases in the tumor groups compared to the plasmid alone or 5-FU alone treatment, although the findings were not statistically significant. On the basis of the combination of interfering plasmid and 5-FU, the additional GH did not increase the incidence of liver metastases (P>0.05), but improved the weight loss of the mice (P<0.05) induced by the inhibition of GHR and toxicity of 5-FU. The present results showed that siRNA targeting hGHR is able to reduce the incidence of liver metastases of human SW480 colon cancer cells in mice. Thus, GHR may be important in tumor metastasis. PMID:26788158