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Sample records for venous infusion 5-fluorouracil

  1. Continuous infusion of chemotherapy: focus on 5-fluorouracil and fluorodeoxyuridine

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    Poorter, R. L.; Bakker, P. J.; Veenhof, C. H.

    1998-01-01

    Continuous infusion of chemotherapy is one of the developments to try to improve the treatment of metastatic cancer. There is a sound theoretical rationale to deliver cytotoxic drugs as a continuous infusion. Furthermore, the development of reliable venous access devices and portable infusion pumps

  2. Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study.

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    Humphreys, A C; Dent, J; Rodwell, S; Crawford, S M; Joffe, J K; Bradley, C; Dodwell, D; Perren, T J

    2004-06-01

    This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.

  3. Preoperative chemoradiation in rectal cancer: Retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil.

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    Yerushalmi, Rinat; Idelevich, Efraim; Dror, Ygael; Stemmer, Salomon M; Figer, Arie; Sulkes, Aaron; Brenner, Baruch; Loven, David; Dreznik, Zeev; Nudelman, Israel; Shani, Adi; Fenig, Eyal

    2006-06-01

    We compared the efficacy and toxicity of oral capecitabine and continuous infusion of 5-fluorouracil (5-FU) in the preoperative chemoradiation treatment of patients with rectal cancer. The files of 89 patients with rectal cancer, 43 treated preoperatively with oral capecitabine and 46 with intravenous 5-FU, were reviewed, and the outcome of the groups was compared. There was no statistically significant difference in the complete pathological response rate between the capecitabine and the 5-FU groups (30% vs. 17%, P = 0.15). The downstaging rate was higher in the capecitabine group (77% vs. 50%, P = 0.009). Toxicity was mild in both groups. The rate of Grade 3 gastrointestinal toxicity was similar in the two groups (diarrhea 2% vs. 4%, proctitis 5% vs. 7%), except for one patient in the 5-FU group (2%) who developed a rectovaginal fistula. In the capecitabine group, one patient (2%) had Grade 3 hand-foot syndrome, and another had an acute myocardial infarction. In the 5-FU group, two patients (4%) had Grade 3 hematological toxicity, and three (6%) had complications from Port-a-Cath insertion. Preoperative chemoradiation with oral capecitabine appears to be safe and well tolerated, and at least as good as continuous 5-FU. Copyright 2006 Wiley-Liss, Inc.

  4. Anti-infective external coating of central venous catheters: a randomized, noninferiority trial comparing 5-fluorouracil with chlorhexidine/silver sulfadiazine in preventing catheter colonization.

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    Walz, J Matthias; Avelar, Rui L; Longtine, Karen J; Carter, Kent L; Mermel, Leonard A; Heard, Stephen O

    2010-11-01

    The antimetabolite drug, 5-fluorouracil, inhibits microbial growth. Coating of central venous catheters with 5-fluorouracil may reduce the risk of catheter infection. Our objective was to compare the safety and efficacy of central venous catheters externally coated with 5-fluorouracil with those coated with chlorhexidine and silver sulfadiazine. Prospective, single-blind, randomized, active-controlled, multicentered, noninferiority trial. Twenty-five US medical center intensive care units. A total of 960 adult patients requiring central venous catheterization for up to 28 days. Patients were randomized to receive a central venous catheter externally coated with either 5-fluorouracil (n = 480) or chlorhexidine and silver sulfadiazine (n = 480). The primary antimicrobial outcome was a dichotomous measure (forming units or ≥ 15 colony-forming units) for catheter colonization determined by the roll plate method. Secondary antimicrobial outcomes included local site infection and catheter-related bloodstream infection. Central venous catheters coated with 5-fluorouracil were noninferior to chlorhexidine and silver sulfadiazine coated central venous catheters with respect to the incidence of catheter colonization (2.9% vs. 5.3%, respectively). Local site infection occurred in 1.4% of the 5-fluorouracil group and 0.9% of the chlorhexidine and silver sulfadiazine group. No episode of catheter-related bloodstream infection occurred in the 5-fluorouracil group, whereas two episodes were noted in the chlorhexidine and silver sulfadiazine group. Only Gram-positive organisms were cultured from 5-fluorouracil catheters, whereas Gram-positive bacteria, Gram-negative bacteria, and Candida were cultured from the chlorhexidine and silver sulfadiazine central venous catheters. Adverse events were comparable between the two central venous catheter coatings. Our results suggest that central venous catheters externally coated with 5-fluorouracil are a safe and effective alternative to

  5. Clinical benefit response of concurrent chemoradiotherapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer

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    Okusaka, Takuji; Okada, Shuichi; Ishii, Hiroshi [National Cancer Center, Tokyo (Japan). Hospital] [and others

    1998-04-01

    Pancreatic cancer is a highly virulent disease with a poor prognosis. Although objective tumor response to chemotherapy and/or radiotherapy is low, some patients show an improvement in their symptoms after treatments, without obvious tumor regression. We assessed the clinical benefit of concurrent chemoradiotherapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer. Sixteen patients were enrolled in this study. The clinical benefit response to the chemoradiotherapy was evaluated by 2 indicators, including pain (intensity of pain and consumption of morphine) and performance status. A patient was defined to be a clinical benefit responder if 1 of these 2 variables was positive, and the other variable was positive or stable. Seven patients (44%) responded. Six patients (38%) were classified as stable, and 3 (19%) as nonresponders. The survival period in responders was significantly longer than that in nonresponders and stable patients. Concurrent external-beam radiation therapy, with protracted 5-fluorouracil infusion, may be a meaningful treatment for locally advanced pancreatic cancer. (author)

  6. Pharmacokinetic study of oxaliplatin iv chronomodulated infusion combined with 5-fluorouracil iv continuous infusion in the treatment of advanced colorectal cancer.

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    Cattel, Luigi; La Grotta, Giovanni; Infante, Lucia; Passera, Roberto; Arpicco, Silvia; Brusa, Paola; Bumma, Cesare

    2003-12-01

    We investigated the pharmacokinetics (PK), preliminary clinical results and toxicity of chronomodulated oxaliplatin (OHP) plus 5-fluorouracil (5-FU) without folinic acid (FA) in 13 patients with metastatic colorectal cancer. 5-FU (200 mg/m2/day as 14-day continuous iv infusion for six cycles) plus OHP at increasing doses (25-30-35 mg/m2/day, as 12 h chronomodulated iv infusion on days 1-2-3-4, every 14 days for six cycles) were administered to reach maximum tolerated dose (MTD). At MTD (30 mg/m2/day), a PK study of 5-FU and OHP (in total and ultrafiltered-UF plasma) was performed. 5-FU plasma levels were fairly stable, below that reported in similar studies and closely related to the lack of the most typical 5-FU toxicities. OHP Cmax occurred 7 h after infusion start; a progressive accumulation of free Pt and ultrafiltered Pt (UF-OHP) through cycles 1-6 was noted. A marked difference between total plasma and UF Pt was seen in the elimination phase. OHP plasma clearance decrease was related to Vz (volume of distribution of late elimination phase), whereas in UF-OHP was due to a change in Ke or t1/2. In conclusion, the association of 5-FU with chronomodulated OHP do not seem to influence PK parameters of either drugs. Toxicity was modest/acceptable and clinical efficacy good: preliminary data showed a threshold neurotoxicity at total plasma Pt concentrations >1500 ng/ml and UF plasma Pt concentrations >150 ng/ml.

  7. Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte Oncology Network

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    Ciuffreda Libero

    2009-11-01

    Full Text Available Abstract Background Well-differentiated neuroendocrine carcinomas are highly vascularized and may be sensitive to drugs administered on a metronomic schedule that has shown antiangiogenic properties. A phase II study was designed to test the activity of protracted 5-fluorouracil (5FU infusion plus long-acting release (LAR octreotide in patients with neuroendocrine carcinoma. Methods Twenty-nine patients with metastatic or locally advanced well-differentiated neuroendocrine carcinoma were treated with protracted 5FU intravenous infusion (200 mg/m2 daily plus LAR octreotide (20 mg monthly. Patients were followed for toxicity, objective response, symptomatic and biochemical response, time to progression and survival. Results Assessment by Response Evaluation Criteria in Solid Tumors (RECIST criteria showed partial response in 7 (24.1%, stable disease in 20 (69.0%, and disease progression in 2 patients. Response did not significantly differ when patients were stratified by primary tumor site and proliferative activity. A biochemical (chromogranin A response was observed in 12/25 assessable patients (48.0%; symptom relief was obtained in 9/15 symptomatic patients (60.0%. There was non significant decrease in circulating vascular epithelial growth factor (VEGF over time. Median time to progression was 22.6 months (range, 2.7-68.5; median overall survival was not reached yet. Toxicity was mild and manageable. Conclusion Continuous/metronomic 5FU infusion plus LAR octreotide is well tolerated and shows activity in patients with well-differentiated neuroendocrine carcinoma. The potential synergism between metronomic chemotherapy and antiangiogenic drugs provides a rationale for exploring this association in the future. Trial registration NCT00953394

  8. Unresectable colorectal liver metastases: the safety and efficacy of conversion therapy using hepatic arterial infusion immunochemotherapy with 5-fluorouracil and polyethylene glycol-interferon α-2a.

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    Nakai, Takuya; Okuno, Kiyotaka; Kitaguchi, Hiroshi; Ishikawa, Hajime; Yamasaki, Mitsuo

    2013-08-01

    Hepatic arterial infusion (HAI) or systemic chemotherapy has been used to treat unresectable colorectal liver metastases. The prognosis of the disease in recent years has been improved because chemotherapy is performed before hepatectomy to reduce tumor size (conversion therapy). The purpose of this study was to investigate the safety and efficacy of conversion therapy following HAI immunochemotherapy. Hepatic arterial infusion of 5-fluorouracil (5-FU)/polyethylene glycol (PEG)-IFNα-2a was performed in 21 patients. The primary endpoint was the safety of HAI and hepatectomy. The secondary endpoints were response rate, rate of conversion to hepatectomy, survival rate, and prognostic factors. With regard to side effects, drugs were discontinued temporarily in one patient because of a decrease in white blood cell count; however, other patients continued chemotherapy. The response rate with HAI was 61.9 %, and the conversion rate was 38.1 %. Hepatectomy was completed successfully without mortality. Median progression-free survival (PFS) was 11.5 months (with and without conversion, 16.7 and 4.8 months, respectively; p = 0.021). Median overall survival was 34.6 months (with and without conversion, 48.4 and 26.6 months, respectively; p = 0.003). Prognosis was poor when the number of metastatic tumors was ≥10 [PFS: hazard ratio (HR) 32.21, p = 0.003; overall survival (OS): HR 9.13, p = 0.07], but prognosis improved after hepatectomy (OS: HR 0.08, p = 0.09). Hepatic arterial infusion immunochemotherapy with 5-FU/PEG-IFNα-2a was performed safely without major side effects. Prognosis is expected to improve after successful conversion to hepatectomy.

  9. Prospective study of daily low-dose nedaplatin and continuous 5-fluorouracil infusion combined with radiation for the treatment of esophageal squamous cell carcinoma

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    Yamada Takanori

    2009-11-01

    Full Text Available Abstract Background Protracted low-dose concurrent chemotherapy combined with radiation has been proposed for enhanced treatment results for esophageal cancer. We evaluated the efficacy and the toxicity of a novel regimen of daily low-dose nedaplatin (cis-diammine-glycolatoplatinum and continuous infusion of 5-fluorouracil (5-FU with radiation in patients with esophageal squamous cell carcinoma. Methods Between January 2003 and June 2008, 33 patients with clinical stage I to IVB esophageal squamous cell carcinoma were enrolled. Nedaplatin (10 mg/body/day was administered daily and 5-FU (500 mg/body/day was administered continuously for 20 days. Fractionated radiotherapy for a total dose of 50.4-66 Gy was administered together with chemotherapy. Additional chemotherapy with nedaplatin and 5-FU was optionally performed for a maximum of 5 courses after chemoradiotherapy. The primary end-point of this study was to evaluate the tumor response, and the secondary end-points were to evaluate the toxicity and the overall survival. Results Twenty-two patients (72.7% completed the regimen of chemoradiotherapy. Twenty patients (60.6% achieved a complete response, 10 patients (30.3% a partial response. One patient (3.0% had a stable disease, and 2 (6.1% a progressive disease. The overall response rate was 90.9% (95% confidence interval: 75.7%-98.1%. For grade 3-4 toxicity, leukopenia was observed in 75.8% of the cases, thrombocytopenia in 24.2%, anemia in 9.1%, and esophagitis in 36.4%, while late grade 3-4 cardiac toxicity occurred in 6.1%. Additional chemotherapy was performed for 26 patients (78.8% and the median number of courses was 3 (range, 1-5. The 1-, 2- and 3-year survival rates were 83.9%, 76.0% and 58.8%, respectively. The 1- and 2-year survival rates were 94.7% and 88.4% in patients with T1-3 M0 disease, and 66.2% and 55.2% in patients with T4/M1 disease. Conclusion The treatment used in our study may yield a high complete response rate and

  10. Preoperative combined modality therapy with paclitaxel, carboplatin, prolonged infusion 5-fluorouracil, and radiation therapy in localized esophageal cancer: preliminary results of a Minnie Pearl Cancer Research Network phase II trial.

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    Meluch, A A; Hainsworth, J D; Gray, J R; Thomas, M; Whitworth, P L; Davis, J L; Greco, F A

    1999-01-01

    To evaluate the feasibility, toxicity, and therapeutic efficacy of 1-hour paclitaxel, carboplatin, continuous low-dose infusional 5-fluorouracil, and concurrent radiation therapy administered preoperatively in patients with localized esophageal cancer. Forty-nine patients with localized esophageal cancer, of either squamous cell carcinoma or adenocarcinoma histology, were enrolled into this phase II trial. All patients were candidates for surgical resection and received the following neoadjuvant therapy: paclitaxel, 200 mg/m2, 1 hour IV on days 1 and 22; carboplatin, AUC 6.0, IV on days 1 and 22; 5-fluorouracil, 225 mg/m2/day, continuous IV infusion on days 1 to 42; and radiation therapy, 45 Gy, administered by 1.8-Gy daily fractions beginning on day 1 of chemotherapy. Upon completion of this neoadjuvant regimen, patients were reevaluated, and all responding patients were resected within 6 weeks of completing neoadjuvant treatment. Administration of this combined modality regimen was associated with moderate toxicity and was tolerated by most patients. Leukopenia (65%) and esophagitis (31%) were the most common toxicities. Most patients did not require nutritional support. There were no treatment-related deaths during neoadjuvant therapy; however, three patients (9%) experienced postoperative death. Preliminary assessment of treatment efficacy is encouraging, with 17 of 37 evaluable patients (46%) achieving pathologic complete remission and an additional 11 patients (30%) having only microscopic residual disease. This novel, combined-modality neoadjuvant approach for the treatment of localized esophageal carcinoma is feasible and can be administered with toxicity that compares favorably to previously reported neoadjuvant regimens containing high-dose cisplatin. Preliminary assessment of efficacy is also encouraging, with 46% of patients having pathologic complete response. Further follow-up and larger numbers of patients are required to assess efficacy more

  11. Clinical effects and safety of intra-arterial infusion therapy of cisplatin suspension in lipiodol combined with 5-fluorouracil versus sorafenib, for advanced hepatocellular carcinoma with macroscopic vascular invasion without extra-hepatic spread: A prospective cohort study.

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    Nakano, Masahito; Niizeki, Takashi; Nagamatsu, Hiroaki; Tanaka, Masatoshi; Kuromatsu, Ryoko; Satani, Manabu; Okamura, Shusuke; Iwamoto, Hideki; Shimose, Shigeo; Shirono, Tomotake; Noda, Yu; Koga, Hironori; Torimura, Takuji

    2017-12-01

    Although sorafenib and hepatic arterial infusion chemotherapy (HAIC) have been proven to improve prognosis in hepatocellular carcinoma (HCC) patients with macroscopic vascular invasion (MVI), the most appropriate approach remains unclear. The present multicenter, non-randomized, prospective cohort study aimed to compare the efficacy and safety of HAIC and sorafenib in patients with advanced HCC and MVI, without extra-hepatic spread (EHS) and Child-Pugh class A disease. The present study was performed between April 2008 and March 2014, and 64 HCC patients with MVI, without EHS and Child-Pugh class A disease were registered. Of these patients, 44 were treated with HAIC and 20 with sorafenib. HAIC involved cisplatin (50 mg fine powder in 5-10 ml lipiodol) and a continuous infusion of 5-fluorouracil (FU) (1,500 mg/5 days), which is referred to as new 5-FU and cisplatin therapy (NFP). The primary outcome was progression-free survival, and the secondary outcome was overall survival (OS). Clinical factors influencing OS and the therapeutic effect were identified using univariate and multivariate analyses. There were no differences in clinical factors between the two groups. The median progression-free survival was 5.1 and 9.5 months in the sorafenib and NFP groups, respectively (P=0.001). The complete response (CR) or partial response (PR) rates were 10 and 71% in the sorafenib and NFP groups, respectively (PNFP groups was 13.2 and 30.4 months, respectively (P=0.013). Multivariate analysis revealed that the independent predictors of survival were Child-Pugh score (5, P=0.022, 95% CI, 0.191-0.892), grade of portal vein invasion (brunch, P=0.009, 95% CI, 0.220-0.752), and therapeutic effect (CR or PR, PNFP, PNFP should be the first choice for patients with advanced HCC and MVI, without EHS and Child-Pugh A disease.

  12. 5-Fluorouracil induces arterial vasocontractions.

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    Südhoff, T; Enderle, M-D; Pahlke, M; Petz, C; Teschendorf, C; Graeven, U; Schmiegel, W

    2004-04-01

    From 2% to 10% of cancer patients treated with 5-fluorouracil (5-FU) will develop symptomatic cardiotoxicity. Nevertheless, the underlying pathophysiology is mostly unknown. We investigated the influence of intravenous chemotherapy (CTX) on the diameter of the brachial artery using high resolution ultrasound in patients with malignant tumors, mostly gastrointestinal cancer. Cytostatic drugs included 30 cases with 5-FU and 30 cases with non-5-FU CTX (cis/carboplatin, anthracycline and cyclophosphamide). In addition, plasma levels of big endothelin were assessed prior to and after CTX. Fifteen of 30 patients (50%) showed a contraction of the brachial artery after the end of 5-FU application (median 11%, range 4.3-18.5), whereas no single contraction was noticed in 30 patients following non-5-FU-based CTX. Vessel tonus generally normalized within 30 min after stopping 5-FU. Five patients positive for 5-FU associated vessel contraction were repeatedly exposed to 5-FU. Vessel contractions reoccurred in 86% (18/21) of these administrations. When patients with 5-FU bolus application were pre-treated with glyceroltrinitrate no contraction of the brachial artery was detected in five out of five occasions. There was a trend towards increased big endothelin plasma levels after 5-FU application (median 1.52 versus 1.99 fmol/ml; P = 0.07), whereas big endothelin levels remained unchanged after non-5-FU CTX (1.83 versus 1.83 fmol/ml; P = 0.99). Application of 5-FU is commonly accompanied by arterial vessel contractions, which is likely to represent the first step in 5-FU-induced cardiotoxicity. 5-FU-associated vessel contractions were highly reproducible on re-exposure and were in the case of bolus application completely preventable by glyceroltrinitrate.

  13. Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing

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    Koucky, Kathrin; Wein, Axel; Konturek, Peter C.; Albrecht, Heinz; Reulbach, Udo; Männlein, Gudrun; Wolff, Kerstin; Ostermeier, Nicola; Busse, Dagmar; Golcher, Henriette; Schildberg, Claus; Janka, Rolf; Hohenberger, Werner; Hahn, Eckhart G.; Siebler, Jürgen; Neurath, Markus F.; Boxberger, Frank

    2011-01-01

    Summary Background The aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV). Material/Methods From 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m2) as 1-h infusion followed by 5-FU (2000 mg/m2) combined with FA (500 mg/m2) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57). Results Median age: 59 years; male/female: 74%/26%; ECOG ≤1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months. Conclusions Combined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin-based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p≤0.001). PMID:21525806

  14. Effects of 5-fluorouracil adjuvant treatment of colon cancer

    NARCIS (Netherlands)

    Kelder, Wendy; Hospers, Geke A. P.; Plukker, John T. M.

    Since the late 1980s and early 1990s, 5-fluorouracil-based chemotherapy has been the standard adjuvant treatment for Stage III colon cancer. After the initial introduction of 5-fluorouracil in standard treatment protocols, several changes have been made based on results of randomized studies on

  15. Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer.

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    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

    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. 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(2)/week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m(2)/week. Resection was performed 4-8 weeks after the completion of chemoradiation. 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). 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. Copyright © 2012 Elsevier Inc. All rights reserved.

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

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    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 [Brown University Oncology Group, Providence, RI (United States); Safran, Howard, E-mail: hsafran@lifespan.org [Brown University Oncology Group, Providence, RI (United States)

    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.

  17. 5-fluorouracil and weekly oxaliplatin combined with radiotherapy for locally advanced rectal cancer: surgical complications and long-term results.

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    Pucciarelli, Salvatore; Urso, Emanuele; DeSalvo, Gian Luca; Aschele, Carlo; Friso, Maria Luisa; Rugge, Massimo; Toppan, Paola; Bruttocao, Andrea; Fabris, Giuliano; Ferraro, Benito; Lonardi, Sara; Frego, Mauro; Finco, Cristiano; Lise, Mario; Nitti, Donato

    2006-10-01

    We undertook this study to evaluate early surgical complications and long-term results after preoperative radiotherapy and chemotherapy (RCT) using 5-fluorouracil (5-FU) and oxaliplatin (OXA) for rectal cancer. Forty six TNM stage II-III rectal cancer patients were studied, who were given preoperative RT (50.4 Gy/28 fractions) combined with 5-FU (200-225 mg/m(2)/day by continuous venous infusion) and weekly OXA (25-60 mg/m(2)). Major complications and reoperations were recorded overall, whereas outcome analyses were performed only for patients who received the recommended regimen dosage. Forty three patients (M:F, 25:18; median age 59 years) were available for analysis. All patients received the planned RT dose. There were no postoperative deaths; seven patients had early major surgical complications, four requiring re-operation. One additional patient had a second surgical procedure due to a duodenal fistula complicating the resection of an aortic aneurysm performed concomitantly with rectal cancer surgery. At a median follow-up of 49 months, two of the 23 patients treated at the recommended doses developed recurrence (one local, and one local and distant), and two died of cancer progression. Following the Kaplan-Meier method, the estimated 5-year overall and disease-free survival rates were 92 and 89%, respectively. The preoperative RCT regimen used in the present study incurs a low rate of recurrence with an acceptable surgical morbidity.

  18. Adjacent central venous catheters can result in immediate aspiration of infused drugs during renal replacement therapy.

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    Kam, K Y R; Mari, J M; Wigmore, T J

    2012-02-01

    Dual-lumen haemodiafiltration catheters enable continuous renal replacement therapy in the critically ill and are often co-located with central venous catheters used to infuse drugs. The extent to which infusions are immediately aspirated by an adjacent haemodiafiltration catheter remains unknown. A bench model was constructed to evaluate this effect. A central venous catheter and a haemodiafiltration catheter were inserted into a simulated central vein and flow generated using centrifugal pumps within the simulated vein and haemodiafiltration circuit. Ink was used as a visual tracer and creatinine solution as a quantifiable tracer. Tracers were completely aspirated by the haemodiafiltration catheter unless the infusion was at least 1 cm downstream to the arterial port. No tracer was aspirated from catheters infusing at least 2 cm downstream. Orientation of side ports did not affect tracer elimination. Co-location of central venous and haemodiafiltration catheters may lead to complete aspiration of infusions into the haemodiafilter with resultant drug under-dosing. Anaesthesia © 2011 The Association of Anaesthetists of Great Britain and Ireland.

  19. Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer – a phase II study

    Directory of Open Access Journals (Sweden)

    Savage Paul

    2002-05-01

    Full Text Available Abstract Background 5-fluorouracil remains the standard therapy for patients with advanced/metastatic colorectal cancer. Pre-clinical studies have demonstrated the biological modulation of 5-fluorouracil by methotrexate and leucovorin. This phase II study was initiated to determine the activity and toxicity of sequential methotrexate – leucovorin and 5-fluorouracil chemotherapy in patients with advanced colorectal cancer. Methods Ninety-seven patients with metastatic colorectal cancer were enrolled onto the study. Methotrexate – 30 mg/m2 was administered every 6 hours for 6 doses followed by a 2 hour infusion of LV – 500 mg/m2. Midway through the leucovorin infusion, patients received 5-fluorouracil – 600 mg/m2. This constituted a cycle of therapy and was repeated every 2 weeks until progression. Results The median age was 64 yrs (34–84 and the Eastern Cooperative Group Oncology performance score was 0 in 37%, 1 in 55% and 2 in 8% of patients. Partial and complete responses were seen in 31% of patients with a median duration of response of 6.4 months. The overall median survival was 13.0 months. The estimated 1-year survival was 53.7%. Grade III and IV toxic effects were modest and included mucositis, nausea and vomiting. Conclusions This phase II study supports previously reported data demonstrating the modest clinical benefit of 5-FU modulation utilizing methotrexate and leucovorin in patients with metastatic colorectal cancer. Ongoing studies evaluating 5-fluorouracil modulation with more novel agents (Irinotecan and/or oxaliplatin are in progress and may prove encouraging.

  20. Venous plasma levels of endothelin-1 are not altered immediately after nitroglycerin infusion in healthy subjects

    DEFF Research Database (Denmark)

    Thomsen, L L; Iversen, Helle Klingenberg; Emmeluth, C

    1995-01-01

    before and immediately (5-30 s) after 80 min infusion of NTG (glyceryl trinitrate) or saline in 12 healthy subjects. On two different days separated by at least 1 week, NTG in four different doses, 0.015, 0.25, 1.0, and 2.0 micrograms. kg-1. min-1, or placebo (isotonic saline) was infused successively...... for 20 min each dose. During the infusion blood pressure and heart rate were measured. NTG infusion significantly decreased systolic blood pressure from 112.4 to 103.4 mmHg and pulse pressure from 39.3 to 29.5 mmHg. Heart rate increased from 62.7 to 73.1 beats. min-1. No changes in endothelin-1 plasma...... levels were induced by NTG infusion (2.4 pg.ml-1 before NTG vs. 2.7 pg.ml-1 after NTG) and placebo infusion also did not affect plasma endothelin-1. It is concluded that venous plasma levels of endothelin-1 are not altered immediately after NTG infusion....

  1. A randomized controlled trial of combined 5-fluorouracil and low-molecular-weight heparin in management of established proliferative vitreoretinopathy.

    Science.gov (United States)

    Charteris, David G; Aylward, G William; Wong, David; Groenewald, Carl; Asaria, Riaz H Y; Bunce, Catey

    2004-12-01

    To determine the efficacy of a combination of 5-fluorouracil and low-molecular-weight heparin (LMWH) to improve the outcome of surgery for established proliferative vitreoretinopathy (PVR). Double-masked, prospective, randomized, placebo-controlled clinical trial. Three tertiary-referral teaching hospital vitreoretinal surgical units. One hundred fifty-seven patients with established PVR (grade C, anterior or posterior) undergoing vitrectomy surgery. All patients underwent vitreoretinal surgery and silicone oil exchange with or without membrane peeling and/or retinectomy. Patients were randomly allocated to perioperative infusion with or without 5-fluorouracil (200 microg/ml) and LMWH (5 IU/ml) in Hartmann's solution for 1 hour. The primary outcome measure was defined as posterior retinal reattachment after removal of silicone oil without any reoperations at 6 months. Secondary outcome measures recorded were posterior retinal reattachment, localized/tractional retinal detachment, visual acuity, macular pucker, hypotony, glaucoma, keratopathy, and cataract. Removal of silicone oil and reoperations were also recorded. Overall, at 6 months 84% of patients had full retinal reattachment and 94% had stable posterior retinal reattachment. There was no significant difference in success in the primary outcome measure (56%, treatment group; 51%, placebo group; P = 0.59) or in secondary outcome measures or rates of complications. Secondary macular pucker occurred less often in the treatment group (6% vs. 17% at 6 months, P = 0.068). A perioperative infusion of combined 5-fluorouracil and LMWH does not significantly increase the success rate of vitreoretinal surgery for established PVR.

  2. 5-Fluorouracil induced late peripheral neuropathy. Case report

    OpenAIRE

    Rondinelli, Marina Flaksman Curi; Cavalcanti, Ismar Lima; Gonçalves,Odiléa Rangel; Verçosa,Nubia

    2017-01-01

    ABSTRACT BACKGROUND AND OBJECTIVES: Peripheral neuropathy caused by chemotherapeutic drugs is today one of the major limiting factors in cancer pharmacological therapy due to its negative influence in the cancer patient's quality of life. Its incidence varies depending on the pharmacological nature of the therapy used. Peripheral neurotoxicity caused by 5-Fluorouracil was scarcely described, being characterized as rare adverse effect of this drug. The objective of this study is to report a 5...

  3. Development of lattice-inserted 5-Fluorouracil-hydroxyapatite nanoparticles as a chemotherapeutic delivery system.

    Science.gov (United States)

    Tseng, Ching-Li; Chen, Jung-Chih; Wu, Yu-Chun; Fang, Hsu-Wei; Lin, Feng-Huei; Tang, Tzu-Piao

    2015-10-01

    Developing an effective vehicle for cancer treatment, hydroxyapatite nanoparticles were fabricated for drug delivery. When 5-Fluorouracil, a major chemoagent, is combined with hydroxyapatite nanocarriers by interclay insertion, the modified hydroxyapatite nanoparticles have superior lysosomal degradation profiles, which could be leveraged as controlled drug release. The decomposition of the hydroxyapatite nanocarriers facilitates the release of 5-Fluorouracil into the cytoplasm causing cell death. Hydroxyapatite nanoparticles with/without 5-Fluorouracil were synthesized and analyzed in this study. Their crystallization properties and chemical composition were examined by X-ray diffraction and Fourier transforms infrared spectroscopy. The 5-Fluorouracil release rate was determined by UV spectroscopy. The biocompatibility of hydroxyapatite-5-Fluorouracil extraction solution was assessed using 3T3 cells via a WST-8 assay. The effect of hydroxyapatite-5-Fluorouracil particles which directly work on the human lung adenocarcinoma (A549) cells was evaluated by a lactate dehydrogenase assay via contact cultivation. A 5-Fluorouracil-absorbed hydroxyapatite particles were also tested. Overall, hydroxyapatite-5-Fluorouracils were prepared using a co-precipitation method wherein 5-Fluorouracil was intercalated in the hydroxyapatite lattice as determined by X-ray diffraction. Energy dispersive scanning examination showed the 5-Fluorouracil content was higher in hydroxyapatite-5-Fluorouracil than in a prepared absorption formulation. With 5-Fluorouracil insertion in the lattice, the widths of the a and c axial constants of the hydroxyapatite crystal increased. The extraction solution of hydroxyapatite-5-Fluorouracil was nontoxic to 3T3 cells, in which 5-Fluorouracil was not released in a neutral phosphate buffer solution. In contrast, at a lower pH value (2.5), 5-Fluorouracil was released by the acidic decomposition of hydroxyapatite. Finally, the results of the lactate

  4. Third-Line Chemotherapy with Irinotecan plus 5-Fluorouracil in Caucasian Metastatic Gastric Cancer Patients.

    Science.gov (United States)

    Pasquini, Giulia; Vasile, Enrico; Caparello, Chiara; Vivaldi, Caterina; Musettini, Gianna; Lencioni, Monica; Petrini, Iacopo; Fornaro, Lorenzo; Falcone, Alfredo

    2016-01-01

    The aim of this study was to evaluate the activity of the combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line chemotherapy (CT) in metastatic gastric cancer (mGC) patients pretreated with platinum derivatives, fluoropyrimidines, and taxanes. We prospectively collected data of mGC patients treated with third-line FOLFIRI at our institution from 2009 to 2014. Eligible patients should be treated with a fluoropyrimidine-platinum first-line CT and a subsequent taxane-based second-line CT. FOLFIRI consisted of irinotecan 180 mg/m2 and leucovorin 200 mg/m2, followed by 5-fluorouracil 2,800 mg/m2 (administered as 48-hour i.v. continuous infusion from day 1 to 3), with cycles repeated every 2 weeks. Response rate (RR) was evaluated according to RECIST version 1.0, while progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. A total of 33 patients were included. The majority (97%) had good performance status (0-1 according to ECOG), while median PFS after first-line and second-line CT was 5.2 and 4.4 months, respectively. Two patients experienced an objective response (RR: 6%), while 14 patients achieved disease stabilization (disease control rate: 42%). Median PFS and OS from the start of third-line CT were 3.3 and 7.5 months, respectively. Hematological and nonhematological grade 3-4 toxicities were uncommon and included neutropenia (6.1%), diarrhea (9.1%), vomiting (3%), and asthenia (3%). Febrile neutropenia was not reported. Third-line CT with FOLFIRI may be an option in heavily pretreated mGC patients with preserved performance status and organ function. This regimen has a favorable safety profile, and signs of activity have been observed after standard first- and second-line CT. © 2016 S. Karger AG, Basel.

  5. Epithelial Downgrowth after Intraocular Surgery Treated with Intracameral 5-Fluorouracil

    Directory of Open Access Journals (Sweden)

    Nina Ni

    2015-01-01

    Full Text Available Purpose. To present the clinical and histopathologic correlation of two cases of epithelial downgrowth (EDG after prior intraocular surgery. Methods. Observational case reports. Results. We present two cases of EDG occurring after intraocular surgery. In both cases, after two anterior chamber injections of 5-fluorouracil (5FU, the area of EDG initially regressed. In Case 1, a limited area of EDG eventually recurred, and penetrating keratoplasty with cryotherapy was curative. In Case 2, subsequent corneal edema required Descemet-stripping automated endothelial keratoplasty, and the patient remained clinically free of EDG without further treatment. Conclusion. Intracameral 5FU may have a role in the treatment of EDG after intraocular surgery, though its precise utilization and impact remain to be defined.

  6. The role of initial 5-fluorouracil trabeculectomy in primary glaucoma.

    Directory of Open Access Journals (Sweden)

    Dastur Y

    1994-10-01

    Full Text Available Sixty-eight patients with primary glaucoma involving 68 eyes were divided into two groups: Group I eyes were subjected to trabeculectomy (n = 38 and Group II eyes underwent trabeculectomy followed by subconjunctival injections of 5-fluorouracil (35 mg (n = 30. After one year follow-up, Group I eyes exhibited reduction of mean intra-ocular tension from 45.7 mm Hg (pre-operative to 16 mm Hg; optic disc cupping remained unchanged and 24/38 eyes (63% were found to have field defects (19/38 i.e. 50% had preoperative field defects. Group II eyes showed a reduction of mean intra-ocular pressure from 47.3 mmHg to 9.3 mmHg after one year. Mean cup disc ratio was lowered from 0.50:1 to 0.46:1 and 17/30 eyes (57% which had field defects initially continued to exhibit the same. Complications in Group I and II eyes were shallow anterior chamber [8/38 eyes (21% from Group I and 8/30 eyes (26% from Group II], posterior synechiae formation in 10/38 eyes (26% and 8/30 eyes (26% and cataract progression in 13/38 eyes (34% and 12/30 eyes (40% respectively; only Group II eyes had transient superficial keratitis in 9/30 eyes (30% and thin blebs in 6/30 eyes (20%. The use of 5-fluorouracil after trabeculectomy for primary glaucoma resulted in lowering of intra-ocular pressure, eliminated the need for antiglaucoma medications post-operatively, reduced the galucomatous cup size, and prevented progression of field loss without having a significantly increased complication rate.

  7. Alteplase infusion versus dwell for clearance of partially occluded central venous catheters in critically ill pediatric patients.

    Science.gov (United States)

    Ragsdale, Carolyn E; Oliver, Maggee R; Thompson, A Jill; Evans, Melissa C

    2014-07-01

    To evaluate the efficacy and safety of alteplase infusions and alteplase local instillations (dwells) to clear partially occluded central venous catheters in critically ill children. Retrospective study. PICU in a single, tertiary care, academic children's hospital. Retrospective review of the medical records of all critically ill pediatric patients less than 18 years old who received an alteplase infusion or dwell as the treatment for a partial central venous catheter occlusion. The typical infusion regimen was to administer 0.1 mg/kg of body weight (maximum, 2 mg/dose) of alteplase in 25 mL of 0.9% sodium chloride over 3 hours. The standard dwell was to administer and aspirate alteplase in a 1 mg/mL concentration as a fixed dose as ordered by the prescriber (maximum, 2 mg/dose). Efficacy was defined as documentation of positive blood return from the catheter. Radiology reports, nursing and physician documentation, and laboratory values were reviewed to assess for bleeding events. None. One hundred fifty occlusion events were included for analysis. Overall, 72 of 84 alteplase infusions (86%) and 53 of 66 alteplase dwells (80%) resulted in resolution of the lumen occlusion event as documented by positive blood return from the catheter after a maximum of two doses (p = 0.39). One major bleeding event occurred in each arm; both were deemed unlikely related to alteplase. Alteplase infusions to clear partially occluded central venous catheters appear to be as efficacious as alteplase dwells in critically ill children. In occlusions treated with an infusion, more occlusions resolved in older and larger patients and in patients with catheters in place less than 7 days. In occlusions treated with a dwell, more occlusions resolved in smaller catheters. The safety profile for both infusions and dwells was acceptable for the pediatric critically ill population.

  8. Effects of intraoperative diltiazem infusion on flow changes in arterial and venous grafts in coronary artery bypass graft surgery

    Directory of Open Access Journals (Sweden)

    Ozan Erdem

    2015-08-01

    Full Text Available Abstract Objective: This study aimed to show the effects of intra-operative diltiazem infusion on flow in arterial and venous grafts in coronary artery bypass graft surgery. Methods: Hundred fourty patients with a total of 361 grafts [205 (57% arterial and 156 (43% venous] underwent isolated coronary surgery. All the grafts were measured by intraoperative transit time flow meter intra-operatively. Group A (n=70 consisted of patients who received diltiazem infusion (dose of 2.5 microgram/kg/min, and Group B (n=70 didn't receive diltiazem infusion. Results: Mean graft flow values of left internal mammary artery were 53 ml/min in Group A and 40 ml/min in Group B (P<0.001. Pulsatility index (PI values of left internal mammary artery for Group A and Group B were 2.6 and 3.0 respectively (P<0.001. No statistically significant difference was found between venous graft parameters. Conclusion: We recommend an effect of diltiazem infusion in increasing graft flows in coronary artery bypass graft operations.

  9. A Randomized Trial Comparing Cisplatin Plus 5-fluorouracil With or Without Levamisole in Operable Gastric Cancer

    Science.gov (United States)

    Choi, Jong Soo; Lee, Kyoo Hyung; Ahn, Myung Ju; Lee, Jung Shin; Lee, Je Han; Zang, Dae Young; Suh, Chel Won; Kim, Sang We; Kim, Woo Gun; Kim, Jin Cheon; Kim, SukKoo; Park, Kun Choon; Lee, Moo Song; Kim, Sang-Hee

    1997-01-01

    Objectives To determine the effectiveness and toxicity when levamisole was added to the adjuvant combination chemotherapy in patients with operable gastric cancer. Methods After en bloc resection of gastric cancer without gross or microscopic evidence of residual disease from April 1991 to December 1992, 100 patients were randomized to 6 months of 5-fluorouracil 1,000mg/m2/day administered as continous infusion for 5 days, cisplatin 60mg/m2/day as intravenous infusion for 1 day with or without levamisole (50mg every eight hours P.O for a period of three days every 2 weeks for 6 months). This chemotherapy treatment was begun within 2 to 4 weeks after the surgery. The chemotherapy consisted of discrete 5-day courses administered at 4-weeks intervals. All 100 patients are assessable. Results The fifty patients were assigned to each treatment group. There was no statistical difference and no bias in the distribution of characteristics of the 100 evaluable patients between the two groups. A total of 274 courses of treatment were given in the levamisole group and 260 courses of treatment in non-levamisole group. Eleven patients in each group did not finish planned 6 courses of treatment mainly due to non-compliance. At median follow up of 39 months, 32 patients relapsed 19 in the levamisole group and 13 in the non-levamisole group (p=0.284). Twenty five patients died of relapsed diseases, 15 in the levamisole group and 10 in the non-levamisole group. The levamisole group tended to show more risk of overall death rate and recurrence than the non-levamisole group. Howerer. this result was not statistically significant at 3 years. The treatment was well tolerated in both treatment groups. The grade 2–3 toxicites were nausea/vomiting (levamisole, non-levamisole group;31.7%, 29.3% of treatment courses respectively), diarrhea (7.6%, 8.4%), mucositis (11.6%, 12.3%), and leukopenia (9.8%, 9.6%). Conclusion Levamisole had negative effects on disease-free survival and overall

  10. Central venous infusion port inserted via high versus low jugular venous approaches: Retrospective comparison of outcome and complications

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hong Suk [Research Institute and Hospital, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-764 (Korea, Republic of); Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)], E-mail: hpark@dreamwiz.com; Kim, Young Il; Lee, Sang Hyun; Kim, Jung Im; Seo, Hyobin; Lee, Sang Min; Lee, Youkyung; Lim, Min Kyung [Research Institute and Hospital, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-764 (Korea, Republic of); Park, Young Suk [Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2009-12-15

    Purpose: To retrospectively compare immediate and long-term outcome of central venous infusion port inserted via right high versus low jugular vein approaches. Materials and methods: The study included 163 patients (125 women patients, 38 men patients; age range, 18-79 years; mean age, 53 years); 142 patients underwent port insertion with low jugular vein approach and 21 patients with high jugular vein approach. The causes of high jugular vein puncture were metastatic lymphadenopathy (n = 7), operation scar (n = 6), radiation scar (n = 5), failure of low jugular vein puncture (n = 2), and abnormal course of right subclavian artery (n = 1). Medical records and radiologic studies were reviewed retrospectively to determine and compare the outcome and the occurrence of complication related to port. Results: The procedure-related complications were all minor (n = 14, 8.6%) in both groups; hematoma (n = 4, 2.8% in low jugular puncture group and n = 1, 4.8% in high jugular puncture group, p = 0.6295), air embolism (n = 2, 1.4% in low jugular puncture group and n = 0 in high jugular puncture group, p = 0.5842) and minor bleeding (n = 5, 3.5% in low jugular vein puncture group and n = 2, 9.5% in high jugular vein puncture group, p = 0.2054). The average length of follow-up was 431 days for low jugular vein puncture group and 284 days for high jugular vein puncture group. The difference between two groups was significant (p = 0.0349). The reasons for catheter removal were patients' death (59 in low jugular puncture group and 14 in high jugular puncture group, p = 0.0465), suspected infection (11 in low jugular vein puncture group and 2 in high jugular vein puncture group, p = 0.8242), catheter occlusion (four in low jugular vein puncture group and one in high jugular vein puncture group, p = 0.6583). The catheter tip migrated upward an average of 1.86 cm (range, -0.5 to 5.0 cm) in low jugular vein puncture group and 1.56 cm (range, 0-3.6 cm) in high jugular vein

  11. Water Infused Surface Protection as an Active Mechanism for Fibrin Sheath Prevention in Central Venous Catheters.

    Science.gov (United States)

    Sutherland, David W; Zhang, Xin; Charest, Joseph L

    2017-10-01

    Protein adhesion in central venous catheters (CVCs) leads to fibrin sheath formation, the precursor to thrombotic and biofilm-related CVC failures. Advances in material properties and surface coatings do not completely prevent fibrin sheath formation and post-formation treatment options are limited and expensive. We propose water infused surface protection (WISP), an active method for prevention of fibrin sheath formation on CVCs, which creates a blood-free boundary layer on the inner surface of the CVC, limiting blood contact with the CVC lumen wall. A hollow fiber membrane (HFM) in a benchtop device served as a CVC testing model to demonstrate the WISP concept. Porcine blood was pumped through the HFM while phosphate buffered saline (PBS) was infused through the HFM wall, creating the WISP boundary layer. Protein adherences on model CVC surfaces were measured and imaged. Analytical and finite volume lubrication models were used to justify the assumption of a blood-free boundary layer. We found a 92.2% reduction in average adherent protein density when WISP is used, compared with our model CVC without WISP flow. Lubrication models matched our experimental pressure drop measurements suggesting that a blood-free boundary layer was created. The WISP technique also provides a novel strategy for drug administration for biofilm treatment. Reduction in adherent protein indicates a restriction on long-term fibrin sheath and biofilm formation making WISP a promising technology which improves a wide range of vascular access treatments. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  12. Molecularly Imprinted Polymers for 5-Fluorouracil Release in Biological Fluids

    Directory of Open Access Journals (Sweden)

    Franco Alhaique

    2007-04-01

    Full Text Available The aim of this work was to investigate the possibility of employing Molecularly Imprinted Polymers (MIPs as a controlled release device for 5-fluorouracil (5-FU in biological fluids, especially gastrointestinal ones, compared to Non Imprinted Polymers (NIPs. MIPs were synthesized using methacrylic acid (MAA as functional monomer and ethylene glycol dimethacrylate (EGDMA as crosslinking agent. The capacity of the polymer to recognize and to bind the template selectively in both organic and aqueous media was evaluated. An in vitro release study was performed both in gastrointestinal and in plasma simulating fluids. The imprinted polymers bound much more 5-Fu than the corresponding non-imprinted ones and showed a controlled/sustained drug release, with MIPs release rate being indeed much more sustained than that obtained from NIPs. These polymers represent a potential valid system for drug delivery and this study indicates that the selective binding characteristic of molecularly imprinted polymers is promising for the preparation of novel controlled release drug dosage form.

  13. Mismatch repair proficiency and in vitro response to 5-fluorouracil.

    Science.gov (United States)

    Carethers, J M; Chauhan, D P; Fink, D; Nebel, S; Bresalier, R S; Howell, S B; Boland, C R

    1999-07-01

    The DNA mismatch repair (MMR) system recognizes certain DNA adducts caused by alkylation damage in addition to its role in recognizing and directing repair of interstrand nucleotide mismatches and slippage mistakes at microsatellite sequences. Because defects in the MMR system can confer tolerance to acquired DNA damage and, by inference, the toxic effects of certain chemotherapeutic agents, we investigated the effect of 5-fluorouracil (5-FU) on colon cancer cell lines. We determined growth selection by cell enrichment assay and cloning efficiency after treatment with 5 micromol/L 5-FU, assayed nucleic 3H-5-FU incorporation, and analyzed the cell cycle by flow cytometry. 5-FU treatment provided a growth advantage for MMR-deficient cell lines, indicating a relative degree of tolerance to 5-FU by the MMR-deficient cell lines. Enhanced survival was statistically significant after 5 days of growth, and a 28-fold reduction in survival was noted in the MMR-proficient cells by clonagenic assays after 10 days of growth. Differences in nucleotide uptake of 5-FU did not account for the observed growth differences, and specific cell cycle checkpoint arrest was not detected. Intact DNA MMR seems to recognize 5-FU incorporated into DNA but may do so in a different manner than other types of alkylation damage. Defective DNA MMR might be one mechanism for tumor resistance to 5-FU.

  14. Controlled release of 5-fluorouracil from microporous zeolites.

    Science.gov (United States)

    Spanakis, Marios; Bouropoulos, Nikolaos; Theodoropoulos, Dimitrios; Sygellou, Lamprini; Ewart, Sinead; Moschovi, Anastasia Maria; Siokou, Angeliki; Niopas, Ioannis; Kachrimanis, Kyriakos; Nikolakis, Vladimiros; Cox, Paul A; Vizirianakis, Ioannis S; Fatouros, Dimitrios G

    2014-01-01

    Zeolite particles with different pore diameter and particle size were loaded with the model anticancer drug 5-fluorouracil. The loaded zeolites were characterized by means of SEM, XRD, DSC, XPS, N2 physisorption and FT-IR. Higher loading of 5-FU was observed for NaX-FAU than BEA. Release studies were carried out in HCl 0.1N. Release of 5-FU from NaX-FAU showed exponential-type behaviour with the drug fully released within 10 min. In the case of BEA, the kinetics of 5-FU shows a multi-step profile with prolonged release over time. Molecular dynamics simulations showed that diffusion of the drug molecule through the BEA framework is lower than for NaX-FAU due to increased van der Waals interaction between the drug and the framework. The effect of zeolitic particles on the viability of Caco-2 monolayers showed that the NaX-FAU particles cause a reduction of cell viability in a more pronounced way compared with the BEA particles. This article describes zeolite-based nanoparticles in generating time-controlled release of 5-FU from zeolite preparations for anti-cancer therapy. © 2013.

  15. The complex mechanism of antimycobacterial action of 5-fluorouracil.

    Science.gov (United States)

    Singh, Vinayak; Brecik, Miroslav; Mukherjee, Raju; Evans, Joanna C; Svetlíková, Zuzana; Blaško, Jaroslav; Surade, Sachin; Blackburn, Jonathan; Warner, Digby F; Mikušová, Katarína; Mizrahi, Valerie

    2015-01-22

    A combination of chemical genetic and biochemical assays was applied to investigate the mechanism of action of the anticancer drug 5-fluorouracil (5-FU), against Mycobacterium tuberculosis (Mtb). 5-FU resistance was associated with mutations in upp or pyrR. Upp-catalyzed conversion of 5-FU to FUMP was shown to constitute the first step in the mechanism of action, and resistance conferred by nonsynonymous SNPs in pyrR shown to be due to derepression of the pyr operon and rescue from the toxic effects of FUMP and downstream antimetabolites through de novo production of UMP. 5-FU-derived metabolites identified in Mtb were consistent with the observed incorporation of 5-FU into RNA and DNA and the reduced amount of mycolyl arabinogalactan peptidoglycan in 5-FU-treated cells. Conditional depletion of the essential thymidylate synthase ThyX resulted in modest hypersensitivity to 5-FU, implicating inhibition of ThyX by fluorodeoxyuridylate as a further component of the mechanism of antimycobacterial action of this drug. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Cardiotoxicity in Asymptomatic Patients Receiving Adjuvant 5-fluorouracil

    DEFF Research Database (Denmark)

    Nielsen, Karin; Polk, Anne; Nielsen, Dorte Lisbet

    2014-01-01

    infusion. Furthermore a 13-fold increase in N-terminal Pro Brain Natriuretic Peptide (NT-pro-BNP) occurred during infusion. No subjective cardiac symptoms were described, but the findings were interpreted as cardiotoxicity. Case report 2 presents a 64-year old woman with a medical history of hypertension...... and hyperlipidemia as well as an incidental finding of negative T-waves in electrocardiogram years before 5-FU treatment. No subjective cardiac symptoms were described during infusion, but approximately 12 hours after infusion she suffered from cardiac arrest but was revived. Subsequent analysis of the Holter...

  17. [A mathematic analysis of different manners of replacement fluid infusion in continuous veno-venous hemofiltration].

    Science.gov (United States)

    Wu, Yunzhen; Wang, Chunting

    2015-05-01

    To establish a mathematical formula for choosing the manner of replacement fluid infusion in continuous renal replacement therapy (CRRT), so as to provide the basis for improving the treatment effect. A mathematical formula for choosing the manner of replacement fluid infusion with continuous veno-venous hemofiltration (CVVH) was taken as an example, and it was compared with the result of standard replacement fluid in order to analyze the effect of different manners of infusion. (1) Comparison parameters: the plasma volume ("Vreturn") and some electrolyte concentration ("Creturn") in back way of CRRT ( if other thing was solute, filter coefficient should be 1.0). (2) Research objects: the actual replacement fluid (for example, the most complex should be sorted into A and B type) mode (pre or post) was compared with the standard replacement fluid (the A and B in one). (3) Based on the formula of standard replacement, four equations in different conditions were derived: pre-dilution and post-dilution mode; same direction and same ratio; same direction and different ratio; different direction and same ratio; different direction and different ratio. The calculated results of "Vreturn" (except hematocrit) and "Creturn" were same to the standard only following the rule of same direction and ratio for A and B no matter pre-dilution mode or post-dilution mode, and it was different from the standard in others. In pre-dilution mode and post-dilution mode, it showed: (1) A and B in same direction and different ratio: "Vreturn" and "Creturn" were different from the standard for the alterative ratio of B. (2) A and B in different direction and same ratio: "Vreturn" was same to the standard, but "Creturn" was different from the standard for the completely different and more complex computational formula. (3) A and B in different direction and different ratio: both "Vreturn" and "Creturn" were different from the standard. The different "Vreturn" was due to the different ratio of

  18. Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer

    Directory of Open Access Journals (Sweden)

    Davidson Neville

    2004-07-01

    Full Text Available Abstract Background This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer. Methods Sixty-three patients received irinotecan (250 or 300 mg/m2, 30- to 90-minute intravenous infusion on day 1, immediately followed by folinic acid (20 mg/m2/day and 5-fluorouracil (425 mg/m2, 15-minute bolus infusion days 1 to 5, every four weeks. Results Diarrhoea was dose limiting at 300 mg/m2 irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose. Grade 3–4 neutropenia was the most frequently reported toxicity. The recommended dose of irinotecan for the phase II part of the study was 250 mg/m2. The response rate for the evaluable patient population was 36% (13/36, and 44% (16 patients had stable disease (including 19% of minor response. For the intention-to-treat population, the response rate was 29% (14/49 and 35% (17 patients stable disease (including 14% of minor response. The median time to progression was 7.0 months and the median survival was 12.0 months. Grade 3–4 non-haematological drug-related toxicities included delayed diarrhoea, stomatitis, fatigue, and nausea/vomiting. There were three deaths due to septic shock that were possibly or probably treatment-related. Conclusions This regimen of irinotecan in combination with the Mayo Clinic schedule of bolus 5-fluorouracil/folinic acid every four weeks showed activity as first-line therapy in patients with advanced colorectal cancer. In keeping with other published results of studies using bolus 5-fluorouracil combined with irinotecan, the use of this regimen is limited by a relatively high rate of grade 3–4 neutropenia, and the combination of irinotecan and infusional 5-fluorouracil

  19. Effect of intralesional 5 fluorouracil injection in primary pterygium

    Science.gov (United States)

    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

  20. Adjuvant chemoradiotherapy combined with cisplatin, 5-fluorouracil and folinic acid for locally advanced gastric cancer

    Directory of Open Access Journals (Sweden)

    Muharrem Kocar

    2016-04-01

    Conclusion: The addition of combination chemotherapy with cisplatin, infusional 5-fluorouracil and folinic acid before and after chemoradiotherapy was found to be safe and effective in patients with operated gastric cancer.

  1. 5-Fluorouracil-induced cardiotoxicity mimicking myocardial infarction: a case report

    Directory of Open Access Journals (Sweden)

    Campbell Norman PS

    2001-11-01

    Full Text Available Abstract Background Severe cardiotoxicity is a documented, but very unusual side-effect of intravenous 5-fluorouracil therapy. The mechanism producing cardiotoxicity is poorly understood. Case presentation A case of 5-fluorouracil-induced cardiotoxicity, possibly due to coronary artery spasm, and mimicking acute anterolateral myocardial infarction is presented and discussed. Electrocardiographs highlighting the severity of the presentation are included in the report along with coronary angiograms demonstrating the absence of significant coronary atherosclerosis. Conclusion Severe 5-fluorouracil-induced cardiotoxicity is rare, but can be severe and may mimic acute myocardial infarction, leading to diagnostic and therapeutic dilemmas. Readministration of 5-fluorouracil is not advised following an episode of cardiotoxicity.

  2. Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by combination of oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI) in metastatic gastric cancer: results of a phase II trial.

    Science.gov (United States)

    Dalla Chiesa, Matteo; Tomasello, Gianluca; Buti, Sebastiano; Rovere, Rodrigo Kraft; Brighenti, Matteo; Lazzarelli, Silvia; Donati, Gianvito; Passalacqua, Rodolfo

    2011-01-01

    To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer. Chemo-naïve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85 mg/m(2) and cisplatin initially 75 mg/m(2) on day 1 [later modified due to toxicity: 70 and 60 mg/m(2) respectively], l-folinic acid 100 mg/m(2) on days 1 and 2, 5-fluorouracil 400 mg/m(2) bolus and then 600 mg/m(2) as a 22 h continuous infusion on day 1 and 2, every 14 days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85 mg/m(2), irinotecan 140 mg/m(2), l-folinic acid 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) on day 1 followed by 2,400 mg/m(2) as a 48 h continuous infusion, every 14 days). In both regimens pegfilgrastim 6 mg subcutaneously on day 3 was included. Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40-70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45-75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3-4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3-4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively. A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients.

  3. Topical 5-Fluorouracil for Women With High-Grade Vaginal Intraepithelial Neoplasia.

    Science.gov (United States)

    Fiascone, Stephen; Vitonis, Allison F; Feldman, Sarah

    2017-12-01

    To examine success rates of 5-fluorouracil, excision, and laser ablation as the initial and secondary management strategies for women with high-grade vaginal intraepithelial neoplasia. We conducted a retrospective case series of women referred to a single center for management of biopsy-proven, high-grade vaginal intraepithelial neoplasia between April 1994 and May 2016. Data including demographic characteristics, human papillomavirus risk factors, antecedent Pap cytology, concurrent or prior cervical and vulvar dysplasia, and treatment outcome including follow-up Pap cytology were recorded. All women were counseled on options of excision, laser ablation, or 5-fluorouracil, which was administered intravaginally according to a standardized regimen. Recurrence was defined as a biopsy showing any vaginal intraepithelial neoplasia diagnosis after primary treatment. Forty-seven patients were treated initially with 5-fluorouracil, 35 were treated with excision, and 22 were treated with laser ablation. Demographics were similar between groups. No recurrence was noted in 35 women treated with 5-fluorouracil (74%; 95% CI 62-87%), 20 treated with excision (57%; 95% CI 41-74%), and nine treated with laser ablation (41%; 95% CI 20-61%). Among 13 patients treated with 5-fluorouracil for recurrence, eight (62%) did not experience a second recurrence. Nine of 58 (16%) patients ever treated with 5-fluorouracil reported a side effect, most commonly irritation and dyspareunia. 5-fluorouracil was associated with a 74% success rate as the initial treatment modality for high-grade vaginal dysplasia. There is also a role for 5-fluorouracil in the management of recurrent or persistent high-grade vaginal intraepithelial neoplasia.

  4. Infiltração de 5-fluorouracil no pré-operatório do pterígio Preoperative 5-fluorouracil infiltration in pterygium surgery

    Directory of Open Access Journals (Sweden)

    Claudia Akemi Shiratori

    2003-08-01

    Full Text Available OBJETIVO: Avaliar o efeito do 5-fluorouracil (5FU injetado intralesionalmente na cabeça do pterígio no período pré-operatório. MÉTODOS: Foram estudados 53 olhos (52 pacientes, sendo 28 pterígios primários e 25 recidivados, divididos em dois grupos: grupo 1 (G1, composto por indivíduos que receberam a injeção de 5-fluorouracil 30 dias antes do procedimento cirúrgico e grupo 2 (G2, no qual o 5-fluorouracil foi injetado 10 dias antes da cirurgia. Todas as cirurgias foram realizadas seguindo-se a mesma técnica cirúrgica, pelo mesmo cirurgião. Os pacientes foram reavaliados 7, 30 e 60 dias após a cirurgia. Os resultados observados foram submetidos à análise estatística. RESULTADOS: A amostra estudada foi constituída por 52,8% de pterígios primários e 47,2% de recidivados, sendo composta igualmente por indivíduos de ambos os sexos. Não ocorreram complicações decorrentes da infiltração da droga. A recidiva foi mais freqüente nos pterígios recidivados e no G1. CONCLUSÃO: O uso intralesional de 5-fluorouracil no pré-operatório do pterígio não provocou efeitos deletérios aos olhos estudados. Houve menor recorrência quando usado o 5-fluorouracil 10 dias antes da exérese cirúrgica, em relação à aplicação 30 dias antes do procedimento.PURPOSE: To assess the effect of 5-fluorouracil (5FU injected in pterygia before surgery. METHODS: 53 eyes of 52 patients (28 primary and 25 recurrent pterygia underwent subconjunctival 5-fluorouracil application 30 days before surgery - group 1 (G1 and 10 days before surgery - group 2 (G2. All surgeries were performed by the same surgeon, who used the same technique in all patients. Patients were assessed 7, 30 and 60 days after surgery. Results were submitted to statistical analysis (p<0,05. RESULTS: There were 52,8% primary and 47,2% recurrent pterygia, equally distributed regarding gender. There were no complications due to the infiltration of the drug. Recurrence occurred more

  5. Electrochemical behavior of an anticancer drug 5-fluorouracil at methylene blue modified carbon paste electrode

    Energy Technology Data Exchange (ETDEWEB)

    Bukkitgar, Shikandar D.; Shetti, Nagaraj P., E-mail: dr.npshetti@gmail.com

    2016-08-01

    A novel sensor for the determination of 5-fluorouracil was constructed by electrochemical deposition of methylene blue on surface of carbon paste electrode. The electrode surface morphology was studied using Atomic force microscopy and XRD. The electrochemical activity of modified electrode was characterized using cyclic voltammetry and differential pulse method. The developed sensor shows impressive enlargement in sensitivity of 5-fluorouracil determination. The peak currents obtained from differential pulse voltammetry was linear with concentration of 5-fluorouracil in the range 4 × 10{sup −5}–1 × 10{sup −7} M and detection limit and quantification limit were calculated to be 2.04 nM and 6.18 nM respectively. Further, the sensor was successfully applied in pharmaceutical and biological fluid sample analysis. - Highlights: • Electrochemical oxidation of 5-fluorouracil has been investigated for first time at methylene blue modified carbon paste electrode • The electrode process was irreversible and diffusion controlled • Probable electrochemical mechanism was proposed which involved two proton and two electron transfer reaction • The LOD and LOQ values were calculated to be 2.04 nM and 6.18 nM, respectively, with good selectivity and sensitivity. • Proposed method was applied to 5-Fluorouracil determination in pharmaceutical and spiked human urine samples.

  6. Economic comparison of capecitabine + oxaliplatin and 5-fluorouracil + oxaliplatin in the adjuvant treatment of colon cancer

    Directory of Open Access Journals (Sweden)

    Colombo GL.

    2012-03-01

    -case scenario.Conclusion: The results of our study indicate that infusion via a central vein catheter represents a significant cost, and that substitution with an oral therapy, even when associated with drugs administered intravenously, represents a consistent saving of hospital resources.Keywords: colorectal cancer, capecitabine, oxaliplatin, 5-fluorouracil, Folfox-4, cost analysis, economic evaluation

  7. Addition of citral controls ROS and reduces toxicity in 5-fluorouracil treated Schizosaccharomyces pombe cells.

    Science.gov (United States)

    Patel, Pinaki B; Thakkar, Vasudev R

    2015-03-01

    In systemic therapy, chemotherapeutic drugs, often, cause considerable side effects; and combination of natural compounds lessen the extent of such effects. In the present study, combined effect of citral and 5-fluorouracil was studied in Schizosaccharomyces pombe cells. The antagonistic combination index found was at 0.01 and 0.025 mM of citral with 40 μg or higher concentration of 5-fluorouracil. The combined treatment was so effective that higher number of cells underwent apoptosis compared to individual treatment of 5-fluorouracil. Citral controlled ROS levels and increased survival of normal cells. Several differentially expressed proteins observed in the citral treatment could further help understanding its mechanism of action.

  8. Novel Strategies to Improve the Anticancer Action of 5-Fluorouracil by Using Drug Delivery Systems

    Directory of Open Access Journals (Sweden)

    José L. Arias

    2008-10-01

    Full Text Available Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of the anticancer drug 5-fluorouracil have been devised. The target is always to provide the proper dose of the antitumor agent only at the desired locus of action, thus reducing the unwanted side effects. In this review, the main strategies and the more significant results in the development of 5-fluorouracil carriers for cancer treatment are discussed.

  9. Should capecitabine replace 5-fluorouracil in the first-line treatment of metastatic colorectal cancer?

    Science.gov (United States)

    Aguado, Carlos; García-Paredes, Beatriz; Sotelo, Miguel Jhonatan; Sastre, Javier; Díaz-Rubio, Eduardo

    2014-01-01

    Fluoropyrimidines play a central role in the first-line treatment of metastatic colorectal cancer. Our aim was to review whether capecitabine was a safer, non-inferior, economically superior and more convenient alternative to 5-fluorouracil. Capecitabine has previously been compared to 5-fluorouracil-either as a monotherapy or in combination with oxaliplatin, irinotecan, or biological drugs-and has been found to have comparable efficacy and safety profiles. Furthermore, pharmacoeconomic data and patients’ preferences for oral chemotherapy further favor capecitabine. Therefore, capecitabine appears to be an effective and safe alternative to fluorouracil in the first-line treatment of metastatic colorectal cancer. PMID:24876731

  10. Effects of endotoxin infusion on mean systemic filling pressure and flow resistance to venous return

    NARCIS (Netherlands)

    M. Hiesmayr (Michael); J.R.C. Jansen (Jos); A. Versprille (Adrian)

    1996-01-01

    textabstractMean systemic filling pressure (Psf) is an indicator of the filling state of the systemic circulation. Cardiac output (Q′) is related linearly to the difference between Psf and central venous pressure (Pcv), according to:Q′ = (Psf -Pcv)/Rsf, where Rsf is the flow resistance downstream

  11. Cardiac tamponade in an infant during contrast infusion through central venous catheter for chest computed tomography; Tamponamento cardiaco durante infusao de contraste em acesso venoso central para realizacao de tomografia computadorizada do torax em lactente

    Energy Technology Data Exchange (ETDEWEB)

    Daud, Danilo Felix; Campos, Marcos Menezes Freitas de; Fleury Neto, Augusto de Padua [Hospital Geral de Palmas, TO (Brazil)

    2013-11-15

    Complications from central venous catheterization include infectious conditions, pneumothorax, hemothorax and venous thrombosis. Pericardial effusion with cardiac tamponade hardly occurs, and in infants is generally caused by umbilical catheterization. The authors describe the case of cardiac tamponade occurred in an infant during chest computed tomography with contrast infusion through a central venous catheter inserted into the right internal jugular vein. (author)

  12. Oral ftorafur versus intravenous 5-fluorouracil. A comparative study in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Andersen, E; Pedersen, H

    1987-01-01

    The toxicities of oral Ftorafur (1 g/m2/day 1-21) and intravenous 5-fluorouracil (5-FU) (500 mg/m2/day 1-5) were compared in a prospective randomized study in patients with colorectal cancer. The treatment courses were repeated every 6th week. Leucopenia was more common after 5-FU. Leucocyte nadir...

  13. Total body topical 5-fluorouracil for extensive non-melanoma skin cancer

    NARCIS (Netherlands)

    van Ruth, Serge; Jansman, Frank G. A.; Sanders, Cornelis J.

    Background Topical 5-fluorouracil 5% cream is one of the treatment modalities for non-melanoma skin cancer (NMSC). There is a lack of suitable therapies to treat patients with extensive NMSC. In this paper we report two patients with extensive NMSC treated by total body application of topical

  14. Extensive hepatic replacement due to liver metastases has no effect on 5-fluorouracil pharmacokinetics

    NARCIS (Netherlands)

    Maring, JG; Piersma, H; van Dalen, A; Groen, HJM; Uges, DRA; DeVries, EGE

    Purpose: The influence of liver metastases on the pharmacokinetics of 5-fluorouracil (5-FU) and its metabolite 5,6-dihydrofluorouracil (DHFU) was studied in patients with liver metastases from gastrointestinal cancer (n = 16) and compared with a control group of patients with nonmetastatic

  15. Spectrofluorimetric determination of 5-fluorouracil by fluorescence quenching of 9-anthracenecarboxylic acid

    Science.gov (United States)

    Khot, M. S.; Bhattar, S. L.; Kolekar, G. B.; Patil, S. R.

    2010-09-01

    Photo-induced intermolecular electron transfer (PET) interaction between excited singlet (S 1) state of 9-anthracene carboxylic acid (9-ANCA) and DNA bases of pyrimidines as uracil and 5-fluorouracil (5-FU) has been studied in water and ethanol solutions using steady-state fluorescence spectroscopy. The intensity of all emission bands of 9-ANCA was quenched in presence of uracil and 5-FU by electron transfer reaction without formation of an exciplex. It was found that uracil and 5-fluorouracil acts as effective electron donors and simultaneously quench the fluorescence of electron-accepting sensitizer 9-ANCA. The quenching by diffusion-controlled rate coincides well with the dynamic Stern-Volmer correlation. The bimolecular quenching rate constant (kqss) and electron transfer rate constant ( ket) observed are seen to be much higher for 5-fluorouracil than those for uracil. The thermodynamic parameters estimated by using the Rehm-Weller equation were used to propose a suitable mechanism for PET occurring between uracils and 9-ANCA. The proposed method was used to determine 5-fluorouracil from pharmaceutical samples with satisfactory results. The technique is more selective, sensitive and relatively free from coexisting substances.

  16. A phase II study using vinorelbine and continuous 5-fluorouracil in patients with advanced head and neck cancer

    DEFF Research Database (Denmark)

    Larsen, Susanne; Serup-Hansen, Eva; Andersen, Lisbeth J

    2007-01-01

    Seventy patients with advanced head and neck cancer were treated with vinorelbine and continuous 5-FU administered in a central venous catheter. Over all response was 36% with 9% complete responses. The most common grade 3 and 4 toxicities were stomatitis (13), infection (5), pain related...... to vinorelbine infusion (4), skin toxicity (3). Thirty one patients had grade 3 or 4 leukopenia. Treatment was complicated by venous thrombosis in the central venous catheter in one case. A majority of patients experienced dose reduction of one or both drugs or treatment delays due to toxicity. Median time...

  17. Alpha- and Beta-Cyclodextrin Inclusion Complexes with 5-Fluorouracil: Characterization and Cytotoxic Activity Evaluation

    Directory of Open Access Journals (Sweden)

    Cristina Di Donato

    2016-12-01

    Full Text Available Cyclodextrins are natural macrocyclic oligosaccharides able to form inclusion complexes with a wide variety of guests, affecting their physicochemical and pharmaceutical properties. In order to obtain an improvement of the bioavailability and solubility of 5-fluorouracil, a pyrimidine analogue used as chemotherapeutic agent in the treatment of the colon, liver, and stomac cancers, the drug was complexed with alpha- and beta-cyclodextrin. The inclusion complexes were prepared in the solid state by kneading method and characterized by Fourier transform-infrared (FT-IR spectroscopy and X-ray powder diffractometry. In solution, the 1:1 stoichiometry for all the inclusion complexes was established by the Job plot method and the binding constants were determined at different pHs by UV-VIS titration. Furthermore, the cytotoxic activity of 5-fluorouracil and its complexation products were evaluated using the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay on MCF-7 (breast cancer cell line, Hep G2 (hepatocyte carcinoma cell line, Caco-2 (colon adenocarcinoma cell line, and A-549 (alveolar basal epithelial carcinoma cell line. The results showed that both inclusion complexes increased the 5-fluorouracil capability of inhibiting cell growth. In particular, 5-fluorouracil complexed with beta-cyclodextrin had the highest cytotoxic activity on MCF-7; with alpha-cyclodextrin the highest cytotoxic activity was observed on A-549. The IC50 values were equal to 31 and 73 µM at 72 h, respectively. Our results underline the possibility of using these inclusion complexes in pharmaceutical formulations for improving 5-fluorouracil therapeutic efficacy.

  18. Alpha- and Beta-Cyclodextrin Inclusion Complexes with 5-Fluorouracil: Characterization and Cytotoxic Activity Evaluation.

    Science.gov (United States)

    Di Donato, Cristina; Lavorgna, Margherita; Fattorusso, Roberto; Isernia, Carla; Isidori, Marina; Malgieri, Gaetano; Piscitelli, Concetta; Russo, Chiara; Russo, Luigi; Iacovino, Rosa

    2016-12-01

    Cyclodextrins are natural macrocyclic oligosaccharides able to form inclusion complexes with a wide variety of guests, affecting their physicochemical and pharmaceutical properties. In order to obtain an improvement of the bioavailability and solubility of 5-fluorouracil, a pyrimidine analogue used as chemotherapeutic agent in the treatment of the colon, liver, and stomac cancers, the drug was complexed with alpha- and beta-cyclodextrin. The inclusion complexes were prepared in the solid state by kneading method and characterized by Fourier transform-infrared (FT-IR) spectroscopy and X-ray powder diffractometry. In solution, the 1:1 stoichiometry for all the inclusion complexes was established by the Job plot method and the binding constants were determined at different pHs by UV-VIS titration. Furthermore, the cytotoxic activity of 5-fluorouracil and its complexation products were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on MCF-7 (breast cancer cell line), Hep G2 (hepatocyte carcinoma cell line), Caco-2 (colon adenocarcinoma cell line), and A-549 (alveolar basal epithelial carcinoma cell line). The results showed that both inclusion complexes increased the 5-fluorouracil capability of inhibiting cell growth. In particular, 5-fluorouracil complexed with beta-cyclodextrin had the highest cytotoxic activity on MCF-7; with alpha-cyclodextrin the highest cytotoxic activity was observed on A-549. The IC 50 values were equal to 31 and 73 µM at 72 h, respectively. Our results underline the possibility of using these inclusion complexes in pharmaceutical formulations for improving 5-fluorouracil therapeutic efficacy.

  19. Single bolus intravenous regadenoson injection versus central venous infusion of adenosine for maximum coronary hyperaemia in fractional flow reserve measurement.

    Science.gov (United States)

    van Nunen, Lokien X; Lenders, Guy D; Schampaert, Stéphanie; van 't Veer, Marcel; Wijnbergen, Inge; Brueren, Guus R G; Tonino, Pim A L; Pijls, Nico H J

    2015-12-01

    The aim of this study was to compare the hyperaemic effect of a single bolus regadenoson injection to a central venous adenosine infusion for inducing hyperaemia in the measurement of fractional flow reserve (FFR). One hundred patients scheduled for FFR measurement were enrolled. FFR was first measured by IV adenosine (140 µg/kg/min), thereafter by IV bolus regadenoson injection (400 µg), followed by another measurement by IV adenosine and bolus injection of regadenoson. The regadenoson injections were randomised to central or peripheral intravenous. Hyperaemic response and duration of steady state maximum hyperaemia were studied, central versus peripheral venous regadenoson injections were compared, and safety and reproducibility of repeated injections were investigated. Mean age was 66±8 years, 75% of the patients were male. The target stenosis was located in the LM, LAD, LCX, and RCA in 7%, 54%, 20% and 19%, respectively. There was no difference in FFR measured by adenosine or by regadenoson (ΔFFR=0.00±0.01, r=0.994, pregadenoson was variable (10-600 s). No serious side effects of either drug were observed. Maximum coronary hyperaemia can be achieved easily, rapidly, and safely by one single intravenous bolus of regadenoson administered either centrally or peripherally. Repeated regadenoson injections are safe. The hyperaemic plateau is variable. Clinical Trial Registration: http://clinicaltrials.gov/ct2/ show/study/NCT01809743?term=NCT01809743&rank=1 (ClinicalTrials.gov Identifier: NCT01809743).

  20. Prevention of venous thrombosis by preoperative glycyrrhizin infusion in a rat model.

    Science.gov (United States)

    Nakata, Nobuaki; Kira, Yukimi; Yabunaka, Yoriko; Takaoka, Kunio

    2008-09-01

    Glycyrrhizin is an agent with the capacity to bind to selectin molecules expressed on vascular endothelial cells and potentially prevent the adherence of neutrophils to the vascular endothelial surface. It has been found to prevent intravenous thrombus formation. Venous thrombosis was induced in male rats by ligation of the inferior vena cava (IVC) for 6 h. Before the ligation, the study rats were given intravenous injections of glycyrrhizin through the IVC. After 6 h of venous ligation, the rats were sacrificed and the IVC segments were harvested. Thrombus within the IVC was collected to measure the wet weight. Gene expression of P-, L-, and E-selectin was detected by reverse transcriptase polymerase chain reaction using extracts of mRNA from the IVC vein wall. As baseline controls, IVC samples without ligation were harvested immediately after laparotomy. Neutrophil adhesion to the luminal surface of IVC was assessed on histological sections stained with hematoxylin and eosin. Blood samples were collected through the IVC proximal to the ligation after 6 h to estimate activated partial thromboplastin time (APTT) and prothrombin time (PT). To investigate the effect of glycyrrhizin on binding capacity of P-selectin to human neutrophils, real-time biospecific interaction analysis was performed with the Biacore 2000 system. The mean weight of thrombus in the glycyrrhizintreated group was 12.9 +/- 11.1 mg, which is significantly lower than that of the saline-treated control group (21.3 +/- 12.5 mg). The expression level of P-and L-selectin mRNA in both saline-and glycyrrhizin-treated groups was significantly higher than that of the baseline control. Histological studies of cross sections of IVC showed significantly fewer neutrophils adhering to the luminal surface with glycyrrhizin treatment than in the saline-treated controls. There was no significant difference in the values of coagulation parameters with or without glycyrrhizin treatment. In vitro analysis showed

  1. A morphometric study of the protective effect of cryotherapy on oral mucositis in cancer patients treated with 5-fluorouracil.

    Science.gov (United States)

    Turkeli, M; Aldemir, M N; Bingol, F; Dogan, C; Kara, A

    2016-10-01

    We investigated cytological changes in oral mucosa smears from patients treated with cryotherapy to determine whether cryotherapy prevented mucositis caused by 5-fluorouracil (5-FU) therapy. Patients with gastrointestinal malignancies were divided into four groups; control patients before 5-FU therapy, patients after 5-FU therapy without cryotherapy, patients with cryotherapy before 5-FU therapy and patients with cryotherapy after 5-FU therapy. Oral mucosa samples from all patients were assessed at the beginning and on day 14 of chemotherapy. We used exfoliative cytology to evaluate cellular changes in the oral mucosa that were caused by 5-FU. Smears from each patient were stained using the Papanicolaou method and analyzed using stereology. Smears were taken from each group before and after 5-FU infusion. We found that nuclear volume was decreased significantly in cells of the 5-FU therapy after cryotherapy patients compared to the 5-FU therapy before cryotherapy patients. We also found significantly decreased cytoplasmic volumes in the 5-FU therapy after cryotherapy patients compared to the 5-FU therapy before cryotherapy patients. The results of cytomorphometric estimations revealed that cryotherapy may be used to prevent damage to oral tissue and may decrease the frequency and duration of oral mucositis caused by 5-FU.

  2. Activity and safety of pegylated liposomal doxorubicin, 5-fluorouracil and folinic acid in inoperable hepatocellular carcinoma: A phase II study

    Science.gov (United States)

    Lorenzo, Giuseppe Di; Rea, Antonio; Carlomagno, Chiara; Pepe, Stefano; Palmieri, Giovannella; Labianca, Roberto; Chirianni, Antonio; Stefano, Alfonso De; Esposito, Vincenzo; Placido, Sabino De; Montesarchio, Vincenzo

    2007-01-01

    AIM: To improve the results of New therapeutic strategies in hepatocellular carcinoma (HCC). We have conducted a phase II study with pegylated liposomal doxorubicin (PLD), 5-fluorouracil (5FU) and folinic acid (FA). METHODS: Thirty-one patients with hystologically-confirmed, inoperable HCC, received combination chemotherapy with PLD 25 mg/mq on d 1, 5FU 1200 mg/mq in 48 h continuous infusion, and oral FA 30 mg on d 1 and 2 every 3 wk until disease progression or intolerable toxicity. RESULTS: The median age was 65 years (range 41-82) and 28 patients were hepatitis C virus seropositive (90%). The majority of patients were Child-Pugh Class B (55%). Two patients showed a partial response (PR), and 16 had stable disease (SD). With a median follow-up of 14 mo, the median time to progression of all evaluable patients was 4 mo (95% CI 1.7-7). Median overall survival was 9 mo (95% CI 3-24 mo). After 1 year, 9 of 18 PR/SD patients were alive. Chemotherapy was well tolerated. CONCLUSION: PLD/FU/FA combination seems capable of achieving durable stabilization of HCC. The manageable toxicity supports a role for combination with other anticancer agents. PMID:18161926

  3. Synthesis and Characterization of 5-Fluorouracil-Loaded Glutaraldehyde Crosslinked Chitosan Hydrogels

    Directory of Open Access Journals (Sweden)

    Zehra ÖZBAŞ

    2016-11-01

    Full Text Available In this work, the characterization and drug release behavior of 5-fluorouracil-loaded glutaraldehyde-crosslinked chitosan hydrogels have been studied. The structure of the hydrogels were investigated by Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction, also their properties were compared with those of the drug-unloaded hydrogels. The equilibrium swelling studies and drug release profiles were determined at 37°C in two different pHs (2.1 and 7.4. The results indicated that increased chitosan concentration in the hydrogel decreased the swelling and drug release values and the hydrogels released nearly the same amount of 5-fluorouracil in both acidic (~59% and basic medium (~50%.

  4. Degradation of the chemotherapy drug 5-fluorouracil on medical-grade silver surfaces

    Science.gov (United States)

    Risinggård, Helene Kjær; Cooil, Simon; Mazzola, Federico; Hu, Di; Kjærvik, Marit; Østli, Elise Ramleth; Patil, Nilesh; Preobrajenski, Alexei; Andrew Evans, D.; Breiby, Dag W.; Trinh, Thuat T.; Wells, Justin W.

    2018-03-01

    The degradation of the chemotherapy drug 5-fluorouracil by a non-pristine metal surfaces is studied. Using density functional theory, X-ray photoelectron spectroscopy and X-ray absorption spectroscopy we show that the drug is entirely degraded by medical-grade silver surfaces, already at body temperature, and that all of the fluorine has left the molecule, presumably as HF. Remarkably, this degradation is even more severe than that reported previously for 5-fluorouracil on a pristine monocrystalline silver surface (in which case 80% of the drug reacted at body temperature) [1]. We conclude that the observed reaction is due to a reaction pathway, driven by H to F attraction between molecules on the surface, which results in the direct formation of HF; a pathway which is favoured when competing pathways involving reactive Ag surface sites are made unavailable by environmental contamination. Our measurements indicate that realistically cleaned, non-pristine silver alloys, which are typically used in medical applications, can result in severe degradation of 5-fluorouracil, with the release of HF - a finding which may have important implications for the handling of chemotherapy drugs.

  5. Development of biomedical 5-fluorouracil nanoplatforms for colon cancer chemotherapy: Influence of process and formulation parameters.

    Science.gov (United States)

    Pretel, Elena; Arias, José L; Cabeza, Laura; Melguizo, Consolación; Prados, José; Mallandrich, Mireia; Suñer, Joaquim; Clares, Beatriz

    2017-09-15

    In the present investigation solvent displacement or nanoprecipitation, and emulsion/solvent evaporation methods were utilized to optimize poly(D,L-lactide-co-glycolide) nanoparticles for the vehiculization of the 5-fluorouracil. Formulation components from both the aqueous and organic phases, as well as, operating conditions were varied. Particles were characterized in terms of particle size and morphology, electrical properties, rheology, drug loading, stability, and drug release. Furthermore, in vitro cytotoxicity on human colon cells and different colon carcinoma cells was evaluated. Four types of nanoparticles were selected for drug loading, revealing differences between variables. Low viscosity values and their Newtonian behavior could assure the suitability of the nanoformulation for the intravenous route of administration. The greatest drug entrapment efficiency and best stability was achieved when the chemotherapeutic agent was incorporated into the internal aqueous phase of particles prepared by double emulsion/solvent evaporation. However, a more sustained drug release at pH 7.4 was possible when 5-fluorouracil was added to the external aqueous phase. These were the nanoformulations reporting the greatest antiproliferative efficacy compared with the free drug. The nanocarrier can optimize the antitumor activity of 5-fluorouracil, thus being a potential nanotool against colon cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Cytotoxicity and radiosensitising activity of synthesized dinitrophenyl derivatives of 5-fluorouracil

    Directory of Open Access Journals (Sweden)

    Khoshayand Mohammad

    2012-07-01

    Full Text Available Abstract Background and the purpose of the study Dual functional agents in which nitroaromatic or nitroheterocyclic compounds are attached through a linker unit to mustards and aziridines have shown higher cytotoxicities than the corresponding counterparts to both aerobic and hypoxic cells and enhanced radiosensitizing activity. In the present investigation cytotoxicity and radiosensitizing activity of 2,4-dinitrobenzyl, 2,4-dinitrobenzoyl, and 2,4-dinitrophenacetyl derivatives of 5-fluorouracil which was assumed to release cytotoxic active quinone methidide and 5-fluorouracil under hypoxic conditions on HT-29 cell line under both aerobic and hypoxic conditions was investigated. Methods 5-fluorouracil derivative X-XIII were prepared by the reaction of the corresponding di-nitro substituted benzyl, benzoyl and phenacetyl halides with 5-fluorouracil protected at N-1 with di-t-butoxydicarbonate (BOC in dimethyl formamide (DMF in the presence of the potassium carbonate followed by hydrolysis of the blocking group by potassium carbonate in methanol. Cytotoxicity of fluorouracil VIII and tested compounds X-XIII against HT-29 cell line under both aerobic and hypoxic conditions after 48 hrs incubation were measured by determination of the percent of the survival cells using 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and percent of the dead cells using propidium iodide(PI-digitonine assay and results were used to calculate the corresponding IC50 values. Radiosensitization experiments were carried out by irradiation of the incubations with a 60Co source and clonogenic assay was performed to determine the cell viabilities following treatment with the tested compounds and/or radiation. Sensitization Enhancement Ratio (SER of each tested compound was obtained from the radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results and major conclusion Findings of the present study

  7. Violacein synergistically increases 5-fluorouracil cytotoxicity, induces apoptosis and inhibits Akt-mediated signal transduction in human colorectal cancer cells

    National Research Council Canada - National Science Library

    Kodach, LL; Bos, CL; Duran, N; Peppelenbosch, MP; Ferreira, CV; Hardwick, JCH

    2006-01-01

    ...) treatment, the results of chemotherapy remain unsatisfactory. 5-Fluorouracil (5-FU) still represents the cornerstone of treatment and resistance to its actions is a major obstacle to successful chemotherapy...

  8. The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer

    DEFF Research Database (Denmark)

    Shoaib, Afzal; Gusella, Milena; Jensen, Søren Astrup

    2011-01-01

    The purpose of this study was to investigate whether specific combinations of polymorphisms in 5-fluorouracil (5-FU) metabolism-related genes were associated with outcome in 5-FU-based adjuvant treatment of colorectal cancer....

  9. Effects of Cycloheximide and 5-Fluorouracil on Formation of Low-Molecular-Weight Ribonucleic Acid in Yeast

    Science.gov (United States)

    Hendricks, D. V.; Andrean, B. A. G.; De Kloet, S. R.

    1969-01-01

    The effects of cycloheximide and 5-fluorouracil on the formation of low-molecular-weight ribonucleic acid (RNA) in yeast were investigated. Both compounds were found to affect the synthesis of low-molecular-weight RNA of ribosomal origin more than transfer RNA but less than the high-molecular-weight ribosomal RNA. 5-Fluorouracil-containing transfer RNA was separated from normal transfer RNA by chromatography on diethylaminoethyl cellulose at 80 C in the presence of 7 m urea. PMID:5773027

  10. Catheter-Directed Thrombolysis with a Continuous Infusion of Low-Dose Urokinase for Non-Acute Deep Venous Thrombosis of the Lower Extremity

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Binbin; Zhang, Jingyong; Wu, Xuejun; Han, Zonglin; Zhou, Hua; Dong, Dianning; Jin, Xing [Shandong Provincial Hospital, Shandong University, Ji' nan (China)

    2011-02-15

    We wanted to evaluate the feasibility of catheter-directed thrombolysis with a continuous infusion of low-dose urokinase for treating non-acute (less than 14 days) deep venous thrombosis of the lower extremity. The clinical data of 110 patients who were treated by catheter-directed thrombolysis with a continuous infusion of low-dose urokinase for lower extremity deep venous thrombosis was analysed. Adjunctive angioplasty or/and stenting was performed for the residual stenosis. Venous recanalization was graded by pre- and posttreatment venography. Follow-up was performed by clinical evaluation and Doppler ultrasound. A total of 112 limbs with deep venous thrombosis with a mean symptom duration of 22.7 days (range: 15-38 days) were treated with a urokinase infusion (mean: 3.5 million IU) for a mean of 196 hours. After thrombolysis, stent placement was performed in 25 iliac vein lesions and percutaneous angioplasty (PTA) alone was done in fi ve iliac veins. Clinically significant recanalization was achieved in 81% (90 of 112) of the treated limbs: complete recanalization was achieved in 28% (31 of 112) and partial recanalization was achieved in 53% (59 of 112). Minor bleeding occurred in 14 (13%) patients, but none of the patients suffered from major bleeding or symptomatic pulmonary embolism. During followup (mean: 15.2 months, range: 3-24 months), the veins were patent in 74 (67%) limbs. Thirty seven limbs (32%) showed progression of the stenosis with luminal narrowing more than 50%, including three with rethrombosis, while one revealed an asymptomatic iliac vein occlusion: 25 limbs (22%) developed mild post-thrombotic syndrome, and none had severe post-thrombotic syndrome. Valvular reflux occurred in 24 (21%) limbs. Catheter-directed thrombolysis with a continuous infusion of low-dose urokinase combined with adjunctive iliac vein stenting is safe and effective for removal of the clot burden and for restoration of the venous flow in patients with non-acute lower

  11. Effect of Astragaloside II combined with 5-fluorouracil treatment on liver cell proliferation

    Directory of Open Access Journals (Sweden)

    Yan-Qing Chen

    2016-09-01

    Full Text Available Objective: To study the effect of astragaloside II combined with 5-fluorouracil treatment on liver cell proliferation and analyze the specific molecular mechanisms. Methods: Liver cancer cell lines HepG2 were cultured, cells of logphase growth were collected and treated with different conditions, blank control group were treated with DMEM without serum, 5-Fu treatment group were treated with 0.5, 1, 5 and 10 μmol/L 5-Fu, and 5-Fu combined with astragaloside II treatment group were treated with 10 μmol/L 5-Fu combined with 20, 40 and 80 μmol/L astragaloside II. 24, 48 and 72 h after treatment, MTS kit was used to determine the cell viability; 24 h after treatment, ELISA kit was used to determine the content of apoptosis protein in cells. Results: Compared with blank control group, 5-Fu treatment could reduce the survival rate of liver cancer cells in time-dependent and dose-dependent manner; compared with 10 μmol/L 5-Fu single drug treatment group, 10 μmol/L 5-Fu combined with astragaloside II treatment could reduce the survival rate of liver cancer cells in time-dependent and dosedependent manner; Fas, FasL, Bax, Caspase-3, Caspase-8 and Caspase-9 expression levels after 10 μmol/L 5-Fu treatment were significantly higher than those of blank control group, and Fas, FasL, Bax, Caspase-3, Caspase-8 and Caspase-9 expression levels after 10 μmol/L 5-Fu combined with 40 μmol/L astragaloside II treatment were significantly higher than those of 10 μmol/L 5-Fu treatment group. Conclusions: Astragaloside II combined with 5-fluorouracil treatment can enhance the inhibitory effect of 5-fluorouracil on liver cancer cell proliferation, and the apoptosis proteins mediating the effect are Fas/FasL and Bax.

  12. Tetrathiomolybdate sensitizes ovarian cancer cells to anticancer drugs doxorubicin, fenretinide, 5-fluorouracil and mitomycin C

    Directory of Open Access Journals (Sweden)

    Kim Kyu Kwang

    2012-04-01

    Full Text Available Abstract Background Our recent study showed that tetrathiomolybdate (TM, a drug to treat copper overload disorders, can sensitize drug-resistant endometrial cancer cells to reactive oxygen species (ROS-generating anticancer drug doxorubicin. To expand these findings in the present study we explore TM efficacy in combination with a spectrum of ROS-generating anticancer drugs including mitomycin C, fenretinide, 5-fluorouracil and doxorubicin in ovarian cancer cells as a model system. Methods The effects of TM alone or in combination with doxorubicin, mitomycin C, fenretinide, or 5-fluorouracil were evaluated using a sulforhodamine B assay. Flow cytometry was used to detect the induction of apoptosis and ROS generation. Immunoblot analysis was carried out to investigate changes in signaling pathways. Results TM potentiated doxorubicin-induced cytotoxicity and modulated key regulators of apoptosis (PARP, caspases, JNK and p38 MAPK in SKOV-3 and A2780 ovarian cancer cell lines. These effects were linked to the increased production of ROS, as shown in SKOV-3 cells. ROS scavenging by ascorbic acid blocked the sensitization of cells by TM. TM also sensitized SKOV-3 to mitomycin C, fenretinide, and 5-fluorouracil. The increased cytotoxicity of these drugs in combination with TM was correlated with the activity of ROS, loss of a pro-survival factor (e.g. XIAP and the appearance of a pro-apoptotic marker (e.g. PARP cleavage. Conclusions Our data show that TM increases the efficacy of various anticancer drugs in ovarian cancer cells in a ROS-dependent manner.

  13. Cytotoxicity and Radiosensitising Activity of Synthesized Dinitrophenyl Derivatives of 5-Fluorouracil

    Directory of Open Access Journals (Sweden)

    Khosrou Abdi

    2012-07-01

    Full Text Available Background and the purpose of the study: Dual functional agents in which nitroaromatic or nitroheterocyclic compounds are attached through a linker unit to mustards and aziridines have shown higher cytotoxicities than the corresponding counterparts to both aerobic and hypoxic cells and enhanced radiosensitizing activity. In thepresent investigation cytotoxicity and radiosensitizing activity of 2,4-dinitrobenzyl, 2,4-dinitrobenzoyl, and 2,4-dinitrophenacetyl derivatives of 5-fluorouracil which was assumed to release cytotoxic active quinone methidide,and 5-fluorouracil under hypoxic conditions on HT-29 cell line under both aerobic and hypoxic conditions wasinvestigated.Methods: 5-fluorouracil derivative X-XIII were prepared by the reaction of the corresponding di-nitro substitutedbenzyl, benzoyl and phenacetyl halides with 5-fluorouracil protected at N-1 with di-t-butoxydicarbonate (BOC in dimethyl formamide (DMF in the presence of the potassium carbonate followed by hydrolysis of the blocking,group by potassium carbonate in methanol. Cytotoxicity of fluorouracil VIII and tested compounds X-XIII against HT-29cell line under both aerobic and hypoxic conditions after 48 hrs incubation were measured by determination of the percent of the survival cells using 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and percent of the dead cells using propidium iodide(PI-digitonine assay and results were used to calculate the corresponding IC50 values. Radiosensitization experiments were carried out by irradiation of the incubations with a 60Co source and clonogenic assay was performed to determine the cell viabilities following treatment with the tested compounds and/or radiation. Sensitization Enhancement Ratio (SER of each tested compound was obtained from the radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively.Results and major conclusion: Findings of the present study showed that

  14. Uso do 5-fluorouracil no intra-operatório da cirurgia do pterígio Intra-operative use of 5-fluorouracil in pterygium surgery

    Directory of Open Access Journals (Sweden)

    Silvana A. Schellini

    2000-04-01

    Full Text Available Objetivo: Avaliar a efetividade e as complicações com a aplicação do 5- fluorouracil (5-FLU no intra-operatório da cirurgia do pterígio. Método: Foram avaliados 28 olhos de 26 indivíduos quanto ao tipo e tamanho do pterígio, cirurgias prévias e a resposta ao tratamento cirúrgico (no 7º , 21º , 60º e 90º dia de pós-operatório. Logo após a exerese do pterígio, aplicou-se 5-FLU (25 mg/ml no leito cirúrgico, durante cinco minutos; a seguir, realizou-se a técnica de deslizamento de retalho conjuntival. Resultados: A maioria dos pacientes tinha mais de 50 anos de idade e apresentava pterígio primário (70,0%, grau II (60,7%, do tipo involutivo (60,7%. No pós-operatório observaram-se: isquemia (10,7%, deiscência da conjuntiva (7,1%, ceratite (3,5%, conjuntivite (3,5% e recidiva da lesão em 1 olho (3,5%.Conclusão: O 5-FLU se mostrou droga segura e efetiva na prevenção das recidivas, podendo ser usado como coadjuvante no tratamento do pterígio para prevenir recidivas.Purpose: To evaluate the effectiveness and the complications on intraoperative application of 5-fluorouracil (5FLU in pterygium surgery. Method: We studied 28 eyes of 26 patients with pterygium, evaluating the type and size of the pterygium, previous surgeries and the response to surgical treatment (on the 7th, 21st, 60th, 90th postoperative day. The application of 5-FLU (25 mg/ml was done soon after resection, for five minutes, followed by the sliding flap technique.Results: Most of the patients were more than 50 years old, presented with primary (70.0%, degree II (60.7%, involu-tionary type (60.7% pterygium. After surgery ischemic area (10.7%, conjunctival deiscence (7.1%, keratitis (3.5%, conjunctivitis (3.5% and lesion relapse (3.5% were observed.Conclusion: 5-FLU is a safe and effective drug and could be of help in the treatment of pterygium to prevent relapse.

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

    Directory of Open Access Journals (Sweden)

    Joshua Runtuwene

    2015-04-01

    Full Text Available 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.

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

    Directory of Open Access Journals (Sweden)

    Yan Wo

    2014-12-01

    Full Text Available 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.

  17. Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide.

    Science.gov (United States)

    Agrawal, Siddarth; Łuc, Mateusz; Ziółkowski, Piotr; Agrawal, Anil Kumar; Pielka, Ewa; Walaszek, Kinga; Zduniak, Krzysztof; Woźniak, Marta

    2017-06-01

    The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.

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

    Science.gov (United States)

    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

  19. [Evaluation of acute cardiotoxicity from the combination cyclophosphamide-mitoxantrone-5-fluorouracil (CMF) with Holter ECG].

    Science.gov (United States)

    Doria, G; Cangemi, F; Tosto, A; Platania, F; Circo, A; Motta, S; Tralongo, P; Aiello, R A; Failla, G

    1990-05-01

    By making use of a twenty-four hour Holter monitoring, it as been possible to compute the acute cardiotoxicity of the cyclophosphamide + mitoxantrone + 5-fluorouracil (CNF) association in twenty oncologic patients (pts) each of whom being immune from organic cardiopathy emerging clinically and at their first cycle of chemotherapy. The following parameters have been computed: meaningful changes in the heart frequency; premature atrial and ventricular depolarizations, both as a first appearance and as a clear growth in the number; the ST dislocation entity; malignant ventricular arrhythmias. The administration of CNF at the doses of: 600 mg/m2 of cyclophosphamide, 12 mg/m2 of mitoxantrone and 600 mg/m2 of 5-fluorouracil , has caused a meaningful increase in the heart frequency on 6 pts (30%), an increase of premature atrial depolarization on 4 pts (20%) with an appearance ex novo on 2 pts (10%), an increase of premature ventricular depolarization, without any passing to superior Lown classes, on 2 pts (10%) with an appearance ex novo on 3 pts (15%). Although the results in the study point out a frequency percentage of simple hyperkinetic arrhythmias equal to the 55%, the lack of more serious hyperkinetic arrhythmias and of intense disorders of ventricular repolarization testified to a synergic effect as a determining factor on the acute cardiotoxicity of the previously discussed association, in our opinion.

  20. Capecitabine versus 5-fluorouracil in colorectal cancer: where are we now?

    Directory of Open Access Journals (Sweden)

    Lakshmi Chintala

    2011-06-01

    Full Text Available Fluorouracil (5-FU remains the most widely used agent for colorectal cancer. Capecitabine is a rationally designed 5-FU pro-drug developed to mimic the continuous infusion of 5-FU while avoiding complications and inconvenience of intravenous administration. Capecitabine is absorbed intact from the gastrointestinal tract, converted enzymatically to active 5-FU, and released directly into the tumor. Capecitabine’s efficacy and safety are shown in multiple phase III trials across different disease stages and therapy lines. Three randomized phase III trials demonstrated the equivalence of capecitabine plus oxaliplatin (XELOX versus 5-FU/leucovorin (LV/oxaliplatin (FOLFOX. The safety of capecitabine compared with 5-FU depends on the regimen of 5-FU used. The adverse event rate with oxaliplatin in combination with infusional 5-FU is similar to that of capecitabine plus oxaliplatin but is associated with more neutropenia and venous thrombotic events; capecitabine plus oxaliplatinbased regimens tend to be associated with more grade 3 diarrhea and hand-foot skin reaction. Combination therapy with capecitabine and irinotecan (CapeIRI versus 5-FU/ LV and irinotecan (FOLFIRI had more variable results; some former schedules resulted in excessive treatmentrelated toxicity. More recent data show that lower capecitabine and irinotecan doses, different schedules, and combination with targeted agents (e.g, bevacizumab have resulted in more favorable outcomes.

  1. Influence of bromoethyl group on biological activity of 5-fluorouracil prodrug: Insights from X-ray crystallography and molecular docking

    Science.gov (United States)

    Li, Xian-Chuan; Liu, Kuan-Guan; Qin, Da-An; Cheng, Chen-Chen; Chen, Bing-Xiong; Hu, Mao-Lin

    2012-11-01

    To develop alkyl halides for a promising prodrug system, a 5-fluorouracil prodrug containing a bromoethyl group (5-FUBr) was synthesized and its hydrophobicity, cytotoxicity and DNA-bonding ability were investigated in detail. Compare with 5-fluorouracil, 5-FUBr exhibits a great advantage of hydrophobicity and shows significant reduction in toxic side effect. To explore the mechanism of action of 5-FUBr at the molecular level, X-ray crystallography and molecular docking were exploited to make a more detailed analysis of the bromoethyl contribution to the construction of meaningful structure-activity relationship. Details of X-ray crystal structure of 5-FUBr suggest that 5-fluorouracil may be more apt to be released from 5-FUBr. The appearance of the bromoethyl group in 5-FUBr makes a remarkable impact on inhibition of thymidylate synthase (TS), and the impact of subtle structural variation between 5-fluorouracil and 5-FUBr should be taken into account in the process of developing this family of 5-fluorouracil prodrugs.

  2. A Phase 1/2 Study of Definitive Chemoradiation Therapy Using Docetaxel, Nedaplatin, and 5-Fluorouracil (DNF-R) for Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ohnuma, Hiroyuki; Sato, Yasushi; Hirakawa, Masahiro; Okagawa, Yutaka; Osuga, Takahiro; Hayashi, Tsuyoshi; Sato, Tsutomu; Miyanishi, Koji; Kobune, Masayoshi; Takimoto, Rishu [Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo (Japan); Sagawa, Tamotsu [Division of Gastroenterology, Hokkaido Cancer Center, Sapporo (Japan); Hori, Masakazu; Someya, Masanori; Nakata, Kensei; Sakata, Koh-ichi [Department of Radiology, Sapporo Medical University School of Medicine, Sapporo (Japan); Takayama, Tetsuji [Department of Gastroenterology and Oncology, University of Tokushima, Tokushima (Japan); Kato, Junji, E-mail: jkato@sapmed.ac.jp [Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo (Japan)

    2015-10-01

    Purpose: Patient survival in esophageal cancer (EC) remains poor. The purpose of this study was to investigate a regimen of definitive chemoradiation therapy (CRT) that exerts good local control of EC. We performed a phase 1/2 study to assess the safety and efficacy of CRT with docetaxel, nedaplatin, and 5-fluorouracil (DNF-R). Methods and Materials: Eligible patients presented with stage IB to IV EC. Patients received 2 cycles of docetaxel (20, 30, or 40 mg/m{sup 2}) and nedaplatin (50 mg/m{sup 2}) on days 1 and 8 and a continuous infusion of 5-fluorouracil (400 mg/m{sup 2}/day) on days 1 to 5 and 8 to 12, every 5 weeks, with concurrent radiation therapy (59.4 Gy/33 fractions). The recommended dose (RD) was determined using a 3 + 3 design. Results: In the phase 1 study, the dose-limiting toxicities were neutropenia and thrombocytopenia. The RD of docetaxel was determined to be 20 mg/m{sup 2}. In the phase 2 study, grade 3 to 4 acute toxicities included neutropenia (42.8%), febrile neutropenia (7.14%), thrombocytopenia (17.9%), and esophagitis (21.4%). Grade 3 to 4 late radiation toxicity included esophagostenosis (10.7%). The complete response rate was 82.1% (95% confidence interval: 67.9-96.3%). Both the median progression-free survival and overall survival were 41.2 months. Conclusions: DNF-R showed good tolerability and strong antitumor activity, suggesting that it is a potentially effective therapeutic regimen for EC.

  3. Gene expression profile of 5-fluorouracil metabolic enzymes in laryngeal cancer cell line: predictive parameters for response to 5-fluorouracil-based chemotherapy.

    Science.gov (United States)

    Galbiatti, Ana Lívia Silva; Caldas, Heloisa Cristina; Maniglia, José Victor; Pavarino, Erika Cristina; Goloni-Bertollo, Eny Maria

    2014-06-01

    5-fluorouracil (5-FU) is an antifolate chemotherapeutic that has become established in many therapeutic regimes, but sensitivity variations and development of resistance are common problems that limit the efficiency of the treatments. Inter-individual variations to 5-FU outcome have been attributed to different expression profiles of genes related to folate metabolism. To elucidate the mechanisms of variations to 5-FU outcome, the authors investigated MTHFR, DHFR, TYMS and SLC19A1 folate genes expression for 5-FU response in laryngeal cancer cell line (Hep-2). Concentrations of 10, 50, and 100 ng/mL of 5-FU chemotherapeutic were added separately in Hep-2 cell line for 24 hours at 37 °C. Cell sensibility was evaluated with fluorescein isothiocyanate (FITC) label Bcl-2 by flow cytometry. The real-time quantitative PCR (qPCR) technique was performed for quantification of gene expression using TaqMan(®) Gene Expression Assay. ANOVA and Bonferroni's post hoc tests were utilized to statistical analysis. The numbers of viable Hep-2 cells with 10, 50, and 100 ng/mL concentrations of 5-FU chemotherapy were 15.87, 28.3 and 68.9%, respectively. Statistical analysis showed significant association between control group and increased expression for TYMS gene in cells treated with 100 ng/mL/5-FU chemotherapy (Pexpression levels for TYMS folate gene in laryngeal cancer cell line. Although these experiments were performed in vitro, the results suggest that genetic factors are thought to play an important role in drug metabolism and may be useful for predicting treatment outcomes. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. Manganese Superoxide Dismtase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cancer Patients Treated with Cyclophosphamide Epirubicin and 5-fluorouracil

    DEFF Research Database (Denmark)

    Ording, Anne Gulbech; Cronin Fenton, Deirdre; Christensen, Mariann

    2012-01-01

    Manganese Superoxide Dismtase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cancer Patients Treated with Cyclophosphamide Epirubicin and 5-fluorouracil...

  5. CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil

    Science.gov (United States)

    Almqvist, Helena; Axelsson, Hanna; Jafari, Rozbeh; Dan, Chen; Mateus, André; Haraldsson, Martin; Larsson, Andreas; Molina, Daniel Martinez; Artursson, Per; Lundbäck, Thomas; Nordlund, Pär

    2016-03-01

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.

  6. Preparation of 5-fluorouracil loaded chitosan microparticle and its drug release properties

    Directory of Open Access Journals (Sweden)

    Li Mingming

    2017-01-01

    Full Text Available Chitosan is one kind of good biocompatible polymer and is suitble for drug carriers. Preparation of 5-fluorouracil (5-Fu loaded chitosan (CS particles and in vitro release experiment were performed using ionic crosslinking method with sodium tripolyphosphate (TPP as crosslinker. The optimal preparing parameters were verified by 5-Fu release experiments. The drug loading, and release behavior of drug loaded microparticles in vitro were investigated. The optimal preparation conditions were: the temperature 25°C, the ratio of CS to TPP 5:1, the CS concentration 1.5g/L, stirring speed 650rpm. Under these conditions, the drug loading of particles was up to 45%.

  7. Treatment of laser resistant granuloma faciale with intralesional triamcinolone acetonide and 5-fluorouracil combination therapy

    Directory of Open Access Journals (Sweden)

    Diana L Norris

    2015-01-01

    Full Text Available This report describes a sixty year old male with biopsy proven Granuloma Faciale (GF. The patient had been unsuccessfully treated with multiple therapies. A mixture 0.8 ml 5-Fluorouracil (5FU and 0.2 ml Kenacort-A was trialled initially to treat this patient, followed by a more varied mixture ratio. These were given at intervals ranging from two weeks to two months. The patient received a total of twenty injections over a period of more than three years. An excellent response was noted and the patient is now able to tolerate long treatment free periods of between nine and twelve months. 5FU is a simple injection material and can be considered by clinicians as an option for treatment of GF.

  8. Treatment of Laser Resistant Granuloma Faciale with Intralesional Triamcinolone acetonide and 5-Fluorouracil Combination Therapy.

    Science.gov (United States)

    Norris, Diana L; Apikian, Martine; Goodman, Greg J

    2015-01-01

    This report describes a sixty year old male with biopsy proven Granuloma Faciale (GF). The patient had been unsuccessfully treated with multiple therapies. A mixture 0.8 ml 5-Fluorouracil (5FU) and 0.2 ml Kenacort-A was trialled initially to treat this patient, followed by a more varied mixture ratio. These were given at intervals ranging from two weeks to two months. The patient received a total of twenty injections over a period of more than three years. An excellent response was noted and the patient is now able to tolerate long treatment free periods of between nine and twelve months. 5FU is a simple injection material and can be considered by clinicians as an option for treatment of GF.

  9. Validation of Photograph-Based Toxicity Score for Topical 5-Fluorouracil Cream Application.

    Science.gov (United States)

    Pomerantz, Hyemin; Korgavkar, Kaveri; Lee, Kachiu C; Lew, Robert; Weinstock, Martin A

    2016-09-01

    An objective tool quantifying the toxicity of 5-fluorouracil (5-FU) from photographs was recently reported, and its reliability was confirmed. The aim of this study was to validate the photograph-based toxicity score. Photograph-based toxicity scores of participants assigned to the 5-FU arm of a randomized placebo-controlled trial were tested for correlations with their patient-reported symptom scores and baseline characteristics. Each pair of individual and overall scores of patient-reported symptoms and photograph-based toxicity was correlated at 2 and 4 weeks (correlation coefficient range, 0.34-0.95; P photograph-based 5-FU toxicity score. The tool can be used to objectively measure 5-FU toxicity in clinical or research setting, and it can be a prototype for toxicity measurements of other topical medications. © The Author(s) 2016.

  10. Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine.

    Science.gov (United States)

    Zhang, Xuan; Chen, Yujuan; Hao, Lijun; Hou, Along; Chen, Xiaozhen; Li, Yifei; Wang, Rui; Luo, Peng; Ruan, Zhihua; Ou, Juanjuan; Shi, Chunmeng; Miao, Hongming; Liang, Houjie

    2016-10-28

    The development of chemoresistance to 5-fluorouracil (5-FU) is a major obstacle for sustained effective treatment of colorectal cancer (CRC), with the mechanisms being not fully understood. Here we demonstrated that tumor associated macrophages (TAMs) became activated during treatment with 5-FU and secreted factors that protected the CRC cells against chemotherapy with 5-FU. By performing metabolomics analysis, we identified putrescine, a member of polyamines, inducing resistance to 5-FU-triggered CRC apoptosis and tumor suppression via JNK-caspase-3 pathway. Noteworthily, either pharmacological or genetic blockage of ornithine decarboxylase (ODC) prevented TAMs-induced chemoresistance to 5-FU in vitro and in vivo. Our findings show that TAMs are potent mediators of resistance to 5-FU chemotherapy and uncover potential targets to enhance chemotherapy sensitivity in patients with CRC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Oxidative damage to guanine nucleosides following combination chemotherapy with 5-fluorouracil and oxaliplatin

    DEFF Research Database (Denmark)

    Afzal, Shoaib; Jensen, Søren Astrup; Sørensen, Jens Benn

    2011-01-01

    ultra performance liquid chromatography and tandem mass spectrometry. Furthermore, we collected information on other clinical and demographic variables hypothesized to be associated with oxidative stress. Repeated measures linear mixed models were used to model the relationship between urinary......PURPOSE: Recent in vitro and animal studies have suggested that the cytotoxicity of 5-fluorouracil and oxaliplatin is linked to increased formation of reactive oxygen species (ROS). This prospective study was undertaken to examine the generation of oxidative stress, in 106 colorectal cancer...... concentrations of 8-oxoGuo and 8-oxodG and the treatment effect and the other variables. RESULTS: The analysis showed that chemotherapy increased the excretion of 8-oxoGuo and 8-oxodG around 15% (P ...

  12. Healing acceleration in hamsters of oral mucositis induced by 5-fluorouracil with topical Calendula officinalis.

    Science.gov (United States)

    Tanideh, Nader; Tavakoli, Parisa; Saghiri, Mohammad Ali; Garcia-Godoy, Franklin; Amanat, Dariush; Tadbir, Azadeh Andisheh; Samani, Soleiman Mohammadi; Tamadon, Amin

    2013-03-01

    This study assessed the potential of topical Calendula officinalis extract on the healing of oral mucositis induced by 5-fluorouracil (5-FU) in hamsters. Oral mucositis was induced in 60 male hamsters by 5-FU (60 mg/kg) on days 0, 5, and 10 of the study. The cheek pouch was scratched with a sterile needle on days 1 and 2. On days 12-17, 5% and 10% C. officinalis gel and gel base groups were treated and then compared with a control group. Macroscopic and microscopic scores and weights were evaluated. Microscopic and macroscopic scores of mucositis were lower in the 5% and 10% C. officinalis gel groups than in the gel base and control groups (P Calendula officinalis extract accelerated the healing of oral mucositis in hamsters. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Cleavage of DNA containing 5-fluorocytosine or 5-fluorouracil by type II restriction endonucleases.

    Science.gov (United States)

    Olszewska, Agata; Dadová, Jitka; Mačková, Michaela; Hocek, Michal

    2015-11-01

    A systematic study of the cleavage of DNA sequences containing 5-fluorocytosine or 5-fluorouracil by type II restriction endonucleases (REs) was performed and the results compared with the same sequences containing natural pyrimidine bases, uracil or 5-methylcytosine. The results show that some REs recognize fluorine as a hydrogen on cytosine and cleave the corresponding sequences where the presence of m5dC leads to blocking of the cleavage. However, on uracil, the same REs recognize the F as a methyl surrogate and cleave the sequences which are not cleaved if uracil is incorporated instead of thymine. These results are interesting for understanding the recognition of DNA sequences by REs and for manipulation of the specific DNA cutting. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Chitosan stabilized Ag-Au nanoalloy for colorimetric sensing and 5-Fluorouracil delivery.

    Science.gov (United States)

    E A K, Nivethaa; S, Dhanavel; Narayanan, V; A, Stephen

    2017-02-01

    Fluorescent CS/Ag-Au (chitosan/silver-gold) nanocomposite containing different weight percentage of Ag and Au was synthesized using the chemical reduction method. 5-Fluorouracil (5-FU) encapsulated nanocomposite was also synthesized and its cytotoxicity towards breast cancer cell lines (MCF-7) studied. The XRD pattern of the nanocomposite shows peaks of chitosan, silver and gold. The peaks corresponding to gold and silver indicate the face centered cubic structure of silver and gold nanoparticles. The polymer matrix nanocomposite structure with chitosan as the matrix and silver-gold as the filler phase is evident from the high resolution transmission electron microscopy (HRTEM) images and an increase in particle size from∼5nm to about 12nm is noticeable on encapsulation of 5-Fluorouracil (5-FU). The presence of fluorine in the case of 5-FU encapsulated nanocomposite and the presence of reflections corresponding to 5-FU in the SAED pattern confirms the encapsulation of 5-FU into the nanocomposite, which is also confirmed by elemental mapping. The presence of a single surface plasmon resonance (SPR) peak in the case of the nanocomposite in a position in between the SPR bands of pure silver and gold nanoparticles confirms the formation of Ag-Au alloy and the elemental mapping results obtained for the nanocomposite also supports the UV-vis results. The photoluminescence (PL) spectrum clearly shows an emission peak in the near infrared region (700-900nm), which makes the nanocomposite suitable for use in cellular imaging. The application of the nanocomposite as a colorimetric sensor was also studied and it was found to be useful for the specific detection of mercury (Hg) without much interference and the detection limit was found to be 5.0×10 -8 M. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma

    Directory of Open Access Journals (Sweden)

    Ide Hiroki

    2012-09-01

    Full Text Available Abstract Background Recently, S-1, a novel 5-fluorouracil (5-FU-based agent containing the strong dihydropyrimidine dehydrogenase (DPD inhibitor, 5-chloro-2,4-dihydropyrimidine (CDHP has been clinically used to treat various non-urothelial carcinomas (UC. High levels of thymidylate synthase (TS, the target enzyme of 5-FU and DPD which degrades the majority of 5-FU, are associated with poor prognosis in some cancers. However, only a few reports have dealt with this in UC. The aim of this study was to investigate the clinical significance of TS and DPD in upper tract urothelial carcinoma (UTUC and evaluate the role of TS and DPD on the sensitivity of 5-FU in UC cell lines and the anti-tumor effect of S-1 in UC xenograft model. Methods Firstly, we evaluated the immunohistochemical expression of TS and DPD in 176 patients with UTUC to determine their prognostic significance. Secondly, the levels of TS and DPD in UC cell lines were measured by ELISA and real-time PCR. Furthermore, the association between their levels and the sensitivity to 5-FU was examined using the small interfering RNA (siRNA specific for TS and DPD. Thirdly, the anti-tumor effect of S-1 was evaluated in UC xenograft model. Results Immunohistochemical evaluation of TS and DPD in UTUC human samples revealed that TS expression was significantly associated with stage, grade, and lymphovascular invasion and DPD expression was significantly associated with grade. Multivariate analysis revealed that high TS expression was an independent predictor of disease-specific survival in them. In in vitro study using UC cell lines, high levels of TS and DPD were associated with low response to 5-FU and these associations were confirmed with siRNA specific for TS and DPD. In in vivo study using UC xenograft model, S-1 treatment dramatically inhibited tumor growth compared to controls, tegafur, or UFT in UC tumor with a high level of DPD. Conclusions TS plays an important role in the prognosis of

  16. Nano-engineering of 5-fluorouracil-loaded magnetoliposomes for combined hyperthermia and chemotherapy against colon cancer.

    Science.gov (United States)

    Clares, Beatriz; Biedma-Ortiz, Rafael A; Sáez-Fernández, Eva; Prados, José C; Melguizo, Consolación; Cabeza, Laura; Ortiz, Raúl; Arias, José L

    2013-11-01

    The present investigation aimed to develop magnetoliposome nanoparticles loaded with 5-fluorouracil by following a reproducible thin film hydration technique. The physicochemical characterization (including electron microscopy analysis, dynamic light scattering, infrared spectrometry, X-ray diffractometry, electrophoresis, and surface thermodynamics) suggested that superparamagnetic magnetite nuclei were successfully embedded into a multilamellar lipid vesicle. Magnetic responsiveness of these nanocomposites was quantitatively analyzed by determining the hysteresis cycle and qualitatively confirmed by microscopic visualizations. A high frequency alternating electromagnetic field was further used to define their heating properties. The absence of cytotoxicity in human colon fibroblast CCD-18 and in human colon carcinoma T-84 cell lines and excellent hemocompatibility of these core/shell particles were demonstrated. Additionally, 5-fluorouracil incorporation was investigated by two procedures: (i) entrapment into the nanoparticulate matrix and (ii) surface deposition onto already formed magnetoliposome particles. The former method reported greater drug loading values and a sustained release profile. Interestingly, 5-fluorouracil release was also triggered by the heating properties of the nanoparticles (hyperthermia-triggered drug release). Hence, we put forward that magnetoliposome particles hold important properties, that is, magnetically targeted delivery, hyperthermia inducing capability, high 5-fluorouracil loading capability, and hyperthermia-triggered burst drug release, suggestive of their potential for a combined antitumor therapy against colon cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Towards a test to predict 5-fluorouracil toxicity: Pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males

    NARCIS (Netherlands)

    Duley, John A.; Ni, Ming; Shannon, Catherine; Norris, Ross L.; Sheffield, Lesley; Harris, Marion; van Kuilenburg, Andre B. P.; Mead, Scott; Cameron, Andrew; Helsby, Nuala; George, Rani; Charles, Bruce G.

    2016-01-01

    The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The

  18. Cytotoxic action of bisabololoxide A of German chamomile on human leukemia K562 cells in combination with 5-fluorouracil.

    Science.gov (United States)

    Ogata-Ikeda, Ikuko; Seo, Hakaru; Kawanai, Takuya; Hashimoto, Erika; Oyama, Yasuo

    2011-03-15

    German chamomile (Matricaria recutita L.) is a popular ingredient in herbal teas. In previous study, micromolar bisabololoxide A, one of main constituents in German chamomile, exerted cytotoxic action on rat thymocyte, a normal non-proliferative cell. This result prompted us to study the effect of bisabololoxide A on proliferative cancer cells and to seek the possibility of its use with 5-fluorouracil, an anticancer agent. In this study, the effect of micromolar bisabololoxide A on human leukemia K562 cells was cytometrically examined. Although the incubation of K562 cells with 10 μM bisabololoxide A for 72h did not significantly increase the percentage populations of dead cells and shrunken cells, the inhibitory action on the growth was obviously observed. It was not the case for the concentrations of less than 5 μM. The threshold concentration of bisabololoxide A to exert the cytotoxic action on K562 cells was ascertained to be 5-10 μM. Bisabololoxide A at 5-10 μM did not exert cytotoxic action on normal non-proliferative cells (rat thymocytes) in our previous study. Since the antiproliferative action of micromolar bisabololoxide A on cancerous cells was expected to be beneficial to cancer treatment, the modification of antiproliferative action of 5-fluorouracil (3-30 μM) by bisabololoxide A was studied. The combination of 5-fluorouracil and bisabololoxide further inhibited the growth of K562 cells although the additive inhibition of growth by bisabololoxide A became smaller as the concentration of 5-fluorouracil increased. Therefore, it is suggested that the simultaneous application of German chamomile containing bisabololoxide A may reduce the dose of 5-fluorouracil. Copyright © 2010. Published by Elsevier GmbH.

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

    Science.gov (United States)

    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.

  20. Definitive Chemoradiation Therapy With Docetaxel, Cisplatin, and 5-Fluorouracil (DCF-R) in Advanced Esophageal Cancer: A Phase 2 Trial (KDOG 0501-P2)

    Energy Technology Data Exchange (ETDEWEB)

    Higuchi, Katsuhiko, E-mail: k.higu@kitasato-u.ac.jp [Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Kanagawa (Japan); Komori, Shouko [Department of Radiology and Radiation Oncology, Kitasato University School of Medicine, Sagamihara, Kanagawa (Japan); Tanabe, Satoshi [Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Kanagawa (Japan); Katada, Chikatoshi [Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa (Japan); Azuma, Mizutomo [Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Kanagawa (Japan); Ishiyama, Hiromichi [Department of Radiology and Radiation Oncology, Kitasato University School of Medicine, Sagamihara, Kanagawa (Japan); Sasaki, Tohru; Ishido, Kenji [Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Kanagawa (Japan); Katada, Natsuya [Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa (Japan); Hayakawa, Kazushige [Department of Radiology and Radiation Oncology, Kitasato University School of Medicine, Sagamihara, Kanagawa (Japan); Koizumi, Wasaburo [Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Kanagawa (Japan)

    2014-07-15

    Purpose: A previous phase 1 study suggested that definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) is tolerable and active in patients with advanced esophageal cancer (AEC). This phase 2 study was designed to confirm the efficacy and toxicity of DCF-R in AEC. Methods and Materials: Patients with previously untreated thoracic AEC who had T4 tumors or M1 lymph node metastasis (M1 LYM), or both, received intravenous infusions of docetaxel (35 mg/m{sup 2}) and cisplatin (40 mg/m{sup 2}) on day 1 and a continuous intravenous infusion of 5-fluorouracil (400 mg/m{sup 2}/day) on days 1 to 5, every 2 weeks, plus concurrent radiation. The total radiation dose was initially 61.2 Gy but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during radiation therapy was reduced from 4 to 3. The primary endpoint was the clinical complete response (cCR) rate. Results: Characteristics of the 42 subjects were: median age, 62 years; performance status, 0 in 14, 1 in 25, 2 in 3; TNM classification, T4M0 in 20, non-T4M1LYM in 12, T4M1LYM in 10; total scheduled radiation dose: 61.2 Gy in 12, 50.4 Gy in 30. The cCR rate was 52.4% (95% confidence interval [CI]: 37.3%-67.5%) overall, 33.3% in the 61.2-Gy group, and 60.0% in the 50.4-Gy group. The median progression-free survival was 11.1 months, and the median survival was 29.0 months with a survival rate of 43.9% at 3 years. Grade 3 or higher major toxicity consisted of leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). Conclusions: DCF-R frequently caused myelosuppression and esophagitis but was highly active and suggested to be a promising regimen in AEC. On the basis of efficacy and safety, a radiation dose of 50.4 Gy is recommended for further studies of DCF-R.

  1. [Analysis of 5-Fluorouracil and Leucovorin Combined with Weekly Paclitaxel in Advanced Gastric Cancer].

    Science.gov (United States)

    Kawada, Junji; Nishino, Masaya; Hosoda, Yohei; Hoshino, Hiromitsu; Okano, Miho; Nagai, Kenichi; Okuyama, Masaki; Kim, Yongkook; Tsujinaka, Toshimasa

    2016-11-01

    Advanced gastric cancer patients with malignant ascites cannot tolerate S-1 plus cisplatin-containing therapy. The good toxicity profile of the FLTAX regimen(5-fluorouracil[5-FU]and Leucovorin[l-LV]combined with weekly paclitaxel) might make it a viable alternative treatment for these patients. We retrospectively evaluated the efficacy and safety of FLTAX in advanced gastric cancer patients. Patients with advanced gastric cancer with malignant ascites were treated with 60mg/m2 paclitaxel, followed by 500 mg/m2 5-FU and 250 mg/m2 l-LV on days 1, 8, and 15. Treatment courses were repeated every 28 days. Patients were treated in our hospital from 2014 to 2016. Three advanced gastric cancer patients with malignant ascites received the FLTAX regimen. The median age was 66 years(range 58-66). The median number of treatment courses was 2(range 1-20). The median progression-free survival and overall survival were 55(95%CI 24-.)and 272(95%CI 108-.)days, respectively. Observed Grade 3-4 adverse events were as follows: hyponatremia(1), anorexia(1), upper gastrointestinal hemorrhage(1), and thromboembolic event(1). No treatment-related death occurred. FLTAX demonstrated an acceptable toxicity profile, and may be a good option for gastric cancer patients with malignant ascites.

  2. Eudragit S100 Coated Citrus Pectin Nanoparticles for Colon Targeting of 5-Fluorouracil

    Directory of Open Access Journals (Sweden)

    M. Biswaranjan Subudhi

    2015-02-01

    Full Text Available In the present study, Eudragit S100 coated Citrus Pectin Nanoparticles (E-CPNs were prepared for the colon targeting of 5-Fluorouracil (5-FU. Citrus pectin also acts as a ligand for galectin-3 receptors that are over expressed on colorectal cancer cells. Nanoparticles (CPNs and E-CPNs were characterized for various physical parameters such as particle size, size distribution, and shape etc. In vitro drug release studies revealed selective drug release in the colonic region in the case of E-CPNs of more than 70% after 24 h. In vitro cytoxicity assay (Sulphorhodamine B assay was performed against HT-29 cancer cells and exhibited 1.5 fold greater cytotoxicity potential of nanoparticles compared to 5-FU solution. In vivo data clearly depicted that Eudragit S100 successfully guarded nanoparticles to reach the colonic region wherein nanoparticles were taken up and showed drug release for an extended period of time. Therefore, a multifaceted strategy is introduced here in terms of receptor mediated uptake and pH-dependent release using E-CPNs for effective chemotherapy of colorectal cancer with uncompromised safety and efficacy.

  3. 5-Fluorouracil Enhances Exosome-Dependent Accumulation of Polyadenylated rRNAs

    Science.gov (United States)

    Fang, Feng; Hoskins, Jason; Butler, J. Scott

    2004-01-01

    The antimetabolite 5-fluorouracil (5FU) is a widely used chemotherapeutic for the treatment of solid tumors. Although 5FU slows DNA synthesis by inhibiting the ability of thymidylate synthetase to produce dTMP, the drug also has significant effects on RNA metabolism. Recent genome-wide assays for 5FU-induced haploinsufficiency in Saccharomyces cerevisiae identified genes encoding components of the RNA processing exosome as potential targets of the drug. In this report, we used DNA microarrays to analyze the effect of 5FU on the yeast transcriptome and found that the drug causes the accumulation of polyadenylated fragments of the 27S rRNA precursor and that defects in the nuclear exoribonuclease Rrp6p enhance this effect. The size distribution of these RNAs and their sensitivity to Rrp6p suggest that they are normally degraded by the nuclear exosome and a 5′-3′ exoribonuclease. Consistent with this hypothesis, 5FU inhibits the growth of RRP6 mutants with defects in the degradation function of the enzyme and it interferes with the degradation of an rRNA precursor. The detection of poly(A)+ pre-RNAs in strains defective in various steps in ribosome biogenesis suggests that the production of poly(A)+ pre-rRNAs may be a general result of defects in rRNA processing. These findings suggest that 5FU inhibits an exosome-dependent surveillance pathway that degrades polyadenylated precursor rRNAs. PMID:15572680

  4. A Molecular Interpretation on the Different Penetration Enhancement Effect of Borneol and Menthol towards 5-Fluorouracil

    Directory of Open Access Journals (Sweden)

    Ran Wang

    2017-12-01

    Full Text Available Borneol and menthol are terpenes that are widely used as penetration enhancers in transdermal drug delivery. To explore their penetration-enhancement effects on hydrophilic drugs, 5-fluorouracil (5-FU was selected as a model drug. An approach that combined in vitro permeation studies and coarse-grained molecular dynamics was used to investigate their penetration-enhancement effect on 5-FU. The results showed that although both borneol and menthol imparted penetration-enhancement effects on 5-FU, these differed in terms of their mechanism, which may account for the observed variations in penetration-enhancement effects. The main mechanism of action of menthol involves the disruption of the stratum corneum (SC bilayer, whereas borneol involves multiple mechanisms, including the disruption of the SC bilayer, increasing the diffusion coefficient of 5-FU, and inducing the formation of transient pores. The findings of the present study improve our understanding of the molecular mechanism that is underlying 5-FU penetration-enhancement by borneol and menthol, which may be utilized in future investigations and applications.

  5. Blend Hydrogel Microspheres of Carboxymethyl Chitosan and Gelatin for the Controlled Release of 5-Fluorouracil

    Directory of Open Access Journals (Sweden)

    Vanarchi Rajini Kanth

    2017-03-01

    Full Text Available Carboxymethyl chitosan (CMCS was synthesized and blended with gelatin (GE to prepare hydrogel microspheres by w/o emulsion cross-linking in the presence of glutaraldehyde (GA, which acted as a cross-linker. 5-Fluorouracil (5-FU was encapsulated to investigate its controlled release (CR characteristics in acidic (pH 1.2 and alkaline (pH 7.4 buffer media. The microspheres which formed were spherical in nature, with smooth surfaces, as judged by the scanning electron microscopy (SEM. Fourier transform infrared spectroscopy (FTIR confirmed the carboxymethylation of CS and the chemical stability of 5-FU in the formulations. Differential scanning calorimetry (DSC and X-ray diffraction (XRD confirmed the physical state and molecular level dispersion of 5-FU. Equilibrium swelling of microspheres was performed in water, in order to understand the water uptake properties. The in vitro release of 5-FU was extended up to 12 h in pH 7.4 phosphate buffer, revealing an encapsulation efficiency of 72%. The effects of blend composition, the extent of cross-linking, and initial drug loading on the in vitro release properties, were investigated. When analyzed through empirical equations, the release data suggested a non-Fickian transport mechanism.

  6. Purification of a polysaccharide from Boschniakia rossica and its synergistic antitumor effect combined with 5-Fluorouracil.

    Science.gov (United States)

    Wang, Zhenghui; Wu, Baojun; Zhang, Xianghong; Xu, Min; Chang, Huimin; Lu, Xiaoyun; Ren, Xiaoyong

    2012-06-05

    Current study we purified a polysaccharide (BRP) from Boschniakia rossica and the antitumor effects of BRP alone or combined with 5-Fluorouracil (5-FU) was examined in S180 tumor bearing mice by intragastric administration. The high performance size-exclusion chromatography (HPGEC) analysis showed that BRP was a homogeneous polysaccharide and had a molecular weight of 2.2 × 10(4) Da. Total carbohydrate content in BRP was determined to be 96.9%, without the presence of protein and nucleic acid. BRP alone or combined with 5-FU could significantly inhibit Sarcoma-180 (S180) tumor growth and increase the spleen index in a dose-dependent manner. Meanwhile a synergistic effect was observed in boosting various immunity functions when the tumor bearing mice receiving BRP plus 5-FU administration, such as stimulating lymphocytes proliferation, increasing NK cell cytotoxicity, enhancing serum interleukin-2 (IL-2) and interferon-gamma (TNF-γ) secretion, as well as augmenting CD4+ and CD8+ spleen T lymphocytes subsets. The results showed that BRP combined with 5-FU presented synergistic effects on antitumor activity in tumor bearing mice. In conclusion, the combination of BRP may boost the suppressed immunity in tumor bearing mice subject to 5-FU chemotherapy, and could serve as a new, promising approach for cancer treatment. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Suberoylanilide hydroxamic acid enhances chemosensitivity to 5-fluorouracil in hepatocellular carcinoma via inhibition of thymidylate synthase.

    Science.gov (United States)

    Liao, Bo; Liang, Huifang; Chen, Jin; Liu, Qiumeng; Zhang, Bixiang; Chen, Xiaoping

    2015-12-01

    Hepatocellular carcinoma (HCC) is associated with a high rate of mortality worldwide. Here, we investigated the effect of combination treatment with suberoylanilide hydroxamic acid (SAHA) and 5-fluorouracil (5-FU) on HCC cells. HepG2, SMMC7721, and BEL7402 cells were treated with SAHA and/or 5-FU and subjected to cell viability, colony formation, and soft agarose assays; cell cycle, apoptosis, and reverse transcription-PCR analyses; western blotting; immunohistochemistry; and xenograft tumorigenicity assay. SAHA and 5-FU inhibited the proliferation of the three cell lines, and combination treatment with SAHA and 5-FU resulted in a combination index 1, indicating a synergistic effect. Co-treatment with SAHA and 5-FU caused G0/G1 phase arrest and induced caspase-dependent apoptosis, inhibiting tumorigenicity in vitro and in vivo. 5-FU upregulated thymidylate synthase, whereas SAHA downregulated its expression. Our results indicate that SAHA and 5-FU act synergistically to inhibit cell growth and tumorigenicity in HCC via the induction of cell-cycle arrest and apoptosis through a mechanism involving the inhibition of thymidylate synthase, suggesting that combination treatment with 5-FU and SAHA may be beneficial for the treatment of inoperable HCC.

  8. 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation.

    Science.gov (United States)

    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

    2016-04-12

    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.

  9. Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer.

    Science.gov (United States)

    Tsujie, Masanori; Nakamori, Shoji; Nakahira, Shin; Takahashi, Yuji; Hayashi, Nobuyasu; Okami, Jiro; Nagano, Hiroaki; Dono, Keizo; Umeshita, Koji; Sakon, Masato; Monden, Morito

    2007-01-01

    The purpose of this study was to find a novel biomarker to predict 5-fluorouracil (5-FU) or gemcitabine (2',2'-difluoro-deoxycytidine) sensitivity in pancreatic cancer. The relationship between 5-FU and gemcitabine sensitivity and the mRNA levels of human equilibrative nucleoside transporter 1 (hENT1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was investigated using seven types of human pancreatic carcinoma cell line (AsPC1, BxPC3, MiaPaCa-2, PSN1, Panc1, PCI6, and KMP-4). Quantitative mRNA expression was measured by LightCycler. A [3H] gemcitabine cellular uptake assay was performed to examine the inhibition of hENT1 by nitrobenzylmercaptoprine ribonucleoside (NBMPR). The expression levels of hENT1 mRNA significantly correlated with the IC50 value of 5-FU in all seven lines and also correlated with gemcitabine resistance in six lines (except AsPC1). No significant association was observed between TS or DPD mRNA levels and 5-FU sensitivity. In the PSN1 cells, [3H] gemcitabine uptake via hENT1 was significantly inhibited by NBMPR, and 5-FU sensitivity was significantly increased when the cells were pretreated with NBMPR. Our results suggest that hENT1 plays an important role in 5-FU resistance and that hENT1 mRNA levels might be a useful marker to predict 5-FU sensitivity in pancreatic cancer.

  10. DTNQ-Pro, a Mimetic Dipeptide, Sensitizes Human Colon Cancer Cells to 5-Fluorouracil Treatment

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    Isabel Gomez-Monterrey

    2013-01-01

    Full Text Available The resistance of growing human colon cancer cells to chemotherapy agents has been correlated to endogenous overexpression of stress proteins including the family of heat shock proteins (HSPs. Previously, we have demonstrated that a quinone-based mimetic dipeptide, named DTNQ-Pro, induced differentiation of growing Caco-2 cells through inhibition of HSP70 and HSP90. In addition, our product induced a HSP27 and vimentin intracellular redistribution. In the present study, we have evaluated whether a decrease of stress proteins induced by DTNQ-Pro in Caco-2 cells could sensitize these cells to treatment with 5-fluorouracil (5-FU cytotoxicity. The pretreatment of Caco-2 with 500 nM of DTNQ-Pro increases lipid peroxidation and decreases expression of p38 mitogen-activated protein kinase (MAPK and FOXO3a. At the same experimental conditions, an increase of the 5-FU-induced growth inhibition of Caco-2 cells was recorded. These effects could be due to enhanced DTNQ-Pro-induced membrane lipid peroxidation that, in turn, causes the sensitization of cancer cells to the cytotoxicity mediated by 5-FU.

  11. Monthly 5-days 5-fluorouracil and low-dose leucovorin for adjuvant chemotherapy in colon cancer.

    Science.gov (United States)

    Ahn, J B; Shim, K Y; Jeung, H C; Rha, S Y; Yoo, N C; Kim, N K; Roh, J K; Min, J S; Kim, B S; Chung, H C

    2001-06-26

    We investigated the dose-related effect of the 5-fluorouracil (5-FU)/leucovorin regimen on survival in 139 colon cancer patients with Dukes' B2 and C2 stage disease. Chemotherapy consisted of 400 mg/m(2) of 5-FU and 20 mg/m(2) of leucovorin injected daily for 5 days in every 4 weeks for a maximum of 12 cycles. The total dose of 5-FU administered per body surface area had a significant effect on the 5-year disease-free survival and 5-year overall survival in stage B2 and C2 colon cancer patients (P=0.0018, P=0.0011). Analysis with reference to the median DSDI demonstrated that there was a significant difference in 5-year survival in Dukes' C2 (P=0.0016), but survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administered per surface area affected the 5-year disease-free survival and 5-year overall survival (P=0.0016, P=0.0007, respectively). It can be concluded that the total dose of 5-FU administered is important in planned dosage schedule of adjuvant chemotherapy in colon cancer.

  12. Effect of 5-fluorouracil incorporation into pre-mRNA on RNA splicing in vitro

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    Doong, S.L.

    1988-01-01

    5-Fluorouracil(FUra) has been proven useful in the chemotherapy of a number of cancers. The mechanism underlying its cytotoxicity is controversial. We are interested in studying the FUra effect on the fidelity of the pre-mRNA splicing process. ({sup 32}P)-labeled human {beta}-globin pre-mRNA containing the first two exons and the first intervening sequence was synthesized in the presence of UTP, FUTP, or both. The appearance of a new minor spliced product was dependent on both the pH of the splicing reaction and the extent of FUra incorporation into pre-mRNA. At least 84% substitution of U by FUra was required to observe the presence of the abnormal splicing pathway. The new spliced product was sequenced and found to contain an additional 20 bases derived from the 3{prime} end of the intervening sequence. Nearest neighbor analysis, RNase T{sub 1} fingerprinting, and short primer extension experiments were carried out to assess the extent of transcription infidelity induced by FUra. Site directed mutagenesis was performed to determine the sequence(s) of FUra substitution which contribute to missplicing in vitro.

  13. Protective effect of Salvia miltiorrhiza Bunge on 5-fluorouracil-induced oral mucositis.

    Science.gov (United States)

    Kim, Do Rim; Kim, Jinsung; Oh, Ja Young; Kim, Ha Young; Kim, Young Joo; Chang, Mun Seog

    2017-07-01

    Oral mucositis is a common side-effect caused by chemotherapy or radiotherapy occurring in the majority of cancer patients and is characterized by inflammation and ulcers in the oral mucosa. In the present study, we examined the protective effects of Salvia miltiorrhiza Bunge (SM) on oral mucositis induced by 5-fluorouracil (5-FU) in human pharyngeal cells and golden Syrian hamsters. We investigated the proliferation and antioxidant abilities of SM using MTT, 2-diphenyl-1-picrylhydrazyl (DPPH) and reactive oxygen species (ROS) assays in vitro. Additionally, TUNEL assay was performed, and the expression levels of nuclear factor-κB (NF-κB), caspase-3 and proinflammatory cytokines were assessed by immunoblotting. The results showed that SM increased the cell proliferation rate in human pharyngeal cells up to 128.97±9.7% compared with this rate in the untreated cells and exerted protective effects on mucosal injury caused by 5-FU treatment. In addition, all concentrations of SM increased DPPH scavenging ability and blocked ROS generation in the treated cells. Taken together, following SM treatment, expression of NF-κB and cleaved caspase-3 were significantly decreased followed by inhibition of cell death. These data suggest that SM could be used for the prevention and treatment of oral mucositis caused by cancer therapies.

  14. Radiosensitization of human breast cancer cells to ultraviolet light by 5-fluorouracil

    Science.gov (United States)

    SASAKI, KAZUHITO; TSUNO, NELSON H.; SUNAMI, EIJI; KAWAI, KAZUSHIGE; SHUNO, YASUTAKA; HONGO, KUMIKO; HIYOSHI, MASAYA; KANEKO, MANABU; MURONO, KOJI; TADA, NORIKO; NIREI, TAKAKO; KITAYAMA, JOJI; TAKAHASHI, KOKI; NAGAWA, HIROKAZU

    2011-01-01

    Ultraviolet light B (UVB) phototherapy is widely used to treat dermatological diseases and therefore may be a potential optional strategy in the treatment of a skin lesion infiltrated by a malignant tumor. Currently, little is known regarding the effect of UVB phototherapy on human breast cancer cells. The present study aimed to investigate the effect of UVB phototherapy, as well as the potential effect of 5-fluorouracil (5-FU), the first-line anticancer drug for breast cancer, on radiosensitizing MCF-7 human breast cancer cells, in an attempt to develop new therapeutic strategies for the treatment of locoregional recurrence of breast cancer. MCF-7 cells were incubated in the presence of 5-FU for 48 h, and UVB irradiation at 750 mJ/cm2 was administered in the midterm of 5-FU treatment. The viability of MCF-7 cells was analyzed by the trypan blue staining method. Apoptosis was quantified by flow cytometry and Hoechst 33258 staining. The cell cycle was evaluated by flow cytometry after the staining of cells with propidium iodide. The combination treatment of 5-FU and UVB resulted in a strong potentiation of the inhibitory effect of MCF-7 cell growth, dependent on the intra-S phase cell cycle arrest and induction of apoptosis, when compared to treatment with 5-FU or UVB alone. In conclusion, 5-FU sensitized human breast cancer cells to UVB phototherapy, and this combination therapy is an effective and promising strategy for the treatment of breast cancer, particularly for locoregional recurrence. PMID:22866105

  15. Clinical observation of needle revision and 5-fluorouracil subconjunctive injection for the dysfunctional filtering blebs

    Directory of Open Access Journals (Sweden)

    Yan-Hua Gao

    2016-07-01

    Full Text Available AIM:To investigate the efficacy and safety of needle revision with 5-fluorouracil(5-FUon the dysfunctional filtering blebs after trabeculectomy and to assess the factors that may impact the success. METHODS:Eighty-three eyes in 76 patients underwent the needle revision and 5-FU subconjunctive injection for the dysfunctional blebs after trabeculectomy and were followed up for 12mo. The intraocular pressure(IOP, the number of drugs, corneal endothclium, bleb morphology and complications were observed and recorded. RESULTS:IOP decreased significantly from 35.3±5.8mmHg(1kPa=7.5mmHgof pre-needling to 17.0±4.3mmHg of post-needling(PPCI: 10.3-11.6. Statistically, there were no significant difference on needling effect with reference to the types of glaucoma, the use of mitomycin C(MMCduring the previous filtration surgery, the ages of patients, the intervals of needling operation from previous trabeculectomy, while there were significant difference on needling effect with reference to bleb appearance before needling, and the mean number of needling in patients that had surgery within 3mo were less than those who had surgery for more than 3mo. CONCLUSION: The needle revision combined with 5-FU is a safe, effective and simple method. Dysfunctional blebs should be treated early after trabeculectomy.

  16. Primary Congenital Glaucoma with Delayed Suprachoroidal Hemorrhage following Combined Trabeculotomy Trabeculectomy and 5-Fluorouracil

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    Roseline Duke

    2015-01-01

    Full Text Available Background. Delayed postoperative suprachoroidal hemorrhage (DSCH may occur following intraocular surgery for the treatment of glaucoma. It is considered to be a rare and debilitating event if not managed appropriately. Reported herewith is a case of Primary Congenital Glaucoma followed by DSCH with successful immediate surgical intervention and visual restoration. Patient and Method. An 8-month-old male child had bilateral Primary Congenital Glaucoma (PCG. Combined Trabeculotomy Trabeculectomy with 5-Fluorouracil (5FU was performed. He developed delayed suprachoroidal hemorrhage (DSCH within 24 hours after intraocular surgery which was drained. In addition, he developed exposure keratopathy and left amblyopia. Outcome. Resolution of the DSCH was seen with surgical drainage in addition to treatments for exposure keratopathy and amblyopia. These resulted in reduced intraocular pressure and improved visual acuities. Conclusion. There appears to be a difference in the overall management of PCG and DSCH between adults and children. A high index of suspicion as well as emergency surgical treatment for DSCH and associated conditions should be performed on pediatric patients that present with these challenges.

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

    Science.gov (United States)

    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.

  18. Treatment schedule-dependent effect of 5-fluorouracil and platinum derivatives in colorectal cancer cells.

    Science.gov (United States)

    Takara, Kohji; Fujita, Megumi; Minegaki, Tetsuya; Yamamoto, Kazuhiro; Takahashi, Minoru; Yokoyama, Teruyoshi; Okumura, Katsuhiko

    2012-02-14

    Combination chemotherapy for treating cancer often is superior in clinical efficacy to monotherapy. The aim of this study was to investigate the schedule-dependent effect of 5-fluorouracil (5-FU) and platinum derivatives (cisplatin or oxaliplatin) in colorectal cancer (CRC) cell lines, and to explore factors affecting it. Two human CRC-derived cell lines, DLD-1 and HCT116, were used. Three treatment schedules were tested, and growth inhibitory effects were evaluated with a WST-1 assay. Combined effects were assessed with isobolograms and a combination index. Cellular accumulation and DNA-binding of platinum were measured with inductively coupled plasma mass spectrometry. Exposure to 5-FU followed by cisplatin produced synergistic effects in DLD-1 cells, and the amount of platinum bound to DNA was substantially increased as compared with that for other schedules. 5-FU and oxaliplatin also tended to be synergistic when 5-FU was given first, but no significant change in the cellular kinetics of platinum was observed. On the other hand, in HCT116 cells, the combined effects of 5-FU and platinum derivatives were comparable among the three schedules. Exposure to 5-FU followed by cisplatin had a synergistic effect in DLD-1 cells, suggesting that the amount of platinum bound to DNA contributes to this result. Also, the effect was dependent on the type of platinum derivative and cell. Copyright © 2011 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Youssef W. Naguib

    2014-02-01

    Full Text Available 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.

  20. The therapy with ethosomes containing 5-fluorouracil for laryngotracheal stenosis in rabbit models.

    Science.gov (United States)

    Mao, Xiaohui; Cheng, Xuefeng; Zhang, Zheng; Wang, Zhaoyan; Wang, Zhentao

    2017-04-01

    The aim of this study is to evaluate the efficacy of ethosomes encapsulated with 5-fluorouracil (5-FU) in treatment of laryngotracheal stenosis in rabbit models. The 5-FU ethosome was prepared by the thin film hydration method, and the amorphous, size distribution and the encapsulation efficiency was investigated. The tracheal mucosa were scraped about 0.5 cm with a nylon brush to induce the scar in airway grow, then models were divided into three groups: 5-FU ethosome group, 5-FU group and saline group, drug were injected into scar of every group by paracentesis guided under endoscope, respectively. The stenosis states were observed under laryngo fiberscope immediate, 7, 14 and 21 days after administrated. Airway stenosis of 5-FU ethosome group has no significant difference when compared with 5-FU group at 7 days after administration, but 5-FU ethosome significantly reduced the airway stenosis after 21-day administration when compared with 5-FU group again and has no restenosis during the period under observation. The fact that ethosomes encapsulated with 5-FU were effective for laryngotracheal stenosis suggests that it has potential as a new method for ameliorating airway stenosis originating from granulation tissue.

  1. A Novel Therapy for Laryngotracheal Stenosis: Treatment With Ethosomes Containing 5-Fluorouracil.

    Science.gov (United States)

    Gu, Jian; Mao, Xiaohui; Li, Cong; Ao, Huafei; Yang, Xizhi

    2015-07-01

    The purpose of our article was to explore the effect of ethosomes containing 5-fluorouracil (5-FU) with different sizes on laryngotracheal stenosis treatment. The physical characteristics of ethosomes containing 5-FU were investigated, including size, shape, and entrapment percentage. The effect of ethosomes containing 5-FU was evaluated on the airway stenosis rabbit model. The formation of fibrous/scar tissue was investigated by hematoxylin and eosin (HE) staining, and the permeation depth was observed under fluorescence microscope. The mean sizes of 5-FU ethosomes extruded by D=50 nm and D=100 nm pore were 60±10 nm and 110±13 nm, respectively. The 5-FU entrapment percentage of ethosomes was determined to be 15% (D=60±10 nm) and 32% (D=110±13 nm). After being treated by ethosomes containing 5-FU (D=60±10 nm), the fibroblast and collagenous fiber distributed sparsely in the deep scar tissue. The permeation capability of ethosomes containing 5-FU (D=60 nm) was significantly better than ethosomes (D=110 nm). Besides, the 5-FU ethosomes resulted in less stenosis than 5-FU only. Topical administration of 5-FU ethosomes may be a novel candidate therapy for laryngotracheal stenosis treatment. © The Author(s) 2015.

  2. Microwave-aided skin drug penetration and retention of 5-fluorouracil-loaded ethosomes.

    Science.gov (United States)

    Khan, Nauman Rahim; Wong, Tin Wui

    2016-09-01

    Skin drug retention is required in local treatment of skin cancer. This study investigated the interplay effects of ethosomes and microwave in transdermal drug delivery. Skin pre-treatment by microwave and applied with liquified medicine is deemed to 'cement' the skin thereby raising skin drug deposition. 5-fluorouracil-loaded ethosomes were prepared and subjected to size, zeta potential, morphology, drug content, drug release and skin permeation tests. The molecular characteristics of untreated, microwave and/or ethosome-treated skins were examined by Fourier transform infrared and raman spectroscopy, thermal and electron microscopy techniques. The skin drug retention was promoted using larger ethosomes with negative zeta potentials that repelled anionic lipids of skin and hindered vesicle permeation into deep layers. These ethosomes had low ethanol content. They were less able to fluidize the lipid and defluidize the protein domains at epidermis to enlarge aqueous pores for drug permeation. Pre-treatment of skin by 2450 MHz microwave for 2.5 min further increased skin drug penetration and retention of low ethanol ethosomes and provided lower drug permeation than cases treated for 1.15 min and 5 min. A 2.5 min treatment might be accompanied by specific dermal protein fluidization via C=O moiety which translated to macromolecular swelling, narrowing of intercellular spaces at lower skin layers, increased drug retention and reduced drug permeation. Ethosomes and microwave synergized to promote skin drug retention.

  3. Possible involvement of oxidative stress in 5-fluorouracil-mediated myelosuppression in mice.

    Science.gov (United States)

    Numazawa, Satoshi; Sugihara, Kazuko; Miyake, Shota; Tomiyama, Hirono; Hida, Ayako; Hatsuno, Misato; Yamamoto, Masayuki; Yoshida, Takemi

    2011-01-01

    Certain chemotherapeutic agents subject cells to oxidative stress, thereby promoting adverse effects. However, the molecular machinery governing 5-fluorouracil (5-FU)-mediated myelotoxicity is obscure. The purpose of this study was to clarify whether 5-FU-induced myelotoxicity is a cause of oxidative stress. Treatment of mice with 5-FU (75 mg/kg, i.p.) caused a significant induction of haem oxygenase-1 and a decrease in glutathione contents in bone marrow cells, both of which are the indicators of oxidative stress. The 5-FU-mediated decrease in the myeloid colony formation was intensified in Nrf2(-/-) mice, in which antioxidant proteins were down-regulated. N-Acetylcysteine reversed the 5-FU-induced decreases in the glutathione content, number of bone marrow cells per femur and myeloid colony formation. Results from the present study reveal that 5-FU induces oxidative stress in bone marrow, which is involved, at least in part, in myelotoxicity in mice. Therefore, Nrf2-dependent genes as well as glutathione levels in bone marrow could be therapeutic targets for decreasing such side-effects in 5-FU-based chemotherapy. © 2010 The Authors. Basic & Clinical Pharmacology & Toxicology © 2010 Nordic Pharmacological Society.

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

    Science.gov (United States)

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

    2014-02-01

    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.

  5. Blend Hydrogel Microspheres of Carboxymethyl Chitosan and Gelatin for the Controlled Release of 5-Fluorouracil.

    Science.gov (United States)

    Kanth, Vanarchi Rajini; Kajjari, Praveen B; Madalageri, Priya M; Ravindra, Sakey; Manjeshwar, Lata S; Aminabhavi, Tejraj M

    2017-03-27

    Carboxymethyl chitosan (CMCS) was synthesized and blended with gelatin (GE) to prepare hydrogel microspheres by w/o emulsion cross-linking in the presence of glutaraldehyde (GA), which acted as a cross-linker. 5-Fluorouracil (5-FU) was encapsulated to investigate its controlled release (CR) characteristics in acidic (pH 1.2) and alkaline (pH 7.4) buffer media. The microspheres which formed were spherical in nature, with smooth surfaces, as judged by the scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FTIR) confirmed the carboxymethylation of CS and the chemical stability of 5-FU in the formulations. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed the physical state and molecular level dispersion of 5-FU. Equilibrium swelling of microspheres was performed in water, in order to understand the water uptake properties. The in vitro release of 5-FU was extended up to 12 h in pH 7.4 phosphate buffer, revealing an encapsulation efficiency of 72%. The effects of blend composition, the extent of cross-linking, and initial drug loading on the in vitro release properties, were investigated. When analyzed through empirical equations, the release data suggested a non-Fickian transport mechanism.

  6. Core Cross-linked Star Polymers for Temperature/pH Controlled Delivery of 5-Fluorouracil

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    Elizabeth Sánchez-Bustos

    2016-01-01

    Full Text Available RAFT polymerization with cross-linking was used to prepare core cross-linked star polymers bearing temperature sensitive arms. The arms consisted of a diblock copolymer containing N-isopropylacrylamide (NIPAAm and 4-methacryloyloxy benzoic acid (4MBA in the temperature sensitive block and poly(hexyl acrylate forming the second hydrophobic block, while ethyleneglycol dimethacrylate was used to form the core. The acid comonomer provides pH sensitivity to the arms and also increases the transition temperature of polyNIPAAm to values in the range of 40 to 46°C. Light scattering and atomic force microscopy studies suggest that loose core star polymers were obtained. The star polymers were loaded with 5-fluorouracil (5-FU, an anticancer agent, in values of up to 30 w/w%. In vitro release experiments were performed at different temperatures and pH values, as well as with heating and cooling temperature cycles. Faster drug release was obtained at 42°C or pH 6, compared to normal physiological conditions (37°C, pH 7.4. The drug carriers prepared acted as nanopumps changing the release kinetics of 5-FU when temperatures cycles were applied, in contrast with release rates at a constant temperature. The prepared core cross-linked star polymers represent advanced drug delivery vehicles optimized for 5-FU with potential application in cancer treatment.

  7. Safety of implanting sustained-release 5-fluorouracil into hepatic cross-section and omentum majus after primary liver cancer resection.

    Science.gov (United States)

    Chen, Jiangtao; Zhang, Junjie; Wang, Chenyu; Yao, Kunhou; Hua, Long; Zhang, Liping; Ren, Xuequn

    2016-09-01

    This study was designed to evaluate the short-term safety of implanting sustained-release 5-fluorouracil (5-FU) into hepatic cross-section and omentum majus after primary liver cancer resection and its impact on related indexes of liver. Forty patients were selected and divided into an implantation group (n = 20) and a control group (n = 20). On the first day after admission, first week after surgery, and first month after surgery, fasting venous blood was extracted from patients for measuring hematological indexes. The reduction rate of alpha fetoprotein (AFP) on the first week and first month after surgery was calculated, and moreover, drainage volume of the abdominal cavity drainage tube, length of stay after surgery, and wound healing condition were recorded. We found that levels of alanine aminotransferase, aspartate amino transferase, blood urea nitrogen, creatinine, total bilirubin, albumin, and white blood cells measured on the first week and first month after surgery, length of stay, and wound healing of patients in the two groups had no significant difference (P >0.05). Drainage volume and reduction rate of AFP of two groups were significantly different on the first week and first month after surgery (P liver cancer resection is proved to be safe as it has little impact on related indexes. © The Author(s) 2016.

  8. Synthesis, Structure and Antitumor Activity of Dibutyltin Oxide Complexes with 5-Fluorouracil Derivatives. Crystal Structure of [(5-Fluorouracil-1-CH2CH2COOSn(n-Bu 2]4O2

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    Zhan Shi

    2001-07-01

    Full Text Available Dibutyltin (IV oxide complex reacts with the fluorouracil compounds 5-fluorouracil-1-propanonic or 5-fluorouracil-1-acetic acid (Fu to give the complexes [(5-Fu-1-(CH2nCOOSn(n-Bu2]4O2 (I, n=2; II, n=1 which were characterized by IR and 1H-NMR. The crystal structure of complex I shows that the molecular is a dimer, in which two [(5-Fu-1-CH2CH2COOSn(n-Bu2]2O units are linked by a bridging oxygen atom, and the tin atoms adopt distorted trigonal bipyramids via two carbons from a dibutyl moiety and three oxygen atoms from 5-Fu and bridging oxygen. These complexes have potential anti-tumour activity: in vitro tests showed that complexes I and II exhibit high cytotoxicity against OVCAR-3 and PC-14.

  9. Efeito do colírio de 5-fluorouracil sobre o epitélio corneano íntegro de coelhos Effects of 5-fluorouracil eye drops on intact rabbit corneal epithelium

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    Lucieni Cristina Barbarini Ferraz

    2003-08-01

    Full Text Available OBJETIVO: Observar os efeitos da aplicação tópica de 5-fluorouracil (5-FU sobre o epitélio corneano íntegro. MÉTODOS: Foram utilizados 10 coelhos albinos (14 olhos, divididos em: grupo controle (GC, 4 olhos nos quais não se administraram drogas, grupo 1 (G1, 5 olhos que receberam 5-fluorouracil na concentração 1,25% e grupo 2 (G2, 5 olhos que receberam 5-fluorouracil na concentração de 2,5%. A droga foi instilada 4 vezes por dia, durante 7 dias, quando os animais foram sacrificados, os olhos removidos, separando-se a córnea que foi preparada de modo convencional para estudo em microscópico eletrônico de varredura. RESULTADOS: GC: observaram-se células de formato hexagonal, claras, escuras e intermediárias, compondo o epitélio corneano de coelhos. Presença de numerosas microplicas, principalmente nas células claras. Cada célula possui cerca de 1 a 3 criptas. Nos animais do G1, observou-se maior número de células escuras, regiões com diminuição no número de criptas; alterações da superfície celular, protusão na região do núcleo e descamação de células epiteliais. Os do G2 tiveram aumento de microprojeções na superfície celular, modificações nas junções intercelulares até separação de células adjacentes; diminuição do número e variabilidade no tamanho das criptas. As alterações mais freqüentes ocorreram nas células da periferia da córnea. CONCLUSÃO: O 5-fluorouracil teve efeitos deletérios no epitélio íntegro corneano de coelhos. As alterações observadas foram mais importantes nos animais que receberam a droga mais concentrada (G2 e mais freqüentes na periferia da córnea.PURPOSE: To assess the influence of the antiproliferative agent (5-FU on the intact rabbit corneal epithelium. METHODS: 10 rabbits (14 eyes,were divided into: control group (CG, 4 eyes without drug administration; G1, 5 eyes underwent treatment with topical 12.5 mg/ml 5-fluorouracil and G2, 5 eyes received 5-fluorouracil

  10. Complications of an implantable venous access device (Port-a-Cath) during intermittent continuous infusion of chemotherapy

    NARCIS (Netherlands)

    Poorter, R. L.; Lauw, F. N.; Bemelman, W. A.; Bakker, P. J.; Taat, C. W.; Veenhof, C. H.

    1996-01-01

    In 149 patients, treated with intermittent continuous infusion of different chemotherapeutic agents, 169 Port-a-Caths were implanted by qualified surgeons and residents in training. The peri- and postoperative complications of implantation of the Port-a-Cath system and the complications during

  11. The increase in the cardiodepressant activity and vasopressin concentration in the sella turcica venous blood during vagal afferents stimulation or after angiotensin II infusion

    Energy Technology Data Exchange (ETDEWEB)

    Goraca, A.; Orlowska-Majdak, M.; Traczyk, W.Z. [Akademia Medyczna, Lodz (Poland). Katedra Fizjologii

    1996-12-31

    It has previously been demonstrated that the cardiodepressant activity is present in the bovine hypothalamic extract and in the fluid incubating the posterior pituitary lobe {sup i}n situ{sup .} The present study was an attempt to reveal if the cardiodepressant factor and vasopressin were simultaneously released from the pituitary into blood. The samples of venous blood flowing from the sella turcica and, for comparison, from the posterior paw were collected in anesthetized rats. Blood from the sella turcica was collected with a fine cannula inserted into the internal maxillary vein. The concentration of vasopressin in blood plasma was determined by radioimmunoassay and cardiodepressant activity-using a biological test on a spontaneously discharged pacemaker tissue of the right auricle of the right heart atrium. Stimulation of the central ends of the cut vagus nerves or intra-arterial infusion of angiotensin II simultaneously caused an increase in the cardiodepressant activity and vasopressin concentration in the sella turcica venous blood. The cardiodepressant activity and vasopressin concentration was also enhanced to some degree in blood outflowing from the posterior paw. Present results indicate that both vasopressin and the cardiodepressant factor are released into blood from the posterior pituitary lobe. (author). 37 refs, 4 figs.

  12. Effects of 5-fluorouracil and 6-azauracil on the synthesis of ribonucleic acid and protein in Saccharomyces carlsbergensis

    Science.gov (United States)

    De Kloet, S. R.

    1968-01-01

    1. Some effects of 6-azauracil and 5-fluorouracil on protein and RNA synthesis in Saccharomyces carlsbergensis were studied. 2. Both analogues caused a severe inhibition of RNA formation, whereas protein synthesis was much less affected. 3. Induced α-glucosidase formation was only slightly impaired. 4. Both analogues caused an inhibition of ribosome formation, although 5-fluorouracil was far more effective. 5. In the presence of the latter analogue abnormal RNA of high molecular weight and of more DNA-like base composition accumulated. On reincubation in medium free of analogue but containing uracil the abnormal RNA disappeared and was replaced by the normally sedimenting high-molecular-weight RNA species. PMID:5756480

  13. The role of intracarotid cold saline infusion on a theoretical brain model incorporating the circle of willis and cerebral venous return.

    Science.gov (United States)

    Neimark, Matthew A; Konstas, Angelos-Aristeidis; Choi, Jae H; Laine, Andrew F; Pile-Spellman, John

    2007-01-01

    This study describes a theoretical model of brain cooling by intracarotid cold saline infusion which takes into account redistribution of cold perfusate through the circle of Willis (CoW) and cold venous return (VR) from the head. This model is developed in spherical coordinates on a four tissue layer hemispherical geometrical configuration. Temperature evolution is modeled according to the Pennes bioheat transfer equation. Simulations were run over a 1 hour period and 30 ml/min of freezing cold saline with the baseline model (no VR, no CoW), VR model (without CoW), and CoW model (with VR). The VR model demonstrates continuing temperature drop in the treatment region of the brain not observed in the baseline model and its final mean ipsilateral anterior temperature was approximately 31 degrees C. The temperature effect in the CoW model was present but less robust in the ipsilateral anterior region, as final temperature was 32 degrees C. However, cooling was also achieved in contralateral and posterior brain regions. This model continues to demonstrate the feasibility of intracarotid cold saline infusion for ischemic stroke therapy.

  14. Biomechanical and Macroscopic Evaluations of the Effects of 5-Fluorouracil on Partially Divided Flexor Tendon Injuries in Rabbits

    OpenAIRE

    Duci, Shkelzen B; Arifi, Hysni M; Ahmeti, Hasan R; Manxhuka-Kerliu, Suzana; Neziri, Burim; Mekaj, Agon Y; Lajqi, Shpetim; Shahini, Labinot

    2015-01-01

    Background: The main goals of flexor tendon surgery are to restore digital motion by providing tendon healing and to preserve tendon gliding. Our purpose was to investigate the effects of 5-fluorouracil (5-FU) on tendon adhesions in partially divided profundus flexor tendons (flexor digitorum profundus [FDPs]) following surgical repair and in partially divided FDPs without surgical repair, and to compare the results of the repair versus the nonrepair of zone two injuries via macroscopic and b...

  15. Comment: The comparison study of 5 Fluorouracil vs. cryotherpy in the treatment of the backhand resistant common wart

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    Antonio Chuh

    2014-07-01

    Full Text Available We refer to the study conducted by Asghariazar R et al comparing the efficacy of 5-fluorouracil against cryotherapy in the management of backhand resistant common warts [1]. We congratulate their success in reporting such a high-quality study. We would humbly like to offer a few pieces of advice, which might further augment the clinical relevance and the scientific content for future studies along similar veins.

  16. Hyperthermia combined with 5-fluorouracil promoted apoptosis and enhanced thermotolerance in human gastric cancer cell line SGC-7901

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    Liu T

    2015-05-01

    Full Text Available Tao Liu,* Yan-Wei Ye,* A-li Zhu, Zhen Yang, Yang Fu, Chong-Qing Wei, Qi Liu, Chun-Lin Zhao, Guo-Jun Wang, Xie-Fu Zhang Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China *These authors contributed equally to this work Abstract: This study was designed to investigate the proliferation inhibition and apo­ptosis-promoting effect under hyperthermia and chemotherapy treatment, at cellular level. Human gastric cancer cell line SGC-7901 was cultivated with 5-fluorouracil at different temperatures. Cell proliferation and apoptosis were determined, and expression of Bcl-2 and HSP70 was measured at different treatments. Cell survival rates and inhibition rates in chemotherapy group, thermotherapy group, and thermo-chemotherapy group were drastically lower than the control group (P<0.05. For tumor cells in the thermo-chemotherapy group, survival rates and inhibition rates at three different temperatures were all significantly lower than those in chemotherapy group and thermotherapy group (P<0.05. 5-Fluorouracil induced apoptosis of SGC-7901 cells with a strong temperature dependence, which increased gradually with increase in temperature. At 37°C and 43°C there were significant differences between the thermotherapy group and chemotherapy group and between the thermo-chemotherapy group and thermotherapy group (P<0.01. The expression of Bcl-2 was downregulated and HSP70 was upregulated, with increase in temperature in all groups. Cell apoptosis was not significant at 46°C (P>0.05, which was probably due to thermotolerance caused by HSP70 accumulation. These results suggested that hyperthermia combined with 5-fluorouracil had a synergistic effect in promoting apoptosis and enhancing thermotolerance in gastric cancer cell line SGC-7901. Keywords: gastric cancer, thermotherapy, 5-fluorouracil, Bcl-2, HSP70, thermotolerance

  17. Curcumin reduces cytotoxicity of 5-Fluorouracil treatment in human breast cancer cells.

    Science.gov (United States)

    Ferguson, Jeannette E; Orlando, Robert A

    2015-04-01

    Antimetabolites have proven successful as therapeutics for advanced-stage breast cancers, but are often accompanied by severe side effects that can limit treatment regimens. 5-Fluorouracil (5-FU), an antimetabolite that inhibits cell proliferation, has served an important role in standard chemotherapy protocols for a variety of solid tumors. Although reasonable response rates have been reported for 5-FU, continued exploration is necessary to improve clinical outcomes and reduce cytotoxic side effects that are an inherent problem for chemotherapeutic interventions. Because of its diverse anticancer properties, we explored whether by combining the natural product curcumin with 5-FU, synergistic improvements in preventing breast cancer cell proliferation and/or provide protection against 5-FU-induced cytotoxicity could be achieved. Indeed both curcumin and 5-FU inhibit DNA synthesis in MDA-MB-231 cells using BrdU incorporation assays; however, combined treatment showed no synergistic improvement. We next established the cytotoxicity profile for 5-FU in MDA-MB-231 cells using a tetrazolium-based cell viability assay and obtained an LD50 value of 28 μM. When 5-FU incubations were repeated with the addition of curcumin, the LD50 value increased to 200-300 μM, representing a 7-10-fold protection by curcumin against 5-FU cytotoxicity. These findings suggest that the addition of curcumin as an adjuvant therapy during 5-FU treatment might enhance the chemotherapeutic effectiveness of 5-FU by protecting normal cells from reduced viability and thus permitting higher dosing or longer treatment times. This would be especially important to those individuals who are plagued with severe cytotoxicities and require frequent interruptions, or even early termination of their treatment regimens.

  18. Acute Reversible Heart Failure Caused by Coronary Vasoconstriction due to Continuous 5-Fluorouracil Combination Chemotherapy

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    Cornelia Dechant

    2012-06-01

    Full Text Available We present the case of a 51-year-old male patient who received adjuvant chemotherapy consisting of oxaliplatin, bolus and continuous 5-fluorouracil (5-FU and leucovorin after anterior resection because of locally advanced rectal cancer. Preoperative chemotherapy with capecitabine (an oral 5-FU prodrug had been well tolerated. Two days after initiation of the first course of chemotherapy, the patient reported typical chest pain. The ECG showed ST elevations and prominent T waves in almost all leads. Due to suspicion of a high-risk acute coronary syndrome, an urgent cardiac catheterization was performed. It showed a generally reduced coronary flow with multiple significant stenoses (including the ostia of the left and right coronary artery, as well as a highly reduced left ventricular function with diffuse hypokinesia. Due to the meanwhile completely stable situation of the patient after medical acute coronary syndrome treatment, no ad hoc intervention was performed to allow further discussion of the optimal management. Thereafter, the patient remained clinically asymptomatic, without any rise in cardiac necrosis parameters; only NT-pro-BNP was significantly elevated. A control cardiac catheterization 2 days later revealed a restored normal coronary artery flow with only coronary calcifications without significant stenoses, as well as a normal left ventricular ejection fraction. Cardiovascular symptoms occurred on the second day of continuous 5-FU treatment. As cardiotoxic effects seem to appear more frequently under continuous application of 5-FU, compared to the earlier established 5-FU bolus regimens, treating medical oncologists should pay special attention to occurring cardiac symptoms and immediately interrupt 5-FU chemotherapy and start a cardiologic work-up.

  19. Dependence of 5-fluorouracil-mediated radiosensitization on DNA-directed effects

    Energy Technology Data Exchange (ETDEWEB)

    Lawrence, T.S.; Davis, M.A.; Maybaum, J. (Univ. of Michigan Medical Center, Ann Arbor, MI (United States))

    1994-06-15

    Although 5-fluorouracil (FUra) has been demonstrated to be a radiation sensitizer both in the laboratory and the clinic, it is not known whether radiosensitization results primary from FUra's DNA or RNA-directed effects. The authors studied the radiosensitizing effects of FUra [+-] thymidine (dThd) on HT29 human colon cancer cells, which are relatively sensitive to the DNA-directed action of FUra, in comparison to SW620 and HuTu80 human colon cancer cells, which are relatively resistant to FUra's DNA-directed effects. They hypothesized that if FUra were acting chiefly through DNA dependent mechanisms, HT29 cells would (a) show greater radiosensitization than SW620 and HuTu80 cells under the same conditions of exposure; and (b) demonstrate selective reversal of radiation sensitivity (compared to cytotoxicity) in the presence of FUra + dThd, compared to FUra alone. They found that the enhancement ratio produced by a 24 h exposure to 10 [mu]M FUra was significantly greater in HT29 cells compared to SW620 and HuTu80 cells (enhancement ratios of 2.1 [+-] 0.1; 1.1 [+-] 0.1, and 1.3 [+-] 0.1, respectively). Furthermore, in HT29 cells, dThd blocked FUra-mediated radiosensitization to a greater extent than FUra-mediated cytotoxicity. Thus, the hypotheses were confirmed. These findings support the concept that the manipulation of FUra's DNA-dependent actions, for example, through modulators of thymidylate synthase (TS) activity, may increase radiosensitization in clinical trials in the treatment of gastrointestinal cancers. However, since resistance to the DNA-directed effects of fluoropyrimidines can result from mechanisms unrelated to TS inhibition, additional strategies will be required to potentiate fluoropyrimidine-mediated radiosensitization. 15 refs., 2 figs., 1 tab.

  20. Genetic variability & chemotoxicity of 5-fluorouracil & cisplatin in head & neck cancer patients: a preliminary study

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    Dipali Dhawan

    2013-01-01

    Full Text Available Background & objectives: The efficacy and toxicity of a given chemotherapy regimen varies widely among patients due to the inherited variability of genes that are involved in drug metabolism. There are several crucial enzymes identified involving metabolism of 5-fluorouracil (5-FU and cisplatin, which are polymorphic. We studied head and neck cancer patients (n=23 on 5-FU and cisplatin combination therapy attending a tertiary care cancer research institute in Gujarat, India, to understand the effect of a particular genotype on toxicity. Methods: The patients were genotyped for dihydropyrimidine (DPYD (85T>C, IVS14+1G>A, 2846A>T, 2194G>A, thymidylate synthase (TYMS [28bp tandem repeat in the promoter enhancer region (TSER], methylenetetrahydrofolate reductase (MTHFR (677C>T, 1298A>C, glutathione S-transferase P1(GSTP1 (Ile105Val, glutathione S-transferase T1 (GSTT1 (null allele and glutathione S-transferase M1 (GSTM1 (null allele by multiplex allele-specific PCR and long range PCR. Results: Of the 23 (19 males 4 females, age range 18-16 yr patients, two had grade 3 and 4 toxicity while the remaining 21 had 0 to 2 grade toxicity after treatment with 5-FU and cisplatin combination therapy. An association between the genotype of GSTM1 (+/- and -/- and the toxicity of cisplatin (P=0.043 was observed. Interpretation & conclusions: The findings of this preliminary study suggested an association between the variants of GSTM1 and toxicity observed due to cisplatin. Well planned studies on a large sample of head and neck cancer patients need to be conducted to understand the effects of these genetic variants on toxicity and efficacy of anticancer drugs.

  1. Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer

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    Chu Edward

    2006-04-01

    Full Text Available Abstract Background Thymidylate synthase (TS is a critical target for cancer chemotherapy and is one of the most extensively studied biomarkers for fluoropyrimidine-based chemotherapy. In addition to its critical role in enzyme catalysis, TS functions as an RNA binding protein to regulate the expression of its own mRNA translation and other cellular mRNAs, such as p53, at the translational level. In this study, a comprehensive gene expression analysis at the levels of both transcriptional and post-transcriptional regulation was conducted to identify response markers using human genome array with TS-depleted human colon cancer HCT-C18 (TS- cells and HCT-C18 (TS+ cells stably transfected with the human TS cDNA expression plasmid. Results A total of 38 genes were found to be significantly affected by TS based on the expression profiles of steady state mRNA transcripts. However, based on the expression profiles of polysome associated mRNA transcripts, over 149 genes were affected by TS overexpression. This indicates that additional post-transcriptionally controlled genes can be captured with profiling polysome associated mRNA population. This unique approach provides a comprehensive overview of genes affected by TS. Additional novel post-transcriptionally regulated genes affected by 5-fluorouracil (5-FU treatment were also discovered via similar approach. Conclusion To our knowledge, this is the first time that a comprehensive gene expression profile regulated by TS and 5-FU was analyzed at the multiple steps of gene regulation. This study will provide candidate markers that can be potentially used for predicting therapeutic outcomes for fluoropyrimidine-based cancer chemotherapy.

  2. Role of genomic factors beyond thymidylate synthase in the prediction of response to 5-fluorouracil.

    Science.gov (United States)

    Peters, Godefridus J; Smid, K; Meijer, E; van Groeningen, C J; Leon, L G

    2016-12-01

    5-Fluorouracil (5FU) is still a major drug in combinations regimens for the treatment of colorectal cancer (CRC) both in the adjuvant and palliative setting. 5FU or its oral prodrug capecitabine is usually combined with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab. Although this improved the outcome, the overall prognosis in patients with metastasized disease is still relatively poor. Although the target for 5FU, thymidylate synthase was shown to have a predictive value, this could only predict response in a subset of patients. Given the heterogeneous and complex nature of CRC, it is likely that other aberrations can affect therapeutic response. As an alternative, we investigated Copy number alterations using oligonucleotide-based high-throughput array-comparative-genomic-hybridization (aCGH) to obtain an unbiased screening of the whole genetic spectrum. Chromosomal aberrations have been identified in 85% of CRC patients and include genomic regions harboring copy number alterations in the DNA. These alterations may change the expression of many genes and might explain the differential response to therapy as shown in recent studies with several 5FU combinations. In order to clarify new predictive parameters for 5FU, we used aCGH in a historical cohort of patients, which received treatment with single agent 5FU, and an unsupervised clustering analysis showed a statistical (p < 0.05) difference between responding and nonresponding patients. We also find that several regions showed differences between responders/non-responders, such as losses in 12p12.3-12q15 and in 18p (where TS is located) in responding patients. Genome-wide analysis may provide an additional tool to discriminate between responders and nonresponders.

  3. 5-fluorouracil Toxicity Mechanism Determination in Human Keratinocytes: in vitro Study on HaCaT

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    Jan Hartinger

    2018-01-01

    Full Text Available 5-fluorouracil (5-FU and capecitabine therapy is often accompanied by palmar-plantar erythrodysesthesia (PPE which is manifestation of 5-FU toxicity in keratinocytes. The main mechanisms of 5-FU action are thymidylate synthase (TS inhibition which can be abrogated by thymidine and strengthened by calciumfolinate (CF and incorporation of fluorouridinetriphosphate into RNA which can be abrogated by uridine. For proper PPE treatment 5-FU mechanism of action in keratinocytes needs to be elucidated. We used the 5-FU toxicity modulators uridine, thymidine and CF to discover the mechanism of 5-FU action in human keratinocyte cell line HaCaT. To measure the cellular viability, we used MTT test and RTCA test. CF did not augment 5-FU toxicity and 5-FU toxicity was weakened by uridine. Therefore, the primary mechanism of 5-FU toxicity in keratinocytes is 5-FU incorporation into RNA. The uridine protective effect cannot fully develop in the presence of CF. Thymidine addition to 5-FU and uridine treated cells not only prevents the toxicity-augmenting CF effect but it also prolongs the 5-FU treated cells survival in comparison to uridine only. Therefore, it can be assumed that in the presence of uridine the 5-FU toxicity mechanism is switched from RNA incorporation to TS inhibition. Although particular 5-FU toxicity mechanisms were previously described in various cell types, this is the first time when various combinations of pyrimidine nucleosides and CF were used for 5-FU toxicity mechanism elucidation in human keratinocytes. We suggest that for PPE treatment ointment containing uridine and thymidine should be further clinically tested.

  4. Thymidylate Synthase Gene Polymorphism and Survival of Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil

    Science.gov (United States)

    Sulzyc-Bielicka, Violetta; Bielicki, Dariusz; Binczak-Kuleta, Agnieszka; Kaczmarczyk, Mariusz; Pioch, Wiesława; Machoy-Mokrzynska, Anna; Ciechanowicz, Andrzej; Gołębiewska, Magdalena

    2013-01-01

    Limited studies indicate a possible association of 5′-UTR thymidylate synthase enhancer region polymorphism and treatment outcome in patients medicated with 5-fluorouracil (5-FU). The study was designed to verify the relationship in patients with colorectal cancer (CRC), a Polish population that received 5-FU-based adjuvant chemotherapy. The study analyzed 145 Astler-Coller B2 and C CRC patients. Genotyping for a variable number of tandem repeats and G to C single-nucleotide polymorphism in the 5′-UTR of the thymidylate synthase (TS) gene was carried out. TS genotypes were classified into high expression (high TS) and low expression types (low TS). High TS was found in 22.8% of patients. The right-side tumors were more frequently associated with high TS than the left-side tumors (p=0.024). High TS was only found in 9.3% of rectal tumors, but in 29.7% of colon cancers (p=0.0042). Disease-free survival after 20 months (DFS 20) was longer in subjects with low TS than in high TS (p=0.043). Patients who underwent chemotherapy had longer DFS 20 in the low TS than in the high TS subgroup (p=0.051). The low TS was found to be an independent good prognostic factor for DFS 20 in the whole group as well as in the subgroup treated with chemotherapy (p=0.024 and p=0.034, respectively). Patients with low TS did not show any differences in DFS 20 whether they were treated with adjuvant chemotherapy or not. Proximal CRC tumors are characterized by higher TS expression genotypes than distal tumors, and are at significantly greater risk of early recurrence during the first 20 months after surgery. PMID:23968134

  5. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system

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    Han Ruolan

    2008-04-01

    Full Text Available Abstract Background Cancer treatment with a variety of chemotherapeutic agents often is associated with delayed adverse neurological consequences. Despite their clinical importance, almost nothing is known about the basis for such effects. It is not even known whether the occurrence of delayed adverse effects requires exposure to multiple chemotherapeutic agents, the presence of both chemotherapeutic agents and the body's own response to cancer, prolonged damage to the blood-brain barrier, inflammation or other such changes. Nor are there any animal models that could enable the study of this important problem. Results We found that clinically relevant concentrations of 5-fluorouracil (5-FU; a widely used chemotherapeutic agent were toxic for both central nervous system (CNS progenitor cells and non-dividing oligodendrocytes in vitro and in vivo. Short-term systemic administration of 5-FU caused both acute CNS damage and a syndrome of progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology. Functional analysis also provided the first demonstration of delayed effects of chemotherapy on the latency of impulse conduction in the auditory system, offering the possibility of non-invasive analysis of myelin damage associated with cancer treatment. Conclusions Our studies demonstrate that systemic treatment with a single chemotherapeutic agent, 5-FU, is sufficient to cause a syndrome of delayed CNS damage and provide the first animal model of delayed damage to white-matter tracts of individuals treated with systemic chemotherapy. Unlike that caused by local irradiation, the degeneration caused by 5-FU treatment did not correlate with either chronic inflammation or extensive vascular damage and appears to represent a new class of delayed degenerative damage in the CNS.

  6. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora

    Energy Technology Data Exchange (ETDEWEB)

    Harris, B.; Manning, B.; Federle, T.; Diasio, R.

    1986-03-01

    5-Fluorocytosine (FC) is used to treat systemic fungal infections in man. Its clinical effectiveness has been limited by hematologic toxicity which may be secondary to the formation of 5-fluorouracil (FU). It is unclear how FU is formed since human cells lack cytosine deaminase. The present study examined if intestinal microflora (IMF) could convert FC to FU in man. An in vitro semicontinuous culture system was inoculated with human feces and maintained with sterile nutrient suspension. The microbial community was assessed for cell count and anaerobes as well as formation of volatile fatty acids and CH/sub 4/. The system approximated that believed to occur in vivo. The study was initiated with addition of purified (6-/sup 14/C)-FC. Unlabelled FC was then added to the system daily for 2 weeks following which (6-/sup 14/C)-FC was again added. Following each addition of (6-/sup 14/C)-FC, samples were removed at 2,4,8,24,48,72, and 96 hr. Utilizing HPLC, FC and FU could be separated with quantitation of radioactivity in each peak. Following the initial dose, no detectable FU was observed during the first 8 hr, but after 24 hr increasing levels were detected (9.42 ..mu..g FU/ml after 4 days). Following chronic administration of FC, increased levles of FU were noted without an 8 hr lag time in the production of FU (31.86 ..mu..g FU/ml after 4 days). In summary, these studies demonstrate that IMF can convert FC to FU possibly accounting for toxicity observed following administration of FC.

  7. Reduction of Orc6 expression sensitizes human colon cancer cells to 5-fluorouracil and cisplatin.

    Directory of Open Access Journals (Sweden)

    Elaine J Gavin

    Full Text Available Previous studies from our group have shown that the expression levels of Orc6 were highly elevated in colorectal cancer patient specimens and the induction of Orc6 was associated with 5-fluorouracil (5-FU treatment. The goal of this study was to investigate the molecular and cellular impact of Orc6 in colon cancer. In this study, we use HCT116 (wt-p53 and HCT116 (null-p53 colon cancer cell lines as a model system to investigate the impact of Orc6 on cell proliferation, chemosensitivity and pathways involved with Orc6. We demonstrated that the down regulation of Orc6 sensitizes colon cancer cells to both 5-FU and cisplatin (cis-pt treatment. Decreased Orc6 expression in HCT-116 (wt-p53 cells by RNA interference triggered cell cycle arrest at G1 phase. Prolonged inhibition of Orc6 expression resulted in multinucleated cells in HCT-116 (wt-p53 cell line. Western immunoblot analysis showed that down regulation of Orc6 induced p21 expression in HCT-116 (wt-p53 cells. The induction of p21 was mediated by increased level of phosphorylated p53 at ser-15. By contrast, there is no elevated expression of p21 in HCT-116 (null-p53 cells. Orc6 down regulation also increased the expression of DNA damaging repair protein GADD45beta and reduced the expression level of JNK1. Orc6 may be a potential novel target for future anti cancer therapeutic development in colon cancer.

  8. Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis

    Directory of Open Access Journals (Sweden)

    Hong-Li Li

    2017-10-01

    Full Text Available Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1, intercellular adhesion molecule-1 (ICAM-1, and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1 and junctional adhesion molecule-A (JAM-A were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-κB and mitogen activated protein kinase (MAPKs in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal

  9. Use of Zeolite ZSM-5 for Loading and Release of 5-Fluorouracil

    Directory of Open Access Journals (Sweden)

    Ruba A. Al-Thawabeia

    2015-01-01

    Full Text Available Samples of zeolite ZSM-5 have been synthesized in both the sodium form (ZSM-5 and the acid activated form (H-ZSM-5. In addition, each of these two forms was prepared in the two molar SiO2/Al2O3 ratios of 169 and 15. All samples of these ZSM-5 derivatives were characterized by X-ray diffraction (XRD, nitrogen adsorption-desorption isotherms, thermal gravimetric analysis (TGA, X-ray fluorescence (XRF, and scanning electron microscopy (SEM. The samples were successfully loaded with the anticancer drug 5-fluorouracil (5-FU with loading capacities varying from 22% (for the sodium form having the lower molar SiO2/Al2O3 ratio of 15, ZSM-5-(15 to 43% (for the corresponding acid form, H-ZSM-5-(15. Percent release of the drug-loaded ZSM-5 samples into simulated body fluid (SBF was measured at pH 7.4 and 37°C. The results showed a slight variation in the % release within the range 84–93%, while the first-order rate constant (k varied from 2.2 h−1 for ZSM-5-(15 to 3.9 h−1 for H-ZSM-5-(15. It was interesting to note that at the higher molar SiO2/Al2O3 ratios of 169, both the sodium form, ZSM-5-(169, and the acid form, H-ZSM-5-(169, exhibit an intermediate efficiency in either % loading (38% or first-order kinetic release constant (k = 2.9 h−1.

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Development of In Situ Gelling and Bio Adhesive 5-Fluorouracil Enema

    Science.gov (United States)

    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

  12. The influence of 5-fluorouracil anticancer drug on the DNA base pairs; A quantum chemical study.

    Science.gov (United States)

    Nakhaei, Ebrahim; Nowroozi, Alireza; Ravari, Fateme

    2018-01-03

    In the present study, various hydrogen bonded complexes between 5-fluorouracil (FU) with AT and GC base pairs were studied. First, to determine the affinity of different sites of the parent structures (FU, AT, and GC) for the hydrogen bond formation, their molecular electrostatic potentials (MEP) are explored. The complexation energies and the strength of individual HBs of the plausible complexes were evaluated by energetic, geometric, spectroscopic, topologic and molecular orbital descriptors. Our results reveal that, the FU-GC complexes (34.76-44.42 kcal mol-1) are more stable than the FU-AT ones (21.00-30.35 kcal mol-1). Among the complexes, the FU3-AT1 and FU3-GC3 are the most stable structures in the both series, which can be related to the sites with the highest affinity. Second, a detail analysis of the hydrogen bond descriptors were performed to elucidate the effect of FU on the strength of HB interactions within the base pairs. Interestingly, due to the formation of various interactions between the active sites of basic molecules, the strength of HB within the base pairs in the most cases increase about +2.75 and +0.57 kcal mol-1 for the GC and AT nucleobases, respectively. Finally, several aromatic indices (HOMA, FLU, NICS (0) and NICS (1)) were applied to evaluate the significance of π-electron delocalization (π-ED) of 5/6 membered rings. These results clearly show that the π-ED of the benchmark systems increase with the formation or strengthening of the HB, which is in line with the resonance assisted hydrogen bond theory.

  13. Pharmacokinetic properties and antitumor efficacy of the 5-fluorouracil loaded PEG-hydrogel

    Directory of Open Access Journals (Sweden)

    Kim Bokyung

    2010-05-01

    Full Text Available Abstract Background We have studied the in vitro and in vivo utility of polyethylene glycol (PEG-hydrogels for the development of an anticancer drug 5-fluorouracil (5-FU delivery system. Methods A 5-FU-loaded PEG-hydrogel was implanted subcutaneously to evaluate the drug retention time and the anticancer effect. For the pharmacokinetic study, two groups of male rats were administered either an aqueous solution of 5-FU (control group/or a 5-FU-loaded PEG-hydrogel (treated group at a dose of 100 mg/kg. For the pharmacodynamic study, a human non-small-cell lung adenocarcinoma (NSCLC cell line, A549 was inoculated to male nude mice with a cell density of 3 × 106. Once tumors start growing, the mice were injected with 5-FU/or 5-FU-loaded PEG-hydrogel once a week for 4 weeks. The growth of the tumors was monitored by measuring the tumor volume and calculating the tumor inhibition rate (IR over the duration of the study. Results In the pharmacokinetic study, the 5-FU-loaded PEG-hydrogel gave a mean residence time (MRT of 8.0 h and the elimination half-life of 0.9 h; these values were 14- and 6-fold, respectively, longer than those for the free solution of 5-FU (p Conclusion We suggest that 5-FU-loaded PEG-hydrogels could provide a useful tool for the development of an anticancer drug delivery system.

  14. Degradation of the cytostatic 5-Fluorouracil in water by Fenton and photo-assisted oxidation processes.

    Science.gov (United States)

    Governo, Mariana; Santos, Mónica S F; Alves, Arminda; Madeira, Luís M

    2017-01-01

    Cytostatics are part of the forefront research topics due to their high prescription, high toxicity, and the lack of effective solutions to stop their entrance and spread in the environment. Among them, 5-Fluorouracil (5-Fu) has received particular attention because is one of the most prescribed active substances in chemotherapy worldwide. The degradation of 5-Fu by advanced oxidation processes (AOPs) is a poorly addressed topic, and this work brings valuable inputs concerning this matter. Herein, the efficacy of Fenton's process in the degradation of 5-Fu is explored for the first time; the study of the main variables and its successful application to the treatment of real wastewaters is demonstrated. Moreover, hydrogen peroxide-based and photo-assisted techniques (direct photolysis, photodegradation with H2O2 and photo-Fenton) are also investigated for purposes of comparison. Under the best operation conditions obtained (T = 30 °C, [Fe2+]0 = 0.5 mM; [H2O2]0 = 240 mM and pH = 3 for [5-Fu]0 = 0.38 mM), 5-Fu was completely eliminated after 2 h of Fenton's reaction and about 50 % of mineralization was reached after 8 h. The best performance was obtained by the photo-Fenton process, with 5-Fu mineralization level as high as 67 %, using an iron dose within the legal limits required for direct water discharge. Toxicity (towards Vibrio fischeri) of the effluents that resulted from the application of the above-mentioned AOPs was also evaluated; it was found that the degradation products generated from the photo-assisted processes are less toxic than the parent compound, putting into evidence the relevance of such technologies for degradation of cytostatics like 5-Fu.

  15. Oral signs of intravenous chemotherapy with 5-Fluorouracil and Leucovorin calcium in colon cancer treatment.

    Science.gov (United States)

    Mazzeo, Marcelo A; Linares, Jorge A; Campos, Maria L; Busamia, Beatriz E; Dubersarsky, Claudio; Lavarda, Marcelo; Jarchum, Gustavo; Finkelberg, Ana B

    2009-03-01

    Several studies have shown how cytostatics may cause hypofunction of salivary glands but failed to elucidate any potentially related side effects. Keeping in mind the sialochemical assistance and the role of saliva on the homeostasis of the stomatognathic system, the aim of this study was to establish potential gland disorders in patients submitted to 5- Fluorouracil (5-Fu) and Leucovorin calcium (LV) as well as their correlation with certain oral health disorders that diminish the quality of life. the focus of this research was observational and longitudinal. Twenty-five patients diagnosed with colon cancer at an initial, intermediate and late phase submitted to specifically devised therapy were assessed. Clinical history, oral health indexes and basal or stimulated saliva samples were recorded. Basal and stimulated flow dropped in the intermediate stage. Stimulated saliva pH decreased during treatment. On basal saliva, urea, sodium and potassium rose during the intermediate phase. Löe and Silness rates as well as simplified bleeding increased during therapy but reverted by the end of the treatment. Depth index of the vestibular gingival sulcus rose during the intermediate phase but did not return. This treatment caused functional salivary gland disorders as evidenced by basal and stimulated hyposialia, and acidification of stimulated saliva pH during the intermediate phase. Increase in basal urea may be due to proteic catabolism arising from plasma or glands. Variation in Na+ and K+ of basal saliva concentrates might be assumed as a possible duct disorder. Recovery of bleeding and Löe and Silness rates may point to a transient inflammatory effect associated to a decrease in salivary flow. Increase in the depth rates of the periodontal vestibular sulcus could be correlated with a higher risk of periodontal disease.

  16. Effect of electromagnetic fields and early postoperative 5-fluorouracil on the healing of colonic anastomoses.

    Science.gov (United States)

    Nayci, Ali; Cakmak, Murat; Renda, Nurten; Aksoyek, Selim; Yucesan, Selcuk

    2003-03-01

    Studies have indicated a deleterious effect of perioperative 5-fluorouracil (5-FU) administration on the healing of intestinal anastomoses. This study examined the effect of early postoperative 5-FU on the healing of colonic anastomoses and investigated the effect of electromagnetic fields (EMF) on colonic anastomotic repair under normal physiological conditions and in the presence of 5-FU therapy in a rat model. Forty male Wistar rats were randomly assigned into four groups and underwent a standardized left colonic resection and anastomoses. The animals then served as control or received intraperitoneal 5-FU (20 mg/kg per day, 5 days), EMF stimulation (10.76 mT, 50 Hz; 2-h on/10-h off cycles, 7 days) or both, starting on the day of surgery. After 7 days anastomotic healing was assessed by measurement of hydroxyproline content and breaking strength. Hydroxyproline content increased in EMF exposed group (1.53+/-0.11 to 1.92+/-0.11 microg/mg) and in EMF + 5-FU group (1.53+/-0.11 to 1.89+/-0.12 microg/mg). Breaking strength also increased in the EMF group (0.23+/-0.02 to 0.27+/-0.01 MPa) and in the EMF + 5-FU group (0.23+/-0.02 to 0.28+/-0.01 MPa. No differences were found in hydroxyproline content or breaking strength between the 5-FU group and controls. Early postoperative 5-FU administration did not impair the healing of colonic anastomoses in rats. Additionally, EMF stimulation provided a significant gain in colonic anastomotic strength, in rat intestines in control animals and in animals exposed to 5-FU.

  17. [Treatment results for different categories of vaginal intraepithelial neoplasia with electrocoagulation, 5-fluorouracil and combined treatment].

    Science.gov (United States)

    Veloz-Martínez, María Guadalupe; Quintana-Romero, Verónica; Contreras-Morales, María del Rosario Sandra; Jiménez-Vieyra, Carlos Ramón

    2015-10-01

    Vaginal intraepithelial neoplasia (VAIN) represents a variety of changes that initiate as an intraepithelial squamous lesion with the possibility of resulting in cancer. To compare the results of the treatment for the different categories of VAIN with electrocoagulation, 5-fluorouracil and combined treatment. Observational an analytical study. We stablished groups according to the category of VAIN evaluating and comparing remission, persistence, recurrence, or progression of the disease ac- cording to the received treatment, with a 1-year follow up. The results were compared by chi2 and Kruskal Wallis. The statistics analysis was done with the SPSS program version 20. One hundred thirty seven patients between 20 and 81 years of age (mean age: 52.49 years) were included. Seventy-four percent of the patients had a history of premalignant or malignant cervical lesions. Seventy-four patients had VAIN I, 34 patients had VAIN II, 22 patients had VAIN III and there were seven cases of vaginal carcinoma in situ. Fifty-eight patients were treated with electrocoagulation, 55 patients were treated with 5-FU, 16 patients had combined treatment, and eight patients received expectant management. Sixty three percent of patients had total remission of the lesion, 34% had persistence and 3% showed progression, and there were no cases of recurrence. Results were better in patients with VAIN I treated with 5-FU (bigger percentage of remission P .026), for the remaining categories of VAIN, no treatment showed superior results. The superior response occurs in patients with VAIN I treated with 5-FU. None of the treatments achieves a 100% remission. The VAIN frequency is high, patients with a history of malignant or premalignant cervical pathology should undergo a closer surveillance through cytocolposcopic control with respect to the remaining population.

  18. A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging.

    Science.gov (United States)

    Hoover, Andrew J; Lazari, Mark; Ren, Hong; Narayanam, Maruthi Kumar; Murphy, Jennifer M; van Dam, R Michael; Hooker, Jacob M; Ritter, Tobias

    2016-04-11

    Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination.

  19. A phase I study of a combination of allopurinol, 5-fluorouracil and leucovorin followed by hydroxyurea in patients with advanced gastrointestinal and breast cancer.

    Science.gov (United States)

    Bhalla, K; Birkhofer, M; Bhalla, M; Lutzky, J; Hindenburg, A; Cole, J; Ince, C

    1991-12-01

    Twenty patients with advanced carcinomas of the colorectum, pancreas, stomach, and breast were enrolled in a Phase I study of a sequential administration of 5-fluorouracil-leucovorin (FU-LV) combination followed by hydroxyurea (HU) with allopurinol protection (HALF regimen). As a weekly regimen for 6 weeks, followed by a rest period of 2 weeks, FU was administered intravenously (i.v.) during infusion of a 2-hour i.v. infusion of LV at a dose of 500 mg/m2. Six hours following the FU-LV combination, HU (1 gm/m2) was administered orally. Allopurinol (300 mg every 8 hours, orally) was given the day before and on the day of the administration of the FU-LV combination. The starting dose of FU was 300 mg/m2, with escalations to 900 mg/m2. Mucositis, diarrhea, and hematologic toxicities were mild and sporadic with FU doses up to 750 mg/m2 and occurred in patients who had received prior treatment with FU and/or radiotherapy. Dose-limiting neurocerebellar toxicity was observed in 2 out of 6 patients who received a FU dose of 900 mg/m2. Three additional patients experienced moderate neuromotor toxicity at this dose level. Among 17 patients evaluable for response, partial responses were seen in 3 of the 9 patients with colorectal cancer, 1 of the 3 patients each with carcinoma of breast and pancreas. Three of the 5 responses occurred in patients who had received prior treatment with FU and/or radiation therapy. An FU dose of 750 mg/m2 is recommended for a Phase II trial of the HALF regimen.

  20. Comparison of cisplatinum/paclitaxel with cisplatinum/5-fluorouracil as first-line therapy for nonsurgical locally advanced esophageal squamous cell carcinoma patients

    National Research Council Canada - National Science Library

    Hu GF; Wang ZH; Wang Y; Zhang QQ; Tang N; Guo J; Liu LY; Han X

    2016-01-01

    ...: To retrospectively evaluate the efficacy and toxicity of definitive concurrent chemoradiotherapy (dCRT) with cisplatinum/paclitaxel versus cisplatinum/5-fluorouracil in patients with locally advanced esophageal squamous cell carcinoma...

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

    Energy Technology Data Exchange (ETDEWEB)

    Araújo, C.V. [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Lazzarotto, C.R. [Laboratório de Biologia Molecular e do Desenvolvimento, Universidade de Fortaleza, Fortaleza, CE (Brazil); Aquino, C.C.; Figueiredo, I.L.; Costa, T.B.; Oliveira Alves, L.A. de [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Ribeiro, R.A. [Laboratório da Inflamação e Câncer, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Bertolini, L.R. [Laboratório de Biologia Molecular e do Desenvolvimento, Universidade de Fortaleza, Fortaleza, CE (Brazil); Lima, A.A.M. [Laboratório de Doenças Infecciosas, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Brito, G.A.C. [Laboratório da Inflamação e Câncer, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Oriá, R.B. [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil)

    2015-04-28

    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{sup -/-}) and wild-type (APOE{sup +/+}) 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{sup -/-} 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{sup +/+} mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE{sup -/-}-challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU

  2. Pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for erythropenia in rats.

    Science.gov (United States)

    Kobuchi, Shinji; Ito, Yukako; Hayakawa, Taro; Nishimura, Asako; Shibata, Nobuhito; Takada, Kanji; Sakaeda, Toshiyuki

    2014-01-01

    The aim of the present study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model in rats that could predict the onset and degree of erythropenia, a severely toxic side effect that severely limits the use of the anticancer agent 5-fluorouracil (5-FU). Total erythrocyte counts, hemoglobin (Hb) concentrations, and hematocrit (Hct) levels were measured in rats following the intravenous bolus administration of 5-FU for 4 days in order to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with two compartments for the PD model and nine structural PK-PD model parameters. After the intravenous bolus administration of 5, 10, or 20 mg/kg of 5-FU to rats, absolute erythrocyte counts, Hb concentrations, and Hct levels transiently decreased, reached minimum levels on Days 7-14, and then returned to baseline levels. The nadir values (Cnadir) for rats treated with 5, 10, or 20 mg/kg of 5-FU were significantly decreased to approximately 79.4, 76.3, or 46.5% of the baseline value (Cbaseline) in erythrocyte counts, 86.3, 83.3, or 45.7% of Cbaseline in Hb concentrations, 88.6, 85.5, or 47.1% of Cbaseline in Hct levels, respectively. The PK-PD model effectively captured the features of erythropenia and Cnadir after 5-FU chemotherapy. This PK-PD model was successfully used to characterize the learner relationship between the area under the plasma 5-FU concentration-time curve (AUC0-∞) following the intravenous bolus administration of 5-FU and the Cnadir in erythrocyte counts, Hb concentrations, and Hct levels after the 5-FU treatment. The results of the present study suggest that the administration of a pharmacokinetically modified dose of 5-FU could minimize the Cnadir in erythrocyte counts, Hb concentrations, and Hct levels following the administration of 5-FU. The PK-PD model and simulation represent valuable approaches for quantifying and predicting erythropenia as well as determining individual doses and the

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

    Directory of Open Access Journals (Sweden)

    C.V. Araújo

    2015-06-01

    Full Text Available 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.

  4. Experimental cystic echinococcosis therapy: In vitro and in vivo combined 5-fluorouracil/albendazole treatment.

    Science.gov (United States)

    Pensel, Patricia E; Elissondo, Natalia; Gambino, Guillermo; Gamboa, Gabriela Ullio; Benoit, J P; Elissondo, María C

    2017-10-15

    Human cystic echinococcosis is a zoonosis caused by the larval stage of the tapeworm Echinococcus granulosus sensu lato (s. l.). Although benzimidazole compounds such as albendazole (ABZ) and mebendazole have been the cornerstone of chemotherapy for the disease, there is often no complete recovery after treatment. Hence, new strategies are required to improve treatment of human cystic echinococcosis. The goals of the current study were as follows: (i) to evaluate the in vitro efficacy of the 5-fluorouracil (5-FU) and ABZ combination against E. granulosus s. l. protoscoleces and cysts, (ii) to compare the clinical efficacy of 5-FU alone or in combination with ABZ in infected mice. The combination of 5-FU+ABZ had a stronger in vitro effect against larval stage than that did both drugs alone. Even at the lowest concentration of 5-FU+ABZ combination (1μg/ml), the reduction of the viability of protoscoleces and cysts was greater than that observed with drugs alone at 10μg/ml. The results were confirmed at the ultrastructural level by scanning electron microscopy. These data helped to justify the in vivo investigations assessing the therapeutic potential of the combination of 5-FU and ABZ suspension in CF-1 mice infected with E. granulosus sensu stricto (s. s.) metacestodes. Treatment with 5-FU (10mg/kg) or 5-FU (10mg/kg) + ABZ suspension (5mg/kg) reduced the weight of cysts recovered from mice compared with control groups. Interestingly, the effect of 5-FU given weekly for 5 consecutive weeks was comparable to that observed with ABZ suspension under a daily schedule during 30days. Co-administration of 5-FU with ABZ did not enhance the in vivo efficacy of drugs alone calculated in relation to cysts weights. However, the combination provoked greater ultrastructural alterations compared to the monotherapy. In conclusion, we demonstrated the efficacy of 5-FU either alone or co-administrated with ABZ against murine experimental cystic echinococcosis. Since 5-FU treatments

  5. The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma.

    Science.gov (United States)

    Feng, Xiaodong; Luo, Qingqiong; Zhang, Han; Wang, Han; Chen, Wantao; Meng, Guangxun; Chen, Fuxiang

    2017-06-21

    5-Fluorouracil (5-FU) is a widely used drug for the therapy of cancer. However, the chemoresistance of tumor cells to 5-FU usually limits its clinical effectiveness. In this study, we explored the role of NLRP3 inflammasome in 5-FU resistance of oral squamous cell carcinoma (OSCC). The mRNA and protein expression levels of NLRP3, Caspase1 and IL-1β in resected OSCC specimens or cell lines were measured respectively by quantitative real time-PCR (qRT-PCR) and western blot. NLRP3 and Ki-67 expression in paraffin-embedded OSCC tissues was determined by immunohistochemistry. The correlation between 5-FU treatment and the expression and activation of NLRP3 inflammasome was further examined by evaluating NLRP3 and IL-1β expression in OSCC cell lines without or with NLRP3 knocked down. Cell viabilities of OSCC cells were determined by the MTT assay. Apoptosis and intracellular reactive oxygen species (ROS) of OSCC cells induced by 5-FU were measured by the flow cytometer. The carcinogen-induced tongue squamous carcinoma mice model was established by continuous oral administration of 4-nitroquinoline 1-oxide in wild-type BALB/c, Nlrp3 -/- and Caspase1 -/- mice. Tumor incidence were observed and tumor area were evaluated. In the clinical analysis, expression and activation of NLRP3 inflammasome was clearly increased in OSCC tissues of patients who received 5-FU-based chemotherapy. Multivariate Cox regression analysis revealed that this high expression was significantly correlated with tumor stage and differentiation, and was associated with poor prognosis. Moreover, 5-FU treatment increased expression and activation of NLRP3 inflammasome in OSCC cells in a cell culture system and xenograft mouse model. Silencing of NLRP3 expression significantly inhibited OSCC cell proliferation and enhanced 5-FU-induced apoptosis of OSCC cells. Further investigation showed that intracellular ROS induced by 5-FU promoted the expression and activation of NLRP3 inflammasome and increased

  6. Cellular cardiomyoplasty into infracted swine's hearts by retrograde infusion through the venous coronary sinus: An experimental study

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    Prifti, Edvin, E-mail: edvinprifti@hotmail.com [Division of Cardiac Surgery, University Hospital Center of Tirana (Albania); Di Lascio, Gabriella [Anesthesiology and Intensive Care Section, Department of Health Sciences, University of Florence, Florence (Italy); Harmelin, Guy [Cardiac Surgery, Department of Experimental and Clinical Medicine, University of Florence, Florence (Italy); Bani, Daniele [Research Unit of Histology & Embryology, Departments of Clinical & Experimental Medicine, University of Florence, Florence (Italy); Briganti, Vittorio [Unit of Nuclear Medicine, Careggi Hospital, Florence (Italy); Veshti, Altin [Division of Cardiac Surgery, University Hospital Center of Tirana (Albania); Bonacchi, Massimo [Cardiac Surgery, Department of Experimental and Clinical Medicine, University of Florence, Florence (Italy)

    2016-06-15

    Objectives: The aim was to create a model of myocardial infarction with a borderline myocardial impairment which would enable evaluation of the retrograde cellular cardiomyoplasty through the venous coronary sinus in a large animal model. Materials and methods: Fifteen (study group) and 10 juvenile farm pigs (control group) underwent distal left anterior descending artery ligation. One month later the study group animals underwent sternotomy and a murine myoblastic line C2-C12 was injected at a constant pressure of 30 mmHg, into the coronary sinus. Thirty days later all animals that survived from both groups underwent transthoracic echocardiography and 99Tc scintigraphy and were later euthanized and specimens were taken for microscopic evaluation. Results: Cardiac output decreased significantly after ligation (p < 0.001) and increased significantly after cardiomyoplasty (p < 0.001). In all animals, the surgical induction of myocardial infarction caused a marked decline in the echocardiographic values of cardiac function; however, the cardiac function and dimensions were significantly improved in the study group after cardiomyoplasty versus the control group. All animals undergoing cardiomyoplasty demonstrated a significant reduction of the perfusion deficit in the left anterior descending artery territory, instead such data remained unchanged in the control group. The histological examination demonstrated the engrafted myoblasts could be distinguished from the activated fibroblasts in the scar tissue because they never showed any signs of collagen secretion and fiber buildup. Conclusions: In conclusion, the venous retrograde delivery route through the coronary sinus is safe and effective, providing a significant improvement in function and viability.

  7. N-Alkynyl Derivatives of 5-Fluorouracil: Susceptibility to Palladium-Mediated Dealkylation and Toxigenicity in Cancer Cell Culture

    Directory of Open Access Journals (Sweden)

    Jason T Weiss

    2014-07-01

    Full Text Available Palladium-activated prodrug therapy is an experimental therapeutic approach that relies on the unique chemical properties and biocompatibility of heterogeneous palladium catalysis to enable the spatially-controlled in vivo conversion of a biochemically-stable prodrug into its active form. This strategy, which would allow inducing local activation of systemically administered drug precursors by mediation of an implantable activating device made of Pd(0, has been proposed by our group as a way to reduce drug’s systemic toxicity while reaching therapeutic levels of the active drug in the affected tissue / organ. In the seminal study of such an approach, we reported that propargylation of the N1 position of 5-fluorouracil suppressed the drug’s cytotoxic properties, showed high stability in cell culture and facilitated the bioorthogonal restoration of the drug’s pharmacological activity in the presence of extracellular Pd(0-functionalized resins. To provide additional insight on the properties of this system, we have investigated different N1-alkynyl derivatives of 5-fluorouracil and shown that the presence of substituents near the triple bond influence negatively on its sensitivity to palladium catalysis under biocompatible conditions. Comparative studies of the N1- versus the N3-propargyl derivatives of 5-fluorouracil revealed that masking each or both positions equally led to inactive derivatives (>200-fold reduction of cytotoxicity relative to the unmodified drug, whereas the depropargylation process occurred faster at the N1 position than at the N3, thus resulting in greater toxigenic properties in cancer cell culture.

  8. Needle revision of failed filtering blebs using 5-Fluorouracil and a combined ab-externo and ab-interno approach.

    Science.gov (United States)

    Pasternack, James J; Wand, Martin; Shields, M Bruce; Abraham, Deepa

    2005-02-01

    To evaluate a surgical technique to revise a failed filtering bleb using subconjunctival 5-Fluorouracil with a combined ab-externo and ab-interno approach. This study is a retrospective review of the outcome of 77 consecutive bleb revisions, with greater than 6-month follow-up, performed by a single glaucoma surgeon (MW). All eyes had previously functioning filtering blebs with currently inadequately controlled intraocular pressures (IOP) prior to the bleb revisions. All surgery was performed in the operating room, using a retrobulbar injection and a microscope. Visco-elastic was injected into the anterior chamber. 5-Fluorouracil (0.1 mL; 50 mg/ml) was infiltrated around the bleb. A 30-gauge needle was used to lyse subconjunctival fibrosis and episcleral scar tissue binding down the scleral flap, and elevate the scleral flap. Through an inferior paracentesis, a cyclodialysis spatula was used to confirm and enlarge the communication with the subconjunctival space. The main outcome measurements were IOP and number of glaucoma medications. A successful outcome was defined as a 20% reduction from baseline IOP and a maximum IOP of 18 mm Hg, with or without medications, and a minimal follow-up of 6 months. 52% of patients achieved success after one revision with an average follow-up of 29.6 +/- 14.4 months. In successful cases, the mean IOP decreased from 22.7 +/- 4.5 mm Hg to 11.3 +/- 3.5 mm Hg and medications were reduced from an average of 2.2 +/- 1.1 to 0.4 +/- 0.7. Kaplan-Meier survival analysis calculated a success of 77% at 1 year, 68% at 2 years, and 58% at 3 years. In failed filtering blebs, needle revision with 5-Fluorouracil and a combined ab-externo and ab-interno approach results in high success and low complication rates. The outcome of this procedure compares favorably with previously reported revision techniques.

  9. Spectroscopic and calorimetric studies on the interaction between PAMAM G4-OH and 5-fluorouracil in aqueous solutions

    Science.gov (United States)

    Buczkowski, Adam; Urbaniak, Pawel; Piekarski, Henryk; Palecz, Bartlomiej

    2017-01-01

    The results of spectroscopic measurements (an increase in solubility, equilibrium dialysis, 1H NMR titration) and calorimetric measurements (isothermal titration ITC) indicate spontaneous (ΔG terminal hydroxyl groups in an aqueous solution. PAMAM G4-OH dendrimer bonds about n = 8 ± 1 molecules of the drug with an equilibrium constant of K = 70 ± 10. The process of saturating the dendrimer active sites by the drug molecules is exothermal (ΔH 0). The parameters of binding 5-fluorouracil by PAMAM G4-OH dendrimer were compared with those of binding this drug by the macromolecules of PAMAM G3-OH and G5-OH.

  10. Ocular surface squamous neoplasia in HIV-positive and HIV-negative patients and response to 5-fluorouracil in Angola

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    Nutt RJ

    2014-12-01

    Full Text Available Robert J Nutt,1 John L Clements,2 William H Dean3 1Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK; 2Boa Vista Eye Clinic, Benguela, Angola; 3Bristol Eye Hospital, Bristol, UK Background: Ocular surface squamous neoplasia (OSSN is becoming increasingly prevalent and aggressive in Sub-Saharan Africa. It is a phenomenon linked with human immunodeficiency virus (HIV infection, although association rates in Angola are currently unknown. A topical treatment that is effective in HIV-positive and HIV-negative individuals may be preferable to surgery in some contexts. We aimed to estimate the proportion of OSSN associated with HIV in Angola and to report on the success of topical 5-fluorouracil as a primary treatment in HIV-positive and HIV-negative patients.Methods: Photographs of OSSNs taken at presentation and following treatment with 5-fluorouracil in patients presenting to Boa Vista Eye Clinic, Angola, between October 2011 and July 2013 were grouped into HIV-positive and HIV-negative groups and analyzed to compare presenting features and treatment response. Eighty-one OSSNs were analyzed for clinical features and 24 met the inclusion criteria for analysis of treatment response.Results: Eighty-two patients presented with OSSN between October 2011 and July 2013. Twenty-one (26% were HIV-positive and typically had OSSNs that exhibited more pathological features than those in HIV-negative patients. Twenty-four (29% patients met the inclusion criteria for analysis of treatment response; of these, 26 (91% OSSNs in both groups displayed at least partial resolution after one treatment course. In the HIV-positive group, five of eight patients displayed complete resolution, two showed partial resolution, and one failed. In the HIV-negative group, five of 16 showed complete resolution, ten of 16 had partial resolution, and one failed.Conclusion: Individuals presenting with OSSN in Angola are more likely to have HIV infection compared

  11. Front-line Bevacizumab in combination with Oxaliplatin, Leucovorin and 5-Fluorouracil (FOLFOX in patients with metastatic colorectal cancer: a multicenter phase II study

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    Touroutoglou Nikolaos

    2007-05-01

    Full Text Available Abstract Purpose To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC. Patients and Methods Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d1, oxaliplatin (85 mg/m2 on d1, leucovorin (200 mg/m2 on days 1 and 2 and 5-Fluorouracil (400 mg/m2 as i.v. bolus and 600 mg/m2 as 22 h i.v. continuous infusion on days 1 and 2 every 2 weeks. Results Fifty three patients (46 with a PS 0–1 were enrolled. Complete and partial response was achieved in eight (15.1% and 28 (52.8% patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%–92%; 11 (20.7% patients had stable disease and six (11.3% progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15% patients underwent metastasectomy with R0 resections. Grade 3–4 neutropenia occurred in 15.1% of patients and one (1.9% of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6% and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9% patient presented pulmonary embolism and one (1.9% cardiac ischaemia. There was one (1.9% sudden death after the first cycle. Conclusion The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.

  12. Impact of Gemcitabine Chemotherapy and 3-Dimensional Conformal Radiation Therapy/5-Fluorouracil on Quality of Life of Patients Managed for Pancreatic Cancer

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    Short, Michala [Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales (Australia); Western Australia Centre for Cancer and Palliative Care/Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia (Australia); Goldstein, David [Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales (Australia); Halkett, Georgia [Western Australia Centre for Cancer and Palliative Care/Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia (Australia); Reece, William [Covance Asia Pacific, Sydney, New South Wales (Australia); Borg, Martin [Adelaide Radiotherapy Centre, Adelaide, South Australia (Australia); Zissiadis, Yvonne [Department of Radiation Oncology, Royal Perth Hospital, Perth, Western Australia (Australia); Kneebone, Andrew [Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales (Australia); Spry, Nigel, E-mail: Nigel.Spry@health.wa.gov.au [Department of Radiation Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia (Australia); Faculty of Medicine, University of Western Australia, Perth, Western Australia (Australia)

    2013-01-01

    Purpose: To report quality of life (QOL) results for patients receiving chemoradiation therapy for pancreatic cancer. Methods and Materials: Eligible patients (n=41 locally advanced, n=22 postsurgery) entered the B9E-AY-S168 study and received 1 cycle of induction gemcitabine (1000 mg/m{sup 2} weekly Multiplication-Sign 3 with 1-week break) followed by 3-dimensional conformal radiation therapy (RT) (54 Gy locally advanced and 45 Gy postsurgery) and concomitant continuous-infusion 5-fluorouracil (5FU) (200 mg/m{sup 2}/d throughout RT). After 4 weeks, patients received an additional 3 cycles of consolidation gemcitabine chemotherapy. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PAN26 questionnaires at baseline, before RT/5FU, at end of RT/5FU, before consolidation gemcitabine, and at treatment completion. Results: The patterns of change in global QOL scores differed between groups. In the locally advanced group global QOL scores were +13, +8, +3, and +1 compared with baseline before RT/5FU (P=.008), at end of RT/5FU, before consolidation gemcitabine, and at treatment completion, respectively. In the postsurgery group, global QOL scores were -3, +4, +15, and +17 compared with baseline at the same time points, with a significant improvement in global QOL before consolidation gemcitabine (P=.03). No significant declines in global QOL were reported by either cohort. Conclusions: This study demonstrates that global QOL and associated function and symptom profiles for pancreatic chemoradiation therapy differ between locally advanced and postsurgery patients, likely owing to differences in underlying disease status. For both groups, the treatment protocol was well tolerated and did not have a negative impact on patients' global QOL.

  13. Combination treatment of renal cell carcinoma with belinostat and 5-fluorouracil: a role for oxidative stress induced DNA damage and HSP90 regulated thymidine synthase.

    Science.gov (United States)

    Kim, Mi Joung; Lee, Jee Suk; Park, Sang Eun; Yi, Hye-Jin; Jeong, In Gab; Kang, Jong Soon; Yun, Jieun; Lee, Joo-Yong; Ro, Seonggu; Lee, Jung Shin; Choi, Eun Kyung; Hwang, Jung Jin; Kim, Choung-Soo

    2015-05-01

    Despite several therapeutic options renal cell carcinoma is associated with a poor clinical outcome. Therefore, we investigated whether combining 5-fluorouracil with the histone deacetylase inhibitor belinostat would exert a synergistic effect on renal cell carcinoma cells in vitro and in vivo. We used SN12C cells treated with 5-fluorouracil and/or belinostat in vitro and in xenograft experiments in vivo. Cell viability and death mechanisms were assessed by MTS assay and Western blot. To investigate the role of reactive oxygen species we used H2DCF-DA, reactive oxygen species scavengers and the roGFP2 construct. Belinostat potentiated the anticancer effect of 5-fluorouracil. It synergistically induced apoptosis by activating caspases and increasing the subG1 cell population. Effects on reactive oxygen species mediated DNA damage included decreased thioredoxin expression and increased levels of TBP-2, γ-H2AX and Ac-H3. Furthermore, belinostat attenuated the 5-fluorouracil mediated induction of thymidylate synthase via HSP90 hyperacetylation. Co-administration of 5-fluorouracil with belinostat similarly reduced tumor volume and weight, and increased γ-H2AX and Ac-H3 levels in the SN12C xenograft model. In combination with 5-fluorouracil the targeted inhibitor of histone deacetylase synergistically inhibited renal cancer cell growth by the blockade of thymidylate synthase induction and the induction of reactive oxygen species mediated DNA damage in vitro and in vivo. Our results suggest that combined treatment with belinostat and 5-fluorouracil may represent a promising new approach to renal cancer. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  14. [Assessment of the value of PEF (cisplatin, epirubicin, 5 fluorouracil) in advanced extrahepatic biliary tract and pancreatic cancer].

    Science.gov (United States)

    Zygulska, Aneta L; Pawlega, Janusz

    2008-01-01

    Extrahepatic biliary tract and pancreatic cancer are relatively rare malignant tumors. Prognosis is usually poor and surgical treatment gives a chance of cure in nonadvanced cases only. Evaluation of efficacy and toxicity of PEF regimen (cisplatin + epirubicin + 5 fluorouracil) in advanced extrahepatic biliary tract and pancreatic cancer. Chemotherapy regimen: cisplatin 20 mg/m2 i.v, epirubicin 25 mg/m2 i.v., 5 fluorouracil was given in 28 patients with advanced extrahepatic biliary tract and pancreatic cancer at the Clinic of Oncology of the Collegium Medicum of the Jagiellonian University in Krakow in years 1997 to 2004. The treatment was repeated every 4 weeks up to 6 cycles. 12 patients with extrahepatic biliary tract cancer and 16 patients with pancreatic cancer were treated. Median time from the diagnosis to death was 8.8 months in patients with extrahepatic biliary tract and 8.7 months in patients with pancreatic cancer. 1-year survival was 25% and 16.7%, respectively. Hematological toxicity G 3 and G 4 occured in 5 patients (17.9% treated). Chemotherapy PEF seems to be an active and well tolerated regimen of palliative chemotherapy for advanced extrahepatic biliary tract carcinomas and pancreas carcinomas. Overall survival in the pancreatic cancer group is comparable to results obtained with gemcitabine monotherapy.

  15. New utilization of Polygonum multiflorum polysaccharide as macromolecular carrier of 5-fluorouracil for controlled release and immunoprotection.

    Science.gov (United States)

    Zhang, Qing; Xu, Yi; Lv, Junjiang; Cheng, Mengxia; Wu, Ying; Cao, Kun; Zhang, Xiaofeng; Mou, Xiuni; Fan, Qi

    2018-02-10

    WPMP-2 is an acid polysaccharide isolated from Polygonum multiflorum, which demonstrated excellent immunomodulatory activity. In order to reduce immunosuppression of 5-fluorouracil (5-Fu), WPMP-2 was utilized as a macromolecular carrier to conjugate the 5-Fu derivatives 5-fluorouracil-1-acetic acid (5-FUAC) through ester bond. The conjugate showed controlled drug release behaviour in vitro at 37°C in phosphate buffer (pH7.4), and only 5-FUAC was detected in the media. The cytotoxicity test in vitro showed that the conjugate exhibited different cytotoxicity to HepG-2 and HT-29 cells. In addition, immunization study in vivo illustrated that the conjugate displayed immunoprotective effect by mitigating inhibition and damage effects of 5-Fu on secretion of cytokines, proliferation of splenocytes, and phagocytosis of peritoneal macrophages. It was indicated that the conjugation of 5-Fu and WPMP-2 could be a potential double effective drug delivery system. Copyright © 2018. Published by Elsevier B.V.

  16. Central venous access related adverse events after trabectedin infusions in soft tissue sarcoma patients; experience and management in a nationwide multi-center study

    NARCIS (Netherlands)

    Verboom, M.C.; Ouwerkerk, J.; Steeghs, N.; Lutjeboer, J.; Kerst, J.M.; Graaf, W.T.A. van der; Reyners, A.K.; Sleijfer, S.; Gelderblom, H.

    2017-01-01

    BACKGROUND: Trabectedin has shown efficacy against soft tissue sarcomas (STS) and has manageable toxicity. Trabectedin is administered through central venous access devices (VAD), such as subcutaneous ports with tunneled catheters, Hickman catheters and PICC lines. Venous access related adverse

  17. The impact of insulin on chemotherapeutic sensitivity to 5-fluorouracil in gastric cancer cell lines SGC7901, MKN45 and MKN28.

    Science.gov (United States)

    Wei, Zhao; Liang, Li; Junsong, Liu; Rui, Chen; Shuai, Chang; Guanglin, Qiu; Shicai, He; Zexing, Wang; Jin, Wang; Xiangming, Che; Shufeng, Wang

    2015-06-18

    The role of insulin in the pathogenesis of cancer has been increasingly emphasized because of the high incidence of obesity and metabolic syndrome and their correlated complication including cancer. This study aimed to explore the impact of insulin on chemoresistance to 5-fluorouracil in gastric cancer and the possible mechanisms. Tissue samples of gastric cancer and adjacent normal gastric mucosa from patients with or without obesity were performed immunohistochemical staining for P-glycoprotein. The follow-up was done after the surgical treatment. The effect of insulin on chemotherapeutic sensitivity of the three gastric cancer cell lines to 5-fluorouracil was evaluated by pre-incubation with insulin before administration of 5-fluorouracil. The expression of P-glycoprotein was determined by Western blotting. P-glycoprotein were overexpressed in tissues from patients who suffered gastric cancer and were higher in those simultaneously suffered gastric cancer and obesity. Addition of 1 μM insulin remarkably promoted the proliferation of SGC7901, MKN45 and MKN28 cells and decreased the cytotoxicity of 5-fluorouracil. In addition, the expression of P-glycoprotein was upregulated in SGC7901, MKN45 and MKN28 cells. Insulin improved the proliferation of gastric cancer cell lines and contributed to chemoresistance of gastric cancer cells to 5-fluorouracil which is likely to involve upregulation of P-glycoprotein.

  18. Phase I/II Trial of 5-Fluorouracil and a Noncytotoxic Dose Level of Suramin in Patients with Metastatic Renal Cell Carcinoma

    Science.gov (United States)

    George, Saby; Dreicer, Robert; Au, Jessie J. L.; Shen, Tong; Rini, Brian I.; Roman, Susan; Cooney, Matthew M.; Mekhail, Tarek; Elson, Paul; Wientjes, Guillaume M.; Ganapathi, Ram; Bukowski, Ronald M.

    2010-01-01

    Background Renal cell carcinoma (RCC) is recognized as a neoplasm resistant to chemotherapy. In vitro experiments demonstrated that suramin, at noncytotoxic doses, enhanced the activity of chemotherapy including 5-fluorouracil (5-FU) in xenograft models. Patients and Methods A phase I/II trial of noncytotoxic suramin in combination with weekly 5-FU in patients with metastatic RCC was conducted. The treatment consisted of intravenous (I.V.) suramin followed by a 500 mg/m2 I.V. bolus of 5-FU given 4.5 hours after starting suramin. In the phase I portion, a cohort of 6 patients received a suramin dose calculated to achieve a plasma level of 10–50 μmol/L. Therapy was administered once weekly for 6 doses, followed by 2 weeks off. This was followed by a phase II portion in which the primary goal was to determine the objective response rate. Results Twenty-three patients were enrolled in the study: 6 in the phase I portion and 17 in phase II. Seventy-eight percent of patients were men, the mean age was 58.8 years, 96% had previous nephrectomy, and 70% had received previous systemic therapy. Histologic subtype was clear cell in 91%. Dose-limiting toxicity was observed in 1 of 6 patients (grade 3 hypersensitivity related to suramin infusion). The suramin dosing nomogram used in phase I and II portions of the trial yielded the desired plasma level of 10–50 μmol/L from 4.5 hours to 48 hours after infusion in 94 of 115 treatments. No objective responses were noted, and the median time to treatment failure was 2.5 months. The major toxicities (all grades) were fatigue (83%), nausea/vomiting (78%), diarrhea (61%), and chills (61%). Conclusion Suramin levels expected to reverse fibroblast growth factor–induced resistance can be achieved with the dosing regimen used in this study. The toxicity observed with suramin and 5-FU was acceptable. The combination does not have clinical activity in patients with metastatic RCC. PMID:18824429

  19. Comparison of Subconjunctival Mitomycin C and 5-Fluorouracil Injection for Needle Revision of Early Failed Trabeculectomy Blebs

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    Wei Liu

    2016-01-01

    Full Text Available Background. To compare the efficacy of needle revision with 5-fluorouracil (5-FU and mitomycin C (MMC on dysfunctional filtration blebs shortly after trabeculectomy. Methods. It is a prospective randomized study comparing needle revision augmented with MMC or 5-FU for failed trabeculectomy blebs. Results. To date 71 patients (75 eyes have been enrolled, 40 eyes in the MMC group and 35 in the 5-FU group. 68 patients (72 eyes have completed 12-month follow-up, 38 eyes in the MMC group and 34 in the 5-FU group. The mean IOP before and that after needle revision in the MMC group were 26.5±4.3 mmHg and 11.3±3.4 mmHg, respectively (P0.05. Conclusions. Needle revision and subconjunctival MMC injection were more effective than needling and subconjunctival 5-FU injection for early dysfunctional filtration blebs after trabeculectomies.

  20. Long-term persistence of acquired resistance to 5-fluorouracil in the colon cancer cell line SW620

    Energy Technology Data Exchange (ETDEWEB)

    Tentes, I.K., E-mail: itentes@med.duth.gr [Department of Biochemistry, Medical School, Democritus University of Thrace, 6th km Alexandroupolis-Komotini (Dragana), 68100 Alexandroupolis (Greece); Schmidt, W.M. [Center for Anatomy and Cell Biology, Waehringer Strasse 13, 1090 Vienna (Austria); Krupitza, G. [Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria); Steger, G.G.; Mikulits, W. [Department of Medicine I, Medical University of Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria); Kortsaris, A. [Department of Biochemistry, Medical School, Democritus University of Thrace, 6th km Alexandroupolis-Komotini (Dragana), 68100 Alexandroupolis (Greece); Mader, R.M. [Department of Medicine I, Medical University of Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria)

    2010-11-15

    Treatment resistance to antineoplastic drugs represents a major clinical problem. Here, we investigated the long-term stability of acquired resistance to 5-fluorouracil (FU) in an in vitro colon cancer model, using four sub-clones characterised by increasing FU-resistance derived from the cell line SW620. The resistance phenotype was preserved after FU withdrawal for 15 weeks ({approx} 100 cell divisions) independent of the established level of drug resistance and of epigenetic silencing. Remarkably, resistant clones tolerated serum deprivation, adopted a CD133{sup +} CD44{sup -} phenotype, and further exhibited loss of membrane-bound E-cadherin together with predominant nuclear {beta}-catenin localisation. Thus, we provide evidence for a long-term memory of acquired drug resistance, driven by multiple cellular strategies (epithelial-mesenchymal transition and selective propagation of CD133{sup +} cells). These resistance phenomena, in turn, accentuate the malignant phenotype.

  1. Efficacy of repeated 5-fluorouracil needling for failing and failed filtering surgeries based on simple gonioscopic examination

    Directory of Open Access Journals (Sweden)

    Rashad MA

    2012-12-01

    Full Text Available Mohammad A RashadOphthalmology Department, Faculty of Medicine, Ain Shams University, Cairo, EgyptPurpose: To evaluate the success rate of a modified bleb needling technique in eyes with previous glaucoma surgery that had elevated intraocular pressure.Methods: A retrospective study of 24 eyes of 24 patients that underwent repeated bleb needling performed for failing and failed blebs on slit lamp with 5-fluorouracil (5-FU injections on demand. This was performed after gonioscopic examination to define levels of filtration block.Results: There was significant reduction of mean IOP from 36.91 mmHg to 14.73 mmHg at the final follow-up (P < 0.001. The overall success rate was 92%.Conclusion: Repeated needling with adjunctive 5-FU proved a highly effective, safe alternative to revive filtration surgery rather than another medication or surgery.Keywords: bleb, failure, 5-FU, needling, gonioscopy

  2. 5-Fluorouracil incorporation into RNA of a rat liver adenocarcinoma after hepatic artery injection together with degradable starch microspheres

    Energy Technology Data Exchange (ETDEWEB)

    Teder, H.; Erichsen, C.; Christensson, P.I.; Joensson, P.E.S.; Stenram, U.

    1987-01-01

    The effect of degradable starch microspheres (DSM) on the cellular incorporation of 5-fluorouracil (FUra) was studied in rats with solitary liver tumors. /sup 3/H-labelled FUra (0.78 mg (6000 nmol)/kg b.wt.) was injected with saline or mixed with DSM, into the hepatic artery. Labelling of the acid soluble fraction (ASF), RNA and DNA of tumor, liver, bone marrow and small intestine was measured 60 minutes after injection. The DSM had no significant effect on the incorporation of FUra into the ASF or RNA, neither in tumor nor liver tissue. Regarding the tumor/normal tissue ratios of specific radioactivities, there was with DSM a higher tumor/liver and a higher tumor/bone marrow ratio in the ASF, indicating an increased tumour drug exposure with DSM. However, this was not accompanied by any significant increase in drug anabolism.

  3. Photochemical cleavage of individual stereoisomers of coumarin-5-fluorouracil crossdimers via single- and two-photon-absorption

    Science.gov (United States)

    Behrendt, Philipp J.; Kim, Hee-Cheol; Hampp, Norbert

    2013-11-01

    Coumarin-5-fluorouracil crossdimers were photochemically synthesized. Three different isomers were isolated and their photo-cycloreversion, induced by single- and two-photon-absorption, was studied. The single-photon absorption quantum yields strongly correlate with the dipole moments and the absorption behavior of the stereoisomers. Between the stereoisomers a maximal factor of 6.5 in cyclobutane cleavage efficiency is observed. The two-photon-absorption cross-sections were determined for all three stereoisomers. A good correlation between the single and two-photon-absorption cross-sections was found. The isomer with the highest light sensitivity is the syn-head-to-head isomer. For most applications, isomer pure preparations seem advisable as the required light intensities may be reduced significantly.

  4. Impact of heterophil granulocyte depletion caused by 5-fluorouracil on infectious bursal disease virus infection in specific pathogen free chickens

    DEFF Research Database (Denmark)

    Kabell, Susanne; Igyarto, Botond-Zoltan; Magyar, Attila

    2006-01-01

    The purpose of this study was to investigate the influence of the cytostatic drug, 5-fluorouracil (5-FU), which causes depletion of heterophil granulocytes, on clinical symptoms and histological lesions during the progress of infectious bursal disease virus ( IBDV) infection in chickens. The aim...... inoculated with the classical IBDV strain F52/70. Bursae of Fabricius were sampled at fixed intervals, and the progress of the infection was monitored by various histological techniques and reverse transcriptase-polymerase chain reaction (RT-PCR). We found correlation between histological observations and RT......-PCR results. In the 5-FU pretreated chickens, IBDV caused only mild clinical symptoms, even though histological alterations similar to alterations caused by IBDV were still observed. The 5-FU pretreatment resulted in severe heterophil granulocyte depletion by days 2 and 3 after infection (post inoculation...

  5. Alteration of the redox state with reactive oxygen species for 5-fluorouracil-induced oral mucositis in hamsters.

    Directory of Open Access Journals (Sweden)

    Fumihiko Yoshino

    Full Text Available Oral mucositis is often induced in patients receiving cancer chemotherapy treatment. It has been reported that oral mucositis can reduce quality of life, as well as increasing the incidence of mortality. The participation of reactive oxygen species (ROS in the pathogenesis of oral mucositis is well known, but no report has actually demonstrated the presence of ROS. Thus, the purpose of this study was thus to demonstrate the involvement of ROS and the alteration of the redox state in oral mucositis using an in vivo L-band electron spin resonance (ESR technique. An oral mucositis animal model induced by treatment of 5-fluorouracil with 10% acetic acid in hamster cheek pouch was used. Lipid peroxidation was measured as the level of malondialdehyde determined by the thiobarbituric acid reaction. The rate constants of the signal decay of nitroxyl compounds using in vivo L-band ESR were calculated from the signal decay curves. Firstly, we established the oral mucositis animal model induced by treatment of 5-fluorouracil with acetic acid in hamster cheek pouch. An increased level of lipid peroxidation in oral mucositis was found by measuring malondialdehyde using isolated hamster cheek pouch ulcer. In addition, as a result of in vivo L-band ESR measurements using our model animals, the decay rate constants of carbamoyl-PROXYL, which is a reagent for detecting the redox balance in tissue, were decreased. These results suggest that a redox imbalance might occur by excessive generation of ROS at an early stage of oral mucositis and the consumption of large quantities of antioxidants including glutathione in the locality of oral mucositis. These findings support the presence of ROS involved in the pathogenesis of oral mucositis with anti-cancer therapy, and is useful for the development of novel therapies drugs for oral mucositis.

  6. Poly(butylcyanoacrylate) and Poly(ε-caprolactone) Nanoparticles Loaded with 5-Fluorouracil Increase the Cytotoxic Effect of the Drug in Experimental Colon Cancer.

    Science.gov (United States)

    Ortiz, Raúl; Cabeza, Laura; Arias, José L; Melguizo, Consolación; Álvarez, Pablo J; Vélez, Celia; Clares, Beatriz; Áranega, Antonia; Prados, Jose

    2015-07-01

    The clinical use of 5-fluorouracil, one of the drugs of choice in colon cancer therapy, is limited by a nonuniform oral absorption, a short plasma half-life, and by the development of drug resistances by malignant cells. We hypothesized that the formulation of biodegradable nanocarriers for the efficient delivery of this antitumor drug may improve its therapeutic effect against advanced or recurrent colon cancer. Hence, we have engineered two 5-fluorouracil-loaded nanoparticulate systems based on the biodegradable polymers poly(butylcyanoacrylate) and poly(ε-caprolactone). Drug incorporation to the nanosystems was accomplished by entrapment (encapsulation/dispersion) within the polymeric network during nanoparticle synthesis, i.e., by anionic polymerization of the monomer and interfacial polymer disposition, respectively. Main factors determining 5-fluorouracil incorporation within the polymeric nanomatrices were investigated. These nanocarriers were characterized by high drug entrapment efficiencies and sustained drug-release profiles. In vitro studies using human and murine colon cancer cell lines demonstrated that both types of nanocarriers significantly increased the antiproliferative effect of the encapsulated drug. In addition, both nanoformulations produced in vivo an intense tumor growth inhibition and increased the mice survival rate, being the greater tumor volume reduction obtained when using the poly(ε-caprolactone)-based formulation. These results suggest that these nanocarriers may improve the antitumor activity of 5-fluorouracil and could be used against advanced or recurrent colon cancer.

  7. Endoscopic Resection and Topical 5-Fluorouracil as an Alternative Treatment to Craniofacial Resection for the Management of Primary Intestinal-Type Sinonasal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Simon Mackie

    2010-01-01

    Conclusion. Trans-nasal endoscopic resection and topical 5-Fluorouracil could potentially offer an acceptable alternative treatment to the standard of cranio-facial resection. This should be investigated in trials with a longer followup period than this paper in order to directly compare the two treatment modalities.

  8. The addition of low-dose leucovorin to the combination of 5-fluorouracil-levamisole does not improve survival in the adjuvant treatment of Dukes' C colon cancer

    NARCIS (Netherlands)

    Bleeker, WA; Mulder, NH; Hermans, J; Otter, R; Plukker, JT

    Purpose: To assess the effect of the addition of leucovorin to the combination of 5-fluorouracil (5-FU)-levamisole on recurrence risk and overall survival in patients after a resection with curative intent of a Dukes' C colon cancer. Patients and methods: Five hundred patients with Dukes' C colon

  9. CHEMOTHERAPY AND SURGERY FOR LOCALLY ADVANCED CANCER OF THE CARDIA AND FUNDUS - PHASE-II STUDY WITH METHOTREXATE AND 5-FLUOROURACIL

    NARCIS (Netherlands)

    PLUKKER, JT; MULDER, NH; SLEIJFER, DT; VERSCHUEREN, RCJ

    Locally advanced cancer of the cardia and fundus might be cured by surgical resection. Poor results after surgery in stage IIIB and stage IV disease prompted a study of neoadjuvant chemotherapy. Treatment included four cycles of high doses of methotrexate (1.5 g/m2) and high doses of 5-fluorouracil

  10. Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity

    NARCIS (Netherlands)

    van Kuilenburg, A.B.P.; Meijer, J.; Mul, A.N.P.M.; Meinsma, R.; Schmid, V.; Dobritzsch, D.; Hennekam, R.C.M.; Mannens, M.M.A.M.; Kiechle, M.; Etienne-Grimaldi, M.C.; Klümpen, H.J.; Maring, J.G.; Derleyn, V.A.; Maartense, E.; Milano, G.; Vijzelaar, R.; Gross, E.

    2010-01-01

    Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD

  11. Influence of different sugar cryoprotectants on the stability and physico-chemical characteristics of freeze-dried 5-fluorouracil plurilamellar vesicles

    Directory of Open Access Journals (Sweden)

    Mohamed Mahmoud Nounou

    2005-07-01

    Full Text Available Lyophilization increases the shelf-life of liposomes by preserving it in a dry form as lyophilized cake to be reconstituted with water immediately prior to administration. Aiming at increasing stability and availability of 5-Fluorouracil liposomal products, 5-Fluorouacil Stable Plurilamellar Vesicles were prepared. Freeze dried liposomal dispersions were prepared with or without cryoprotectants. The cryoprotectants used were glucose, mannitol or trehalose in 1, 2 and 4 grams per gram phospholipids. The results showed that lyophilized cake of liposomes without cryoprotectants was compact and difficult to reconstitute, in comparison with fluffy cakes which reconstituted easily and quickly when using cryoprotectants. The percentage of 5-Fluorouracil retained in liposomes freeze-dried without cryoprotectants was 18.29% ± 0.96% and the percentage of 5-Fluorouracil retained in stable plurilamellar vesicles was 31.22% ± 0.62% using 4 grams trehalose as cryoprotectant per gram of lipid. Physico-chemical and release stability studies showed superior potentials of the lyophilized product after reconstitution in comparison to dispersion product. It may be concluded that all tested sugars have cryoprotectant effects that stabilized liposomes in the freeze dried state, where trehalose offered the most superior cryoprotectant effect for freeze dried 5-fluorouracil liposomes.

  12. Formulation, in vitro drug release and in vivo human X-ray investigation of polysaccharide based drug delivery systems for targeting 5-fluorouracil to the colon

    Directory of Open Access Journals (Sweden)

    Sidramappa Mallikarjun Chickpetty

    2013-06-01

    Full Text Available The purpose of this research study was to develop 5-fluorouracil compression coated tablets by using biodegradable polysaccharide polymer locust bean gum (LBG and hydroxyl propyl methyl cellulose (HPMC as coating materials. The fast disintegrating core tablets containing 50 mg of 5-fluorouracil were compression coated with LBG and HPMC in different ratios (8:1, 7:2 and 6:3 with a coat weight of 300, 400 and 500 mg. In vitro dissolution data indicated that the formulation (CLH63 with a coat weight of 500 mg containing LBG and HPMC in the ratio 6:3 gave the best release profile (0% in first 5 hour and 96.18% in 24 hours. DSC and FTIR results indicated no possibility of interaction between drug and polymers or other excipients. In vivo human X-ray studies revealed that formulation CLH63 was able to resist breakdown in the stomach and small intestine. The disintegration of the tablet occurred in the colon between 8 to 16 hours of post dose. By the present study, it can be concluded that the LBG and HPMC based compression coated tablets of 5-fluorouracil will be useful strategy for colonic delivery of 5-fluorouracil without being released in upper gastrointestinal region for the safe and effective management of colon cancer.

  13. Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-fluorouracil with or without docetaxel: a subset analysis of EORTC 24971 study

    NARCIS (Netherlands)

    Psyrri, A.; Fortpied, C.; Koutsodontis, G.; Avgeris, M.; Kroupis, C.; Goutas, N.; Menis, J.; Herman, L.; Giurgea, L.; Remenar, E.; Degardin, M.; Pateras, I.S.; Langendijk, J.A.; Herpen, C.M.L. van; Awada, A.; Germa-Lluch, J.R.; Kienzer, H.R.; Licitra, L.; Vermorken, J.B.

    2017-01-01

    Background: EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5-fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell

  14. Preoperative radiation with concurrent 5-fluorouracil for locally advanced T4-primary rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Roedel, C.; Grabenbauer, G.G.; Sauer, R. [Erlangen-Nuernberg Univ., Erlangen (Germany). Dept. of Radiation Oncology; Schick, C.; Hohenberger, W. [Erlangen-Nuernberg Univ., Erlangen (Germany). Chirurgische Klinik mit Poliklinik; Papadopoulos, T. [Erlangen-Nuernberg Univ., Erlangen (Germany). Abt. fuer Klinische Pathologie

    2000-04-01

    Herein we report on the curative resectability rate, acute toxicities, surgical complications, local control and 5-year survival rates achieved with a more aggressive multimodality regimen, including preoperative radiochemotherapy. Patients and Methods: Between 1/1990 and 12/1998, a total of 31 patients with cT4-rectal cancer were treated at our institution. All patients presented with tumor contiguous or adherent to adjacent pelvic organs. Eight patients had synchronous distant metastases. A total radiation dose of 50.4 Gy with a small-volume boost of 5.4 to 9 Gy was delivered (single dose: 1.8 Gy). 5-FU was scheduled as a continuous infusion of 1000 mg/m{sup 2} per 24 hours on days 1 to 5 and 29 to 33. Six weeks after completion of radiochemotherapy, patients were reassessed for resectability. Results: After preoperative radiochemotherapy, 29/31 patients (94%) underwent surgery with curative intent. Resection of the pelvic tumor with negative margins was achieved in 26/31 patients (84%), 3 patients had microscopic residual pelvic disease. In 3/8 patients with distant spread at presentation a complete resection of metastases was finally accomplished. Toxicity of radiochemotherapy occurred mainly as diarrhea (NCI-CTC Grade 3: 23%), dermatitis (Grade 3: 16%) and leucopenia (Grade 3: 10%). Surgical complications appeared as anastomotic leakage in 3, wound infection in 2, fistula, abscess and hemorrhage in 1 patient, respectively. With a median follow-up of 33 months, local failure after curative resection was observed in 4 patients (19%), 3 patients (14%) developed distant metastases. The 5-year overall survival rate for the entire group of 31 patients was 51%, following curative surgery 68%. (orig.) [German] Wir analysierten die Rate an kurativen (R0) Resektionen nach praeoperativer Radiochemotherapie, die Toxizitaet der Radiochemotherapie, die chirurgische Morbiditaet sowie die lokale Kontrolle und das Fuenf-Jahres-Gesamtueberleben nach multimodaler Therapie

  15. Postoperative subconjunctival bevacizumab injection as an adjunct to 5-fluorouracil in the management of scarring after trabeculectomy

    Directory of Open Access Journals (Sweden)

    Freiberg FJ

    2013-06-01

    Full Text Available Florentina Joyce Freiberg,1 Juliane Matlach,1 Franz Grehn,1 Sabine Karl,2 Thomas Klink1 1Department of Ophthalmology, Julius Maximilian University, Wuerzburg, Germany; 2Institute of Mathematics, University of Wuerzburg, Wuerzburg, Germany Purpose: Scarring after glaucoma filtering surgery remains the most frequent cause for bleb failure. The aim of this study was to assess if the postoperative injection of bevacizumab reduces the number of postoperative subconjunctival 5-fluorouracil (5-FU injections. Further, the effect of bevacizumab as an adjunct to 5-FU on the intraocular pressure (IOP outcome, bleb morphology, postoperative medications, and complications was evaluated. Methods: Glaucoma patients (N = 61 who underwent trabeculectomy with mitomycin C were analyzed retrospectively (follow-up period of 25 ± 19 months. Surgery was performed exclusively by one experienced glaucoma specialist using a standardized technique. Patients in group 1 received subconjunctival applications of 5-FU postoperatively. Patients in group 2 received 5-FU and subconjunctival injection of bevacizumab. Results: Group 1 had 6.4 ± 3.3 (0–15 (mean ± standard deviation and range, respectively 5-FU injections. Group 2 had 4.0 ± 2.8 (0–12 (mean ± standard deviation and range, respectively 5-FU injections. The added injection of bevacizumab significantly reduced the mean number of 5-FU injections by 2.4 ± 3.08 (P ≤ 0.005. There was no significantly lower IOP in group 2 when compared to group 1. A significant reduction in vascularization and in cork screw vessels could be found in both groups (P < 0.0001, 7 days to last 5-FU, yet there was no difference between the two groups at the last follow-up. Postoperative complications were significantly higher for both groups when more 5-FU injections were applied. (P = 0.008. No significant difference in best corrected visual acuity (P = 0.852 and visual field testing (P = 0.610 between preoperative to last follow

  16. A novel drug delivery of 5-fluorouracil device based on TiO{sub 2}/ZnS nanotubes

    Energy Technology Data Exchange (ETDEWEB)

    Mendonça Faria, Henrique Antonio, E-mail: henrique.fisica@ifsc.usp.br [Institute of Physics and Chemistry, Federal University of Itajubá (UNIFEI), Av. BPS, 1303, Pinheirinho, Itajubá, MG, PO Box 50, CEP: 37500-903 (Brazil); Nanomedicine and Nanotoxicology Laboratory, São Carlos Institute of Physics, University of São Paulo. Av. Trabalhador São-carlense, 400, Arnold Schimidt, São Carlos, SP CEP: 13566-590 (Brazil); Alencar de Queiroz, Alvaro Antonio, E-mail: alencar@unifei.edu.br [Institute of Physics and Chemistry, Federal University of Itajubá (UNIFEI), Av. BPS, 1303, Pinheirinho, Itajubá, MG, PO Box 50, CEP: 37500-903 (Brazil)

    2015-11-01

    The structural and electronic properties of titanium oxide nanotubes (TiO{sub 2}) have attracted considerable attention for the development of therapeutic devices and imaging probes for nanomedicine. However, the fluorescence response of TiO{sub 2} has typically been within ultraviolet spectrum. In this study, the surface modification of TiO{sub 2} nanotubes with ZnS quantum dots was found to produce a red shift in the ultra violet emission band. The TiO{sub 2} nanotubes used in this work were obtained by sol–gel template synthesis. The ZnS quantum dots were deposited onto TiO{sub 2} nanotube surface by a micelle-template inducing reaction. The structure and morphology of the resulting hybrid TiO{sub 2}/ZnS nanotubes were investigated by scanning electron microscopy, transmission electron microscopy and X-ray diffraction techniques. According to the results of fluorescence spectroscopy, pure TiO{sub 2} nanotubes exhibited a high emission at 380 nm (3.26 eV), whereas TiO{sub 2}/ZnS exhibited an emission at 410 nm (3.02 eV). The TiO{sub 2}/ZnS nanotubes demonstrated good bio-imaging ability on sycamore cultured plant cells. The biocompatibility against mammalian cells (Chinese Hamster Ovarian Cells—CHO) suggesting that TiO{sub 2}/ZnS may also have suitable optical properties for use as biological markers in diagnostic medicine. The drug release characteristic of TiO{sub 2}/ZnS nanotubes was explored using 5-fluorouracil (5-FU), an anticancer drug used in photodynamic therapy. The results show that the TiO{sub 2}/ZnS nanotubes are a promising candidate for anticancer drug delivery systems. - Highlights: • TiO{sub 2}/ZnS nanotubes showed a redshift in fluorescence spectrum. • Cytotoxicity against mammalian cells revealed biocompatibility of the nanotubes. • TiO{sub 2}/ZnS proved an efficient delivery system for anti-tumor 5-fluorouracil.

  17. Treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5-fluorouracil and capecitabine using suboptimal doses.

    Science.gov (United States)

    Cioffi, Joseph H; Estes, Derek J; Florou, Vaia; Ardalan, Bach

    2017-11-27

    A 32-year-old female with stage IV colorectal cancer and metastasis to the liver experienced cardiotoxic reactions after treatment with 5-fluorouracil and its oral prodrug capecitabine even at two-thirds the recommended dose. After careful considerations, the decision was made to attempt capecitabine retrial at a further suboptimal dose with combination chemotherapy where she no longer experienced cardiac events. As a result, the liver tumour shrank and rectal mass stabilised, tumour markers dropped and she underwent surgical resection of both masses. Later there was local recurrence of disease near the previous liver tumour, so the suboptimal capecitabine therapy was restarted without complaint. The patient became a candidate for a NanoKnife procedure, offering a potentially curative therapy. This case report summarises a novel treatment strategy for those patients with advanced colorectal cancer who experience cardiotoxic reactions to fluoropyrimidines, the active agent of gold standard treatment. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. Intratumoural thymidylate synthase and dihydropyrimidine dehydrogenase activities are good predictors of 5-fluorouracil sensitivity in colorectal cancer.

    Science.gov (United States)

    Ishibiki, Y; Kitajima, M; Sakamoto, K; Tomiki, Y; Sakamoto, S; Kamano, T

    2003-01-01

    To identify factors that influence the clinical response to 5-fluorouracil (5-FU), we studied the correlation between in vitro sensitivity to 5-FU and the expression of seven biological markers. The markers, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), pyrimidine nucleoside phosphorylase, p53 (wild/mutant), p21, cyclo-oxygenase-2, and inducible nitric oxide synthase were measured in tumour tissues from 32 colorectal cancer patients. The activities of TS and DPD were significantly lower in the tumours sensitive to 5-FU compared with those that were not sensitive to 5-FU. In tumours with TS < 3.7 pmol/min per mg protein and DPD < 98 pmol/min per mg protein, the percentage of cases sensitive to 5-FU (67%) and the mean percentage inhibition of tumour cells by 5-FU (42.8%) were significantly higher than in the other tumours (0% and 13.1%, respectively). The other biological markers did not correlate with in vitro sensitivity to 5-FU. Tumour sensitivity to 5-FU can be more precisely predicted by taking the activities of both TS and DPD into consideration than by using either alone.

  19. Acquired resistance to 5-fluorouracil via HSP90/Src-mediated increase in thymidylate synthase expression in colon cancer.

    Science.gov (United States)

    Ahn, Ji-Young; Lee, Ji-Sun; Min, Hye-Young; Lee, Ho-Young

    2015-10-20

    5-fluorouracil (5-FU), one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU-sensitive HCT116 colon cancer cells morphologic, molecular, and behavioral characteristic of the epithelial-mesenchymal transition (EMT), contributing to emergence of acquired resistance to 5-FU. HCT116/R, a HCT116 colon cancer cell subline carrying acquired resistance to 5-FU, showed increased expression and activation of HSP90's client proteins and transcriptional up-regulation of TYMS. Forced overexpression of HSP90 or constitutive active Src in HCT116 cells increased TYMS expression. Conversely, pharmacological blockade of HSP90 or Src in HCT116/R cells effectively suppressed the changes involved in 5-FU resistance in vitro and xenograft tumor growth, hematogenous spread, and metastatic tumor development in vivo. This study suggests a novel function of HSP90-Src pathway in regulation of TYMS expression and acquisition of 5-FU resistance. Thus, therapeutics targeting this pathway may be an effective clinical strategy to overcome 5-FU resistance in colon cancer.

  20. Severe Encephalopathy, Lactic Acidosis, Vegetative Instability and Neuropathy with 5-Fluorouracil Treatment – Pyrimidine Degradation Defect or Beriberi

    Directory of Open Access Journals (Sweden)

    A. Rosen

    2011-08-01

    Full Text Available We present the case of a 19-year-old female with nasopharyngeal carcinoma, who received two courses of chemotherapy with 5-fluorouracil (5-FU in combination with folic acid and cisplatin. Upon developing esophageal strictures in the course of her radiotherapy, she required total parenteral nutrition. In the course of therapy, the patient developed severe multisystem failure with encephalopathy, lactic acidosis, vegetative instability and neuropathy. The treatment with 5-FU can lead to severe toxicity due to enzyme deficiencies in the degradation of pyrimidines, but it can also lead to thiamine deficiency with the classic symptoms of beriberi. Beriberi is a rare disorder, usually attributed to malnutrition or alcoholism. 5-FU has been shown to induce thiamine depletion. Reduced food intake or total parenteral nutrition devoid of vitamin supplements may aggravate symptoms. We were unable to find a genetic cause for increased 5-FU toxicity in our patient, ruling out deficiencies of dihydropyrimidine dehydrogenase, dihydropyrimidinase or β-ureidopropionase and double-strand break repair deficits. We come to the conclusion that, even without any definable enzyme deficiency, treatment with 5-FU can lead to high toxicity due to thiamine deficiency if vitamin supplementation is not undertaken.

  1. Neem (Azadirachta indica) leaf preparation prevents leukocyte apoptosis mediated by cisplatin plus 5-fluorouracil treatment in Swiss mice.

    Science.gov (United States)

    Ghosh, Diptendu; Bose, Anamika; Haque, Enamul; Baral, Rathindranath

    2009-01-01

    Neem (Azadirachta indica) is widely regarded as a wonder tree because of its diverse medicinal applications. We investigated the ability of neem leaf preparation (NLP) to protect against apoptosis of circulating blood cells induced by cisplatin and 5-fluorouracil (cis + 5-FU) in carcinoma-bearing mice. Apoptosis was studied by annexin V-propidium iodide method. Total white blood cell count was performed using 3% glacial acetic acid on hemocytometer. Cytotoxicity was determined by LDH release assay and T/NK cell status was determined by flow cytometry. In comparison to untreated control, during cis + 5-FU therapy, significant down-regulation of leukocyte apoptosis was noted in mice pretreated with NLP or granulocyte colony stimulating factor (GCSF) during cis + 5-FU therapy. This enhanced cytotoxicity may be associated with NLP-induced increase of the cytotoxic T and NK cell pool. Efficacy of NLP is comparable to GCSF in its ability to protect against leukocyte apoptosis induced by cis + 5-FU. NLP would be a better choice of treatment because GCSF is tumor promoting, angiogenic and expensive. Copyright 2009 S. Karger AG, Basel.

  2. tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells.

    Directory of Open Access Journals (Sweden)

    Mayumi Okamoto

    2014-09-01

    Full Text Available Nonessential tRNA modifications by methyltransferases are evolutionarily conserved and have been reported to stabilize mature tRNA molecules and prevent rapid tRNA decay (RTD. The tRNA modifying enzymes, NSUN2 and METTL1, are mammalian orthologs of yeast Trm4 and Trm8, which are required for protecting tRNA against RTD. A simultaneous overexpression of NSUN2 and METTL1 is widely observed among human cancers suggesting that targeting of both proteins provides a novel powerful strategy for cancer chemotherapy. Here, we show that combined knockdown of NSUN2 and METTL1 in HeLa cells drastically potentiate sensitivity of cells to 5-fluorouracil (5-FU whereas heat stress of cells revealed no effects. Since NSUN2 and METTL1 are phosphorylated by Aurora-B and Akt, respectively, and their tRNA modifying activities are suppressed by phosphorylation, overexpression of constitutively dephosphorylated forms of both methyltransferases is able to suppress 5-FU sensitivity. Thus, NSUN2 and METTL1 are implicated in 5-FU sensitivity in HeLa cells. Interfering with methylation of tRNAs might provide a promising rationale to improve 5-FU chemotherapy of cancer.

  3. Oxidation and pH responsive nanoparticles based on ferrocene-modified chitosan oligosaccharide for 5-fluorouracil delivery.

    Science.gov (United States)

    Xu, Youqian; Wang, Liang; Li, Ya-Kun; Wang, Cai-Qi

    2014-12-19

    Stimuli-responsive nanoparticles based on biodegradable and biocompatible saccharides are potentially superior carriers under different physical conditions. In this study, we present a detailed investigation on the oxidation and pH responses of ferrocene-modified chitosan oligosaccharide (FcCOS) nanoparticles for 5-Fluorouracil (5-FU) Delivery. The dispersion of FcCOS nanoparticles depends strongly on pH change. NaClO, H2O2 and oxygen, as oxidant models, in a weak acid solution displayed varying accelerations as the disassembly progressed. 5-FU, as a drug model, is efficiently uploaded in FcCOS nanoparticle (approximately 238 nm). The in vitro release of 5-FU from FcCOS nanoparticles studies show that the accumulative release increased with the decrease of pH under bubbled N2. Interestingly, the sample under bubbled air has a higher accumulative release up to 59.64% at pH 3.8, compared with samples under bubbled N2 just 49.02%. The results suggested that FcCOS nanoparticles disassembled faster and the release of drug molecules was accelerated because of the synergistic effect of oxidative agent and low pH. Thus, FcCOS can be developed as an effective pH and oxidation dual-responsive carrier to enhance drug efficacy for cancer treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Bioactive Glass Nanoparticles as a New Delivery System for Sustained 5-Fluorouracil Release: Characterization and Evaluation of Drug Release Mechanism

    Directory of Open Access Journals (Sweden)

    Abeer M. El-Kady

    2015-01-01

    Full Text Available Bioactive glass nanoparticles were synthesized and tested for the first time as a new delivery system for sustained 5-fluorouracil (5-FU release. They were characterized by TEM, DTA, TGA, and FT-IR. The porosity % and specific surface area of glass nanoparticles were 85.59% and 378.36 m2/g, respectively. The in vitro bioactivity evaluation confirmed that bioactive glass disks prepared from these nanoparticles could induce hydroxyapatite layer over their surfaces in simulated body fluid. The in vitro drug release experiment indicated that glass nanoparticles could serve as long-term local delivery vehicles for sustained 5-FU release. The release profile of 5-FU showed an initial fast release stage followed by a second stage of slower release. The initial burst release of 5-FU in the first day was about 23% (28.92 mg·L−1 of the total amount of loaded 5-FU, while the final cumulative percentage of the 5-FU released after 32 days was about 45.6% (57.31 mg·L−1 of the total amount of loaded 5-FU. The application of different mathematical models indicated that 5-FU was released by diffusion controlled mechanism and suggested that its release rate was dependent on glass particles dissolution, changes of surface area as well as diameter of glass particles, and concentration of loaded drug.

  5. Semi-physiological pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats.

    Science.gov (United States)

    Kobuchi, Shinji; Ito, Yukako; Hayakawa, Taro; Nishimura, Asako; Shibata, Nobuhito; Takada, Kanji; Sakaeda, Toshiyuki

    2015-01-01

    1. The aim of this study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model that could characterize the complete time-course of alterations in platelet counts to predict the onset and degree of thrombocytopenia, which severely limits the use of the anticancer agent 5-fluorouracil (5-FU), in rats. 2. Platelet counts were measured in rats following the intravenous administration of various doses of 5-FU for 4 days to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with three compartments for the PD model and 10 structural PK-PD model parameters. 3. After the 5-FU treatment, platelet counts transiently decreased to a nadir level, showed a rebound to above the baseline level before recovering to baseline levels. Nadir platelet counts and rebounds varied with the AUC0-∞ level. The final PK-PD model effectively characterized platelet count data and final PD parameters were estimated with high certainty. 4. This PK-PD model and simulation may represent a valuable tool for quantifying and predicting the complete time-course of alterations in blood cell counts, and could contribute to the development of therapeutic strategies with 5-FU and assessments of various novel anticancer agents that are difficult to examine in humans.

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

    Directory of Open Access Journals (Sweden)

    Erika Evangelina Coronado-Cerda

    2016-01-01

    Full Text Available 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Yang, H.; Gan, L.; Yang, X., E-mail: luxinpei@hotmail.com, E-mail: yangxl@mail.hust.edu.cn [College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074 (China); Lu, R. [School Hospital of Huazhong University of Science and Technology, Wuhan, Hubei 430074 (China); Xian, Y.; Lu, X., E-mail: luxinpei@hotmail.com, E-mail: yangxl@mail.hust.edu.cn [State Key Laboratory of Advanced Electromagnetic Engineering and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074 (China)

    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.

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

    Science.gov (United States)

    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.

  9. Protective effect of anthocyanin-rich extract from bilberry (Vaccinium myrtillus L.) against myelotoxicity induced by 5-fluorouracil.

    Science.gov (United States)

    Choi, Eun Hye; Ok, Hyun Ee; Yoon, Yoosik; Magnuson, Bernadene A; Kim, Mi Kyung; Chun, Hyang Sook

    2007-01-01

    The toxicities associated with 5-fluorouracil (5-FU), a potent broad-spectrum chemotherapeutic agent, can not only affect the morbidity and the efficacy of chemotherapy but also limit its clinical use. The objective of this study is to investigate the effects of a commercial anthocyanin-rich extract from bilberry (AREB) against 5-FU-induced myelotoxicity in vivo, and against chemosensitivity to 5-FU in vitro. A single injection of 5-FU at 200 mg/kg induced severe peripheral erythrocytopenia, thrombocytopenia and leucopenia as well as hypocellularity of the spleen and bone marrow in C57BL/6 mice. Oral administration of 500 mg/kg of AREB for 10 days significantly increased the number of red blood cells, neutrophils, and monocytes in peripheral blood to 1.2-fold, 9-fold, and 6-fold, respectively, compared with those seen after treatment with 5-FU alone (p< 0.05-0.001). The hypocellularity of the spleen and bone marrow caused by 5-FU was also distinctly alleviated in the AREB-treated group. Furthermore, AREB treatment with 50 and 100 microg/ml as a monomeric anthocyanin did not interfere with, but rather enhanced the chemotherapeutic efficacy of 5-FU in vitro. These results suggest that AREB may have protective potential against 5-FU-induced myelotoxiciy and/or the ability to enhance the chemotherapeutic effectiveness of 5-FU.

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

    Science.gov (United States)

    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. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Xuejing Zou

    2016-08-01

    Full Text Available 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.

  12. Antitumor effects and the underlying mechanism of licochalcone A combined with 5-fluorouracil in gastric cancer cells

    Science.gov (United States)

    Lin, Xiaolin; Tian, Lei; Wang, Lisha; Li, Wenyan; Xu, Qi; Xiao, Xiuying

    2017-01-01

    Licochalcone A (LCA) is a flavonoid extracted from licorice root that has antiparasitic, antibacterial and antitumor properties. Previous studies have revealed that LCA may be a novel treatment for gastric cancer. The present study further assessed the potential antitumor effects of LCA alone or in combination with 5-fluorouracil (5-FU), and the underlying mechanisms responsible for those effects in gastric cancer cells. The effects of LCA alone or in combination with 5-FU on SGC7901 and MKN-45 gastric cancer cell lines were studied using Cell Counting Kit-8, cell cycle, apoptosis and western blot analyses of cell check points and apoptosis-associated proteins. The results revealed that LCA inhibited cell proliferation, blocked cell cycle progression at the G2/M transition and induced apoptosis. Western blot analysis demonstrated that LCA treatment increased the levels of tumor proteins 21 and 27, as well as mouse double minute 2 homolog in gastric cancer cells. In addition, LCA treatment increased the expression levels of Bax, cleaved-poly ADP ribose polymerase, tumor protein 53 and caspase 3, and decreased the expression levels of Bcl-2. Therefore, the present study demonstrated that LCA alone or in combination with 5-FU may have significant anticancer effects on gastric cancer cells, and may be a novel therapeutic for the treatment of gastric cancer in the future. PMID:28454311

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

    Science.gov (United States)

    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

  14. Topical 5% 5-fluorouracil in the treatment of multifocal basal cell carcinoma of the face: A novel chemotherapeutic approach.

    Science.gov (United States)

    Naik, Mayuresh P; Mehta, Anuj; Abrol, Sangeeta; Kumar, Sandeep; Gupta, Vishnu S

    2016-12-01

    To determine the safety and efficacy of topical 5-fluorouracil (5-FU) 5% ointment in treatment of non-syndromic multifocal basal cell carcinoma. A 55-year-old male patient, with 8 hours of daily sun exposure, having histologically proven and radiologically non-syndromic, multifocal basal cell carcinoma with involvement of 6 sites on the face, was treated with topical 5-FU 5% ointment twice daily over all sites except the site involving lid margin to prevent corneal toxicity. Left lid lesion underwent wide surgical excision with 5-mm clear margins and reconstruction with nasal septal mucoperichondrium and local skin mobilization. Pharmacologic effects first appeared at 4 weeks and by 8 weeks, the lesions had scabbed and had fallen off with no induration but residual mild perilesional erythema. Patient had post-op histopathological clear margins and recovered uneventfully. No recurrence in 6 months. A topical 5-FU 5% ointment represents a paradigm shift in the treatment of BCC from invasive and disfiguring options (surgery and chemoradiotherapy) to cheap, convenient, effective, non-invasive, non-disfiguring topical chemotherapy. Topical 5% 5-FU is a safe and effective modality of treatment of superficial spreading multifocal basal carcinoma, especially lesions larger than 10 mm, where margins cannot be identified clearly and recurrent lesions.

  15. Sequential Curettage, 5-Fluorouracil, and Photodynamic Therapy for Field Cancerization of the Scalp and Face in Solid Organ Transplant Recipients.

    Science.gov (United States)

    Jambusaria-Pahlajani, Anokhi; Ortman, Stephanie; Schmults, Chrysalyne D; Liang, Christine

    2016-01-01

    Field cancerization with actinic keratoses and squamous cell carcinoma in situ (AK/SCCIS) represents a common therapeutic challenge in solid organ transplant recipients (SOTRs). These patients often show inadequate responses to methods traditionally used as monotherapy (e.g., topical chemotherapy). To describe the clinical outcomes and feasibility of a sequential approach to treatment of field cancerization in SOTRs. Four SOTRs with field cancerization of the scalp and/or face were treated using a sequential approach. Light curettage of hypertrophic lesions was followed by application of 5-fluorouracil 5% cream twice daily for 5 days and photodynamic therapy (PDT) with 1-hour incubation on day 6. Pain level during and after PDT was recorded. Photographs were obtained immediately before and after treatment and at follow-up appointments. All 4 patients tolerated this approach well and demonstrated excellent responses to treatment with complete or near-complete clinical resolution of AK/SCCIS lesions. Patients remained free of AK/SCCIS based on clinical examination 1 to 6 months after treatment. For SOTRs with field cancerization, sequential therapy represents a viable therapeutic regimen with good tolerability and durable clinical response. This approach warrants further investigation to determine which therapeutic combinations have optimal tolerability and efficacy.

  16. Novel carbopol-based transfersomal gel of 5-fluorouracil for skin cancer treatment: in vitro characterization and in vivo study.

    Science.gov (United States)

    Khan, Mohammed Ashif; Pandit, Jayamanti; Sultana, Yasmin; Sultana, Sarwat; Ali, Asgar; Aqil, Mohammed; Chauhan, Meenakshi

    2015-01-01

    5-fluorouracil (5-Fu) is an antineoplastic drug, topically used for the treatment of actinic keratosis and nonmelanoma skin cancer. It shows poor percutaneous permeation through the conventionally applicable creams and thus inefficient for the treatment of deep-seated skin cancer. In the present article, transfersomal gel containing 5-Fu was investigated for the treatment of skin cancer. Different formulation of tranfersomes was prepared using Tween-80 and Span-80 as edge activators. The vesicles were characterized for particle size, shape, entrapment efficiency, deformability and in vitro skin permeation. Optimized formulation was incorporated into 1% carbopol 940 gel and evaluated for efficacy in the treatment of skin cancer. 5-Fu-loaded transfersomes (TT-2) has the size of 266.9 ± 2.04 nm with 69.2 ± 0.98% entrapment efficiency and highest deformability index of 27.8 ± 1.08. Formulation TT-2 showed maximum skin deposition (81.3%) and comparable transdermal flux of 21.46 µg/cm(2) h. The TT-2-loaded gel showed better skin penetration and skin deposition of the drug than the marketed formulation. Composition of the transfersomal gel has been proved nonirritant to the skin. We concluded that the developed 5-Fu-loaded transfersomal gel improves the skin absorption of 5-Fu and provide a better treatment for skin cancer.

  17. Potentiation of 5-fluorouracil encapsulated in zeolites as drug delivery systems for in vitro models of colorectal carcinoma.

    Science.gov (United States)

    Vilaça, Natália; Amorim, Ricardo; Machado, Ana F; Parpot, Pier; Pereira, Manuel F R; Sardo, Mariana; Rocha, João; Fonseca, António M; Neves, Isabel C; Baltazar, Fátima

    2013-12-01

    The studies of potentiation of 5-fluorouracil (5-FU), a traditional drug used in the treatment of several cancers, including colorectal (CRC), were carried out with zeolites Faujasite in the sodium form, with different particle sizes (NaY, 700nm and nanoNaY, 150nm) and Linde type L in the potassium form (LTL) with a particle size of 80nm. 5-FU was loaded into zeolites by liquid-phase adsorption. Characterization by spectroscopic techniques (FTIR, (1)H NMR and (13)C and (27)Al solid-state MAS NMR), chemical analysis, thermal analysis (TGA), nitrogen adsorption isotherms and scanning electron microscopy (SEM), demonstrated the successful loading of 5-FU into the zeolite hosts. In vitro drug release studies (PBS buffer pH 7.4, 37°C) revealed the release of 80-90% of 5-FU in the first 10min. To ascertain the drug release kinetics, the release profiles were fitted to zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Weibull kinetic models. The in vitro dissolution from the drug delivery systems (DDS) was explained by the Weibull model. The DDS efficacy was evaluated using two human colorectal carcinoma cell lines, HCT-15 and RKO. Unloaded zeolites presented no toxicity to both cancer cells, while all DDS allowed an important potentiation of the 5-FU effect on the cell viability. Immunofluorescence studies provided evidence for zeolite-cell internalization. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Competitive binding of (-)-epigallocatechin-3-gallate and 5-fluorouracil to human serum albumin: A fluorescence and circular dichroism study

    Science.gov (United States)

    Yuan, Lixia; Liu, Min; Liu, Guiqin; Li, Dacheng; Wang, Zhengping; Wang, Bingquan; Han, Jun; Zhang, Min

    2017-02-01

    Combination therapy with more than one therapeutic agent can improve therapeutic efficiency and decrease drug resistance. In this study, the interactions of human serum albumin (HSA) with individual or combined anticancer drugs, (-)-epigallocatechin-3-gallate (EGCG) and 5-fluorouracil (FU), were investigated by fluorescence and circular dichroism (CD) spectroscopy. The results demonstrated that the interaction of EGCG or FU with HSA is a process of static quenching and EGCG formed a more stable complex. The competitive experiments of site markers suggested that both anti-carcinogens mainly bound to site I (subdomain IIA). The interaction forces which play important roles in the binding process were discussed based on enthalpy and entropy changes. Moreover, the competition binding model for a ternary system was proposed so as to precisely calculate the binding parameters. The results demonstrated that one drug decreased the binding affinity of another drug with HSA, resulting in the increasing free drug concentration at the action sites. CD studies indicated that there was an alteration in HSA secondary structure due to the binding of EGCG and FU. It can be concluded that the combination of EGCG with FU may enhance anticancer efficacy. This finding may provide a theoretical basis for clinical treatments.

  20. Influence of Spray-dried Hydroxyapatite-5-Fluorouracil Granules on Cell Lines Derived from Tissues of Mesenchymal Origin

    Directory of Open Access Journals (Sweden)

    Tim Scharnweber

    2008-11-01

    Full Text Available In our previous work we described the preparation and characterization of spray dried hydroxyapatite micro granules loaded with 5-fluorouracil (5-FU. These loaded particles are used as a model drug delivery system (DDS. In this study we examined the in vitro response of two cell lines derived from different tissues to 5-FU loaded granules (LG. Both cell lines, either L929 cells of a mouse fibroblast lineage or cells originating from a rat osteosarcoma (ROS 17/2.8 showed a dose dependent decrease in cell proliferation in response to 5-FU-, either dissolved in the culture medium or loaded onto particles. The response of the two cell lines to loaded and nonloaded particles was different. The effect of LG and of a corresponding concentration of free 5-FU was practically the same for the ROS 17/2.8 cells indicating that ROS 17/2.8 cells were not affected by the carrier material. In contrast, L929 cells showed a slight decrease in cell proliferation also in the presence of granules not loaded with 5-FU. This is thought to be attributed to the inhibition of mitogenesis by phosphocitrates, already demonstrated in fibroblasts. In summary, we found that the loaded 5-FU kept its effectivity after the spray drying process and that the response towards the granules varied with cell type. This is the first step towards a tissue specific DDS.

  1. Retrospective Analysis of the Risk Factors for Grade IV Neutropenia in Oesophageal Cancer Patients Treated with a Docetaxel, Cisplatin, and 5-Fluorouracil Regimen.

    Science.gov (United States)

    Naito, Masahito; Yamamoto, Tomoya; Shimamoto, Chikao; Miwa, Yoshihiro

    2017-01-01

    Previous Japanese trials of the docetaxel, cisplatin, and 5-fluorouracil regimen for oesophageal cancer have demonstrated that a large proportion of patients also develop grade IV neutropenia. Our aim was to examine the risk factors for neutropenia in patients treated with this regimen. We retrospectively analysed the risk factors for developing grade IV neutropenia in 66 patients with oesophageal cancer using a multivariate analysis. After administering the docetaxel, cisplatin, and 5-fluorouracil regimen, 49 patients (74.2%) developed grade IV neutropenia. Grade IV neutropenia was significantly associated with platelet count (p neutropenia. The receiver operating characteristic area for grade IV neutropenia was increased by including patients that were administered a proton-pump inhibitor and alanine transaminase level (updated model; sensitivity and specificity, 75.5 and 88.2%, respectively). Our findings suggest that a platelet count is the most significant predictor of grade IV neutropenia. © 2017 S. Karger AG, Basel.

  2. The impact of insulin on chemotherapeutic sensitivity to 5-fluorouracil in gastric cancer cell lines SGC7901, MKN45 and MKN28

    OpenAIRE

    Wei, Zhao; Liang, Li; Junsong, Liu; Rui, Chen; Shuai, Chang; Guanglin, Qiu; Shicai, He; Zexing, Wang; Jin, Wang; Xiangming, Che; Shufeng, Wang

    2015-01-01

    Background The role of insulin in the pathogenesis of cancer has been increasingly emphasized because of the high incidence of obesity and metabolic syndrome and their correlated complication including cancer. This study aimed to explore the impact of insulin on chemoresistance to 5-fluorouracil in gastric cancer and the possible mechanisms. Methods Tissue samples of gastric cancer and adjacent normal gastric mucosa from patients with or without obesity were performed immunohistochemical stai...

  3. Ablative Fractional Laser Resurfacing With Laser-Assisted Delivery of 5-Fluorouracil for the Treatment of Cicatricial Ectropion and Periocular Scarring.

    Science.gov (United States)

    Lee, Bradford W; Levitt, Alexandra E; Erickson, Benjamin P; Ko, Audrey C; Nikpoor, Neda; Ezuddin, Nisreen; Lee, Wendy W

    2017-06-27

    Cicatricial ectropion and periocular scarring can cause significant functional and cosmetic deficits. Surgical treatments can be associated with recicatrization, donor site morbidity, and textural and pigmentary abnormalities. This case series reports on efficacy and safety of a novel nonsurgical approach to treating cicatricial ectropion using ablative fractional laser resurfacing and laser-assisted delivery of 5-fluorouracil. A retrospective review was conducted of all patients at a single institution who received ≥3 rounds of ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil. Six patients with cicatricial ectropion and periocular scarring secondary to reconstructive surgery, traumatic lacerations, and facial burns were included. Aesthetic and functional improvement were evaluated via fluorescein staining, tear breakup time, external photography, questionnaires gauging dry eye symptoms, and scar appearance. All patients showed functional improvement based on fluorescein staining (mean improvement 6.0 ± 1.4; p = 0.0007) and other indicators of dry eye. All 4 patients with lagophthalmos improved and 2 showed complete resolution. All patients demonstrated significant cosmetic improvement based on a validated scar assessment questionnaire (mean improvement 37.5 ± 18.9; p = 0.004), and 5 of 6 patients reported improved satisfaction with scar appearance (mean improvement 19.3 ± 12.8; p = 0.014). There were no adverse effects reported. Ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil appears to be a safe and effective modality for treating the functional and aesthetic abnormalities associated with periocular scarring, yielding results that are difficult to attain through surgery alone. Optimal management of cicatricial ectropion and periocular scarring often requires multimodality treatment, and ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil may be

  4. Chemoradiotherapy with or without consolidation chemotherapy using cisplatin and 5-fluorouracil in anal squamous cell carcinoma: long-term results in 31 patients

    Directory of Open Access Journals (Sweden)

    Roh Jae

    2008-01-01

    Full Text Available Abstract Background The objectives of this study were to evaluate long-term results of concurrent chemoradiotherapy (CRT with 5-fluorouracil and cisplatin and the potential benefit of consolidation chemotherapy in patients with anal squamous cell carcinoma (ASCC. Methods Between January 1995 and February 2006, 31 patients with ASCC were treated with CRT. Radiotherapy was administered at 45 Gy over 5 weeks, followed by a boost of 9 Gy to complete or partial responders. Chemotherapy consisted of 5-fluorouracil (750 or 1,000 mg/m2 daily on days 1 to 5 and days 29 to 33; and, cisplatin (75 or 100 mg/m2 on day 2 and day 30. Twelve patients had T3–4 disease, whereas 18 patients presented with lymphadenopathy. Twenty-one (67.7% received consolidation chemotherapy with the same doses of 5-fluorouracil and cisplatin, repeated every 4 weeks for maximum 4 cycles. Results Nineteen patients (90.5% completed all four courses of consolidation chemotherapy. After CRT, 28 patients showed complete responses, while 3 showed partial responses. After a median follow-up period of 72 months, the 5-year overall, disease-free, and colostomy-free survival rates were 84.7%, 82.9% and 96.6%, demonstrating that CRT with 5-fluorouracil and cisplatin yields a good outcome in terms of survival and sphincter preservation. No differences in 5-year OS and DFS rates between patients treated with CRT alone and CRT with consolidation chemotherapy was observed. Conclusion our study shows that CRT with 5-FU and cisplatin, with or without consolidation chemotherapy, was well tolerated and proved highly encouraging in terms of long-term survival and the preservation of anal function in ASCC. Further trials with a larger patient population are warranted in order to evaluate the potential role of consolidation chemotherapy.

  5. Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand.

    Science.gov (United States)

    Liljenfeldt, Lina; Gkirtzimanaki, Katerina; Vyrla, Dimitra; Svensson, Emma; Loskog, Angelica Si; Eliopoulos, Aristides G

    2014-03-01

    Bystander immune activation by chemotherapy has recently gained extensive interest and provided support for the clinical use of chemotherapeutic agents in combination with immune enhancers. The CD40 ligand (CD40L; CD154) is a potent regulator of the anti-tumor immune response and recombinant adenovirus (RAd)-mediated CD40L gene therapy has been effective in various cancer models and in man. In this study we have assessed the combined effect of local RAd-CD40L and 5-fluorouracil (5-FU) administration on a syngeneic MB49 mouse bladder tumor model. Whereas MB49 cells implanted into immunocompetent mice responded poorly to RAd-CD40L or 5-FU alone, administration of both agents dramatically decreased tumor growth, increased survival of the mice and induced systemic MB49-specific immunity. This combination treatment was ineffective in athymic nude mice, highlighting an important role for T cell mediated anti-tumor immunity for full efficacy. 5-FU up-regulated the expression of Fas and immunogenic cell death markers in MB49 cells and cytotoxic T lymphocytes from mice receiving RAd-CD40L immunotherapy efficiently lysed 5-FU treated MB49 cells in a Fas ligand-dependent manner. Furthermore, local RAd-CD40L and 5-FU administration induced a shift of myeloid-derived suppressor cell phenotype into a less suppressive population. Collectively, these data suggest that RAd-CD40L gene therapy is a promising adjuvant treatment to 5-FU for the management of bladder cancer.

  6. PCL foamed scaffolds loaded with 5-fluorouracil anti-cancer drug prepared by an eco-friendly route.

    Science.gov (United States)

    Salerno, Aurelio; Domingo, Concepción; Saurina, Javier

    2017-06-01

    This study describes a new preparation method, which combines freeze drying and supercritical CO2 foaming approaches, for the preparation of drug delivery scaffolds of polycaprolactone loaded with 5-fluorouracil, an anti-cancer drug, with low solubility in scCO2. It is a principal objective of this work to design a scCO2 strategy to reduce 5-Fu solubility limitations in its homogeneous distribution into a PCL scaffold through the design of an innovative processing method. The design of this process is considered valuable for the development of clean technology in pharmacy and medicine, since most of the active agents have a null solubility in scCO2·Supercritical CO2 is used as a blowing agent to induce polymer foaming by means of the low temperature pressure quench process. The resulting samples have been prepared under different operational conditions focused on enhancing the performance of the release process. In this case, design of experiments (DOE) was considered for a more comprehensive and systematic optimization of the product. In particular, drug amount, equals to 4.8 or 9.1wt%, process temperature, of 45 or 50°C and depressurization rate, equals to 0.1MPas(-1) or 2MPas(-1) were selected as the factors to be investigated by a three-factor at two-level full factorial design. Samples were characterized to establish porosity data, drug loading percentage and, especially, release profile chromatographically monitored. Results from DOE have concluded which are the best samples providing a sustained drug release for several days, which may be of great interest to develop materials for tissue engineering and sustained release applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients.

    Science.gov (United States)

    Abdallah, Emne Ali; Fanelli, Marcello Ferretti; Buim, Marcilei Eliza Cavicchioli; Machado Netto, Marcelo Calil; Gasparini Junior, José Luiz; Souza E Silva, Virgílio; Dettino, Aldo Lourenço Abbade; Mingues, Natalia Breve; Romero, Juliana Valim; Ocea, Luciana Menezes Mendonça; Rocha, Bruna Maria Malagoli; Alves, Vanessa Silva; Araújo, Daniel Vilarim; Chinen, Ludmilla Thomé Domingos

    2015-09-15

    Thymidylate synthase (TYMS) is an important enzyme for 5-fluorouracil (5-FU) metabolism in metastatic colorectal cancer (mCRC) patients. The search for this enzyme in circulating tumor cells (CTCs) can be a powerful tool to follow-up cancer patients. mCRC patients were enrolled before the beginning of 5-FU-based chemotherapy. The blood was filtered on Isolation by Size of Epithelial Tumor Cells (ISET), and the analysis of TYMS expression in CTCs was made by immunocytochemistry. Additionally, we verified TYMS staining in primary tumors and metastases from the same patients. There were included 54 mCRC patients and 47 of them received 5-FU-based chemotherapy. The median CTCs number was 2 per mL. We were not able to analyze immunocytochemistry in 13 samples (9 patients with absence of CTCs and 4 samples due to technical reasons). Therefore, TYMS expression on CTCs was analyzed in 34 samples and was found positive in 9 (26.5%). Six of these patients had tumor progression after treatment with 5-FU. We found an association between CTC TYMS staining and disease progression (DP), although without statistical significance (P = 0.07). TYMS staining in primary tumors and metastases tissues did not have any correlation with disease progression (P = 0.67 and P = 0.42 respectively). Patients who had CTC count above the median (2 CTCs/mL) showed more TYMS expression (P = 0.02) correlating with worse prognosis. Our results searching for TYMS staining in CTCs, primary tumors and metastases suggest that the analysis of TYMS can be useful tool as a 5-FU resistance predictor biomarker if analyzed in CTCs from mCRC patients. © 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  8. The Impact of Thymidylate Synthase and Methylenetetrahydrofolate Reductase Genotypes on Sensitivity to 5-Fluorouracil Treatment in Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Fakhraddin Naghibalhossaini

    2018-01-01

    Full Text Available 5-fluorouracil (5-FU is one of the major components of many standard regimens for chemotherapy of colorectal cancer (CRC and some other malignancies. Given the known relationship between thymidylate synthase (TS and methylenetetrahydrofolate reductase (MTHFR activity and 5-FU metabolism, this study investigated the impact of selected functional polymorphisms of the TS and MTHFR genes on chemotherapy resistance in 5 human CRC cell lines. HCT116, SW1116, HT29/219, LS180, and Caco-2 CRC cells were cultured as monolayer and their chemosensitivity to 5-FU, oxaliplatin, and irinotecan was determined by MTT assay. Genomic DNA was extracted from the cultured cells, and a 6-bp insertion or deletion (6-bp ins/del polymorphism in 3´-UTR of the TS gene was determined by the PCR-RFLP method. Genotyping of MTHFR 677 C/T and 1298A/C single nucleotide polymorphism (SNP was also performed by MS-PCR and PCR-RFLP, respectively. Caco-2 with the homozygous TS 6-bp ins/ins and MTHFR 677 T/T and 1298 C/C genotype, was the most 5-FU resistant cell line. HCT116 with the homozygous TS 6-bp del/del and MTHFR 1298 A/A and heterozygous MTHFR 677 C/T genotype was the least 5-FU resistant cell. LS180, the second most 5-FU resistant cell line, was heterozygous for all three polymorphic sits. HT29/219 and SW1116 cells with homozygous TS 6-bp ins/ins and heterozygous MTHFR 677 C/T and 1298 A/C genotypes had intermediate 5-FU sensitivity. The results indicate that TS 3´-UTR 6-bp insertion and MTHFR 677T and 1298C alleles increase 5-FU resistance in CRC cells. No relationship was observed between TS and MTHFR genotypes and oxaliplatin or irinotecan sensitivity in these cells.

  9. The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma

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    Angkana Thongkum

    2017-06-01

    Full Text Available Argininosuccinate synthetase (ASS, a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC. Similar to previous reports, we have found the decrease in ASS expression in poorly differentiated HCC. These ASS(- tumors are auxotrophic for arginine. Pegylated arginine deiminase (ADI-PEG20, which degrades arginine, has shown activity in these tumors, but the antitumor effect is not robust and hence combination treatment is needed. Herein, we have elucidated the effectiveness of ADI-PEG20 combined with 5-Fluorouracil (5-FU in ASS(-HCC by targeting urea cycle and pyrimidine metabolism using four HCC cell lines as model. SNU398 and SNU387 express very low levels of ASS or ASS(- while Huh-1, and HepG2 express high ASS similar to normal cells. Our results showed that the augmented cytotoxic effect of combination treatment only occurs in SNU398 and SNU387, and not in HepG2 and Huh-1 (ASS(+ cells, and is partly due to reduced anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP, myeloid leukemia cell differentiation protein (Mcl-1 and B-cell lymphoma-2 (Bcl-2. Importantly, lack of ASS also influences essential enzymes in pyrimidine synthesis (carbamoyl-phosphate synthetase2, aspartate transcarbamylase and dihydrooratase (CAD and thymidylate synthase (TS and malate dehydrogenase-1 (MDH-1 in TCA cycle. ADI-PEG20 treatment decreased these enzymes and made them more vulnerable to 5-FU. Transfection of ASS restored these enzymes and abolished the sensitivity to ADI-PEG20 and combination treatment. Overall, our data suggest that ASS influences multiple enzymes involved in 5-FU sensitivity. Combining ADI-PEG20 and 5-FU may be effective to treat ASS(-hepatoma and warrants further clinical investigation.

  10. 5-Fluorouracil as an enhancer of aminolevulinate-based photodynamic therapy for skin cancer: New use for a venerable agent?

    Science.gov (United States)

    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.

  11. Pretreatment with S-1, an oral derivative of 5-fluorouracil, enhances gemcitabine effects in pancreatic cancer xenografts.

    Science.gov (United States)

    Nakahira, Shin; Nakamori, Shoji; Tsujie, Masanori; Takeda, Setsuo; Sugimoto, Keishi; Takahashi, Yuji; Okami, Jiro; Marubashi, Shigeru; Miyamoto, Atsushi; Takeda, Yutaka; Nagano, Hiroaki; Dono, Keizo; Umeshita, Koji; Sakon, Masato; Monden, Morito

    2008-01-01

    The systemic administration of gemcitabine (GEM) has been accepted as a standard treatment for patients with advanced pancreatic cancer. The major mediator of cellular uptake of GEM is the human equilibrative nucleoside transporter 1 (hENT1) whose expression is up-regulated by thymidylate synthase inhibitors, such as 5-fluorouracil (5-FU). S-1 is a novel oral derivative of the 5-FU prodrug tegafur combined with two modulators. Recent clinical trials have reported the promising effect of S-1 in pancreatic cancer. The purpose of this study was to evaluate the relationship between different schedules and the effects of GEM/S-1 combination therapy on pancreatic cancer xenograft models. Human pancreatic tumor xenografts were prepared by subcutaneous implantation of MiaPaCa-2 into nude mice. Expression of hENT1 was determined by quantitative RT-PCR. GEM cellular uptake was determined using [3H] GEM. Significant increases in hENT1 expression and GEM cellular uptake were observed after S-1 treatment. Six different treatment schedules (no treatment, single agent of GEM or S-1, combination treatment with GEM either before, simultaneously or following administration of S-1) were compared. Significant tumor growth inhibition was observed in the mice treated with S-1 followed by GEM compared to either untreated mice or the mice treated with the other schedules. Based on the effects of S-1 on the uptake of GEM, S-1 should be used before GEM treatment. The GEM/S-1 combination therapy in patients with pancreatic cancer may be promising and should be tested in clinical trials.

  12. In vitro cytotoxicity and genotoxicity studies of gold nanoparticles-mediated photo-thermal therapy versus 5-fluorouracil

    Energy Technology Data Exchange (ETDEWEB)

    Gomaa, Iman E., E-mail: iman.gomaa@guc.edu.eg; Abdel Gaber, Sara A. [German University in Cairo (GUC), Faculty of Pharmacy and Biotechnology (Egypt); Bhatt, Samarth; Liehr, Thomas [Friedrich Schiller University, Jena University Hospital, Institute of Human Genetics (Germany); Glei, Michael [Friedrich Schiller University, Faculty of Biology and Pharmacy, Institute of Nutrition (Germany); El-Tayeb, Tarek A. [Cairo University, The National Institute for Laser Enhanced Sciences (NILES) (Egypt); Abdel-Kader, Mahmoud H. [German University in Cairo (GUC), Faculty of Pharmacy and Biotechnology (Egypt)

    2015-02-15

    This study evaluates tumour cell-killing efficacy of metallic gold nanoparticles (AuNPs)-mediated photo-thermal therapy (PTT) in comparison to 5-fluorouracil (5-FU) as a standard chemotherapeutic drug. It also focuses on the possible genetic abnormalities of both drugs in normal blood lymphocytes. Both 5-FU and light-activated spherical AuNPs of 15± nm diameter were used to target MCF-7 breast cancer cell line. Alkaline comet assay, standard karyotyping and multiplex fluorescent in situ hybridization were applied in order to investigate the respective possible genotoxic and mutagenic side effects that might result from the application of each therapeutic modality. Results showed that the LC25 of AuNPs-mediated PTT was achieved at a concentration of 100 µM for 12-h incubation and exposure to light energy of 50 J/cm{sup 2}, while the same cytotoxic effect was obtained by incubating the MCF-7 cells with the same concentration of the chemotherapeutic drug 5-FU for 24 h. On the other hand, AuNPs showed insignificant genotoxic effect of DNA damage represented by 4.6 % in comparison to 18.58 % exerted by 5-FU. The chromosomal studies resulted in normal karyotypes for cells treated with AuNPs-mediated PTT, while those treated with 5-FU showed several types of numerical as well as structural chromosomal aberrations. In conclusion, compared to 5-FU, light-activated AuNPs-mediated PTT provides considerable efficacy in breast cancer cells killing with no genetic side effects under the proposed experimental conditions.

  13. Biomechanical and Macroscopic Evaluations of the Effects of 5-Fluorouracil on Partially Divided Flexor Tendon Injuries in Rabbits

    Directory of Open Access Journals (Sweden)

    Shkelzen B Duci

    2015-01-01

    Full Text Available Background: The main goals of flexor tendon surgery are to restore digital motion by providing tendon healing and to preserve tendon gliding. Our purpose was to investigate the effects of 5-fluorouracil (5-FU on tendon adhesions in partially divided profundus flexor tendons (flexor digitorum profundus [FDPs] following surgical repair and in partially divided FDPs without surgical repair, and to compare the results of the repair versus the nonrepair of zone two injuries via macroscopic and biomechanical evaluations of tendon adhesions. Methods: We used 32 adult male European rabbits (Oryctolagus cunniculus weighing from 2.5 to 3.5 kg. The study was performed on the deep flexor tendons of the second and third digits of the right hind paws of the rabbits; thus, a total of 64 tendons were examined in this study. Results: Based on the results achieved in our experimental study, the load (N significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared with subgroup 2a in which tendons were surgically repaired and treated with 5-FU. Conclusions: The load (N significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared to subgroup 2a in which the tendons were surgically repaired and treated with 5-FU. Therefore, these results revealed a decrease in adhesion formation in the subgroup that was treated with 5-FU due to increased resistance to tendon adhesions during their excursion through the tendon sheath, which in this case required greater traction force.

  14. Biomechanical and Macroscopic Evaluations of the Effects of 5-Fluorouracil on Partially Divided Flexor Tendon Injuries in Rabbits

    Science.gov (United States)

    Duci, Shkelzen B; Arifi, Hysni M; Ahmeti, Hasan R; Manxhuka-Kerliu, Suzana; Neziri, Burim; Mekaj, Agon Y; Lajqi, Shpetim; Shahini, Labinot

    2015-01-01

    Background: The main goals of flexor tendon surgery are to restore digital motion by providing tendon healing and to preserve tendon gliding. Our purpose was to investigate the effects of 5-fluorouracil (5-FU) on tendon adhesions in partially divided profundus flexor tendons (flexor digitorum profundus [FDPs]) following surgical repair and in partially divided FDPs without surgical repair, and to compare the results of the repair versus the nonrepair of zone two injuries via macroscopic and biomechanical evaluations of tendon adhesions. Methods: We used 32 adult male European rabbits (Oryctolagus cunniculus) weighing from 2.5 to 3.5 kg. The study was performed on the deep flexor tendons of the second and third digits of the right hind paws of the rabbits; thus, a total of 64 tendons were examined in this study. Results: Based on the results achieved in our experimental study, the load (N) significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared with subgroup 2a in which tendons were surgically repaired and treated with 5-FU. Conclusions: The load (N) significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared to subgroup 2a in which the tendons were surgically repaired and treated with 5-FU. Therefore, these results revealed a decrease in adhesion formation in the subgroup that was treated with 5-FU due to increased resistance to tendon adhesions during their excursion through the tendon sheath, which in this case required greater traction force. PMID:26063369

  15. Development and characterization of chitosan-polycarbophil interpolyelectrolyte complex-based 5-fluorouracil formulations for buccal, vaginal and rectal application

    Directory of Open Access Journals (Sweden)

    Pendekal Mohamed S

    2012-10-01

    Full Text Available Abstract Background of the study The present investigation was designed with the intention to formulate versatile 5-fluorouracil (5-FU matrix tablet that fulfills the therapeutic needs that are lacking in current cancer treatment and aimed at minimizing toxic effect, enhancing efficacy and increasing patient compliance. The manuscript presents the critical issues of 5-FU associate with cancer and surpasses issues by engineering novel 5-FU matrix tablets utilizing chitosan- polycarbophil interpolyelectrolyte complex (IPEC. Methods Precipitation method is employed for preparation of chitosan and polycarbophil interpolyelectrolyte complex (IPEC followed by characterization with Fourier transform infrared spectroscopy (FT-IR, Differential Scanning calorimeter (DSC and X-ray Diffraction (XRD. 5-FU tablets were prepared by direct compression using IPEC. Six formulations were prepared with IPEC alone and in combination with chitosan, polycarbophil and Sodium deoxycholate. The formulations were tested for drug content, hardness, friability, weight variation, thickness, swelling studies, in vitro drug release (buccal, vaginal and rectal pH, ex vivo permeation studies, mucoadhesive strength and in vivo studies. Results FT-IR studies represent the change in spectra for the IPEC than single polymers.DSC study represents the different thermo gram for chitosan, polycarbophil and IPEC whereas in X-ray diffraction, crystal size alteration was observed. Formulations containing IPEC showed pH independent controlled 5-FU without an initial burst release effect in buccal, vaginal and rectal pH. Furthermore, F4 formulations showed controlled release 5-FU with highest bioadhesive property and satisfactory residence in both buccal and vaginal cavity of rabbit. 3% of SDC in formulation F6 exhibited maximum permeation of 5-FU. Conclusion The suitable combination of IPEC, chitosan and polycarbophil demonstrated potential candidate for controlled release of 5-FU in buccal

  16. Administration of probiotic mixture DM#1 ameliorated 5-fluorouracil-induced intestinal mucositis and dysbiosis in rats.

    Science.gov (United States)

    Tang, Yan; Wu, Yingtao; Huang, Ziyi; Dong, Weiwei; Deng, Ying; Wang, Fengjiao; Li, Ming; Yuan, Jieli

    2017-01-01

    The use of probiotics to alleviate chemotherapy-induced intestinal mucositis is supported by clinical consensus. However, no studies to date, to our knowledge, have systematically analyzed the effects of a probiotic mixture on chemotherapy-induced mucositis or assessed changes in the intestinal microbiota after probiotic treatment. The aim of this study was to report the effects of a probiotic mixture, DM#1, on intestinal mucositis and dysbiosis of rats treated with 5-fluorouracil (5-FU). Twenty-eight male Sprague Dawley rats weighing 180 to 220 g were randomly divided into four groups: control, 5-FU, probiotic high (PH), and probiotic low (PL). Except for the control group, all other groups received intraperitoneal injections of 5-FU for 5 d, and the PH and PL groups received DM#1 intragastrically (1 × 109 or 1 × 108 colony-forming units/kg, respectively) for 8 d. One day after the last administration, rats were sacrificed and the ilea were removed for histopathologic assessment and evaluation of permeability, myeloperoxidase activity, levels of cytokines (interleukin [IL]-4, IL-6, tumor necrosis factor [TNF]-α), and mRNA of toll-like receptors (TLR; TLR2, TLR4, and TLR9). Additionally, intestinal microbiota profiles were analyzed by polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis and quantitative real-time PCR. Treatment with DM#1 ameliorated 5-FU-induced intestinal mucosal injury in rats, possibly by reducing proinflammatory cytokine levels and neutrophil infiltration. The increased intestinal permeability caused by 5-FU was ameliorated. These results were closely associated with the reestablishment of intestinal microbial homeostasis and alteration of the TLR2/TLR4 signaling pathway. Administration of the probiotic mixture DM#1 ameliorated 5-FU-induced intestinal mucositis and dysbiosis in rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Factors affecting the sensitivity of human-derived esophageal carcinoma cell lines to 5-fluorouracil and cisplatin

    Science.gov (United States)

    MINEGAKI, TETSUYA; TAKARA, KOHJI; HAMAGUCHI, RYOHEI; TSUJIMOTO, MASAYUKI; NISHIGUCHI, KOHSHI

    2013-01-01

    Effective chemotherapy against esophageal carcinoma is considered achievable with a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP). However, chemo-therapy remains ineffective in certain patients. The aim of this study was to clarify the factors which affect sensitivity to 5-FU and CDDP. The effects of factors known to influence sensitivity to 5-FU and CDDP, namely transporters, DNA repair enzymes and metabolic enzymes, were examined. mRNA levels of four transporters, SLC22A2, SLC23A2, ABCB1 and ABCC2, two DNA repair-related enzymes, Rad51 and MSH2, and one metabolic enzyme, dihydropyrimidine dehydrogenase (DPYD), showed a strong correlation (|r|>0.7) with IC50 values for 5-FU. In addition, the mRNA levels of ABCC2, MSH2 and DPYD showed a strong correlation (|r|>0.7) with the IC50 values for CDDP. Gimeracil, a DPYD inhibitor, enhanced the sensitivity of some cells to 5-FU but decreased the sensitivity of all the cells to CDDP. The inhibitory effects of ABCC2 with MK571 did not correspond to those observed in the correlation analysis. In conclusion, mRNA levels of SLC22A2, SLC23A2, ABCB1, ABCC2, Rad51, MSH2 and DPYD were confirmed to be strongly correlated with IC50 values for 5-FU, and mRNA levels of ABCC2, MSH2 and DPYD were confirmed to be strongly correlated with IC50 values for CDDP. In addition, the inhibition of DPYD appeared to affect the cytotoxicity of CDDP. PMID:23420099

  18. Enhanced antitumor activity of irofulven in combination with 5-fluorouracil and cisplatin in human colon and ovarian carcinoma cells.

    Science.gov (United States)

    Poindessous, Virginie; Koeppel, Florence; Raymond, Eric; Cvitkovic, Esteban; Waters, Stephen J; Larsen, Annette K

    2003-11-01

    Irofulven (6-hydroxymethylacylfulvene, MGI-114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product obtained from the Omphalotus mushroom. Irofulven has demonstrated potent activity against a broad range of solid tumors in both cellular and xenograft models and has shown promising activity in clinical trials. To guide the clinical use of irofulven, the present study used the MTT viability assay to examine the cytotoxic effects obtained by combining irofulven with two other anticancer agents: cisplatin and 5-fluorouracil (5-FU). The study was carried out with HT-29 and HCT-116 colorectal and A2780 ovarian carcinoma cells as well as with their irofulven- (HT-29/IF2, HCT-116/IF27) or cisplatin-resistant (A2780/CP70) variants. The combinations showed strong sequence specificity. Simultaneous exposure to cisplatin and irofulven was at least additive for four cell lines including the cisplatin-resistant A2780/CP70 ovarian cells which exhibit a multifactorial resistance phenotype. Cisplatin followed by irofulven was additive for parental HCT-116 and A2780 cells whereas irofulven followed by cisplatin was antagonistic in all cellular models. Simultaneous exposure to 5-FU and irofulven was at least additive for all six cell lines. 5-FU followed by irofulven was additive for the parental HT-29 and A2780 cells and synergistic for the irofulven-resistant HCT-116 cell line. Irofulven followed by 5-FU was synergistic for the two ovarian cell lines and additive for the two parental colon cell lines. These studies demonstrate that simultaneous exposure to irofulven and cisplatin is at least additive for most cell lines whereas simultaneous exposure to irofulven and 5-FU is additive to synergistic for all the cell lines tested, including the irofulven- and cisplatin-resistant variants. The enhanced cytotoxicity of irofulven in combination with cisplatin and 5-FU support the clinical application of these regimens.

  19. Biomechanical and Macroscopic Evaluations of the Effects of 5-Fluorouracil on Partially Divided Flexor Tendon Injuries in Rabbits.

    Science.gov (United States)

    Duci, Shkelzen B; Arifi, Hysni M; Ahmeti, Hasan R; Manxhuka-Kerliu, Suzana; Neziri, Burim; Mekaj, Agon Y; Lajqi, Shpetim; Shahini, Labinot

    2015-06-20

    The main goals of flexor tendon surgery are to restore digital motion by providing tendon healing and to preserve tendon gliding. Our purpose was to investigate the effects of 5-fluorouracil (5-FU) on tendon adhesions in partially divided profundus flexor tendons (flexor digitorum profundus [FDPs]) following surgical repair and in partially divided FDPs without surgical repair, and to compare the results of the repair versus the nonrepair of zone two injuries via macroscopic and biomechanical evaluations of tendon adhesions. We used 32 adult male European rabbits (Oryctolagus cunniculus) weighing from 2.5 to 3.5 kg. The study was performed on the deep flexor tendons of the second and third digits of the right hind paws of the rabbits; thus, a total of 64 tendons were examined in this study. Based on the results achieved in our experimental study, the load (N) significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared with subgroup 2a in which tendons were surgically repaired and treated with 5-FU. The load (N) significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared to subgroup 2a in which the tendons were surgically repaired and treated with 5-FU. Therefore, these results revealed a decrease in adhesion formation in the subgroup that was treated with 5-FU due to increased resistance to tendon adhesions during their excursion through the tendon sheath, which in this case required greater traction force.

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

    Directory of Open Access Journals (Sweden)

    Roberto Madeddu

    2013-08-01

    Full Text Available 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.

  1. Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil.

    Science.gov (United States)

    Gustafsson, Sofia B; Lindgren, Theres; Jonsson, Maria; Jacobsson, Stig O P

    2009-03-01

    Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [(3)H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, alpha-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer.

  2. Development, characterization and in vivo localization study of topical 5-fluorouracil gels: a comparative study with conventional formulation.

    Science.gov (United States)

    Jain, Subheet Kumar; Puri, Richa

    2014-01-01

    5-Fluorouracil (5-FU) is one of the most effective antineoplastic agents used for the treatment of skin cancers and actinic keratosis (AK). Currently commercial formulation for topical 5-FU administration is available in the form of solution or cream. Commercial topical formulations are associated with the limitation of very short retention time at the administration site resulting in very poor skin permeation and deposition of drug. In the present study attempt was made for the preparation, optimization and characterization of bioadhesive gel formulations for localized delivery of 5-FU. Four bioadhesive gel formers, Carbopol 934, Carbopol 980, Methylcellulose (MC) and Poloxamer 188 were selected for the preparation of 5-FU bioadhesive gel formulations. The formulations were characterized for characteristic parameters including bioadhesive strength, skin deposition and interaction study. Carbopol 934 based bioadhesive gel formulation at the concentration of 1.5% w/w showed the best physicochemical properties such as viscosity (2670±12.2 cP), which was similar to the value obtained with the marketed cream (2870±14.4 cP), highest skin deposition (1290±56.4μg) and bioadhesive strength (18.62 gf). Cutaneous irritation of optimized bioadhesive gel formulations was also tested using the Draize test and only very slight erythema and no oedema was observed. In comparison, marketed formulation showed well defined erythema along with oedema formation. The result of the present study demonstrated that formulation of Carbopol 934 based 5-FU bioadhesive gel is a better alternative to the traditional cream base for enhanced topical delivery of 5-FU. The developed formulation will have the ease of application, better skin deposition and sustained release characteristic with reduced skin toxicity.

  3. Treatment of prostate carcinoma with (galectin-3)-targeted HPMA copolymer-(G3-C12)-5-Fluorouracil conjugates.

    Science.gov (United States)

    Yang, Yang; Zhou, Zhou; He, Shuang; Fan, Tingting; Jin, Yun; Zhu, Xi; Chen, Chunhui; Zhang, Zhi-rong; Huang, Yuan

    2012-03-01

    Galectin-3 (Gal-3), over-expressed on a variety of human tumor cells, is a potential binding site for targeted metastatic prostate cancer therapy. The aim of this study was to develop a G3-C12-mediated drug delivery system based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers targeting to Gal-3-expressed human PC-3 prostate carcinoma cells. 5-Fluorouracil (5-Fu), an anti-tumor agent, was selected as a model drug. G3-C12, a binding peptide, which specifically binds to the carbohydrate-recognition domain (CRD) of Gal-3, was attached to HPMA copolymers as a targeting moiety. Compared with non-targeted conjugates (P-Fu), Gal-3-targeted HPMA copolymer-(G3-C12)-5-Fu conjugates (P-(G3-C12)-Fu) displayed a superior intracellular internalization followed by enhanced cytotoxicity and apoptosis-induction. Subsequently, the in vitro migration study on PC-3 cells indicated that P-(G3-C12)-Fu was able to efficiently inhibit the cell migration ability after wounding. On PC-3 tumor-bearing mice model, G3-C12-modified copolymers showed a higher tumor accumulation coupled with a faster clearance from blood circulation than non-modified ones. Finally, Gal-3-targeted conjugates significantly improved the anti-tumor activity of 5-Fu in nude mice bearing PC-3 tumor xenografts. Consequently, G3-C12 would be a promising targeting moiety for cell-specific prostate cancer therapy in future. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. An Inhalable Powder Formulation Based on Micro- and Nanoparticles Containing 5-Fluorouracil for the Treatment of Metastatic Melanoma

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    Kelly Cristine Zatta

    2018-01-01

    Full Text Available Melanoma is the most aggressive and lethal type of skin cancer, with a poor prognosis because of the potential for metastatic spread. The aim was to develop innovative powder formulations for the treatment of metastatic melanoma based on micro- and nanocarriers containing 5-fluorouracil (5FU for pulmonary administration, aiming at local and systemic action. Therefore, two innovative inhalable powder formulations were produced by spray-drying using chondroitin sulfate as a structuring polymer: (a 5FU nanoparticles obtained by piezoelectric atomization (5FU-NS and (b 5FU microparticles of the mucoadhesive agent Methocel™ F4M for sustained release produced by conventional spray drying (5FU-MS. The physicochemical and aerodynamic were evaluated in vitro for both systems, proving to be attractive for pulmonary delivery. The theoretical aerodynamic diameters obtained were 0.322 ± 0.07 µm (5FU-NS and 1.138 ± 0.54 µm (5FU-MS. The fraction of respirable particles (FR% were 76.84 ± 0.07% (5FU-NS and 55.01 ± 2.91% (5FU-MS. The in vitro mucoadhesive properties exhibited significant adhesion efficiency in the presence of Methocel™ F4M. 5FU-MS and 5FU-NS were tested for their cytotoxic action on melanoma cancer cells (A2058 and A375 and both showed a cytotoxic effect similar to 5FU pure at concentrations of 4.3 and 1.7-fold lower, respectively.

  5. Mucoadhesive formulation of Bidens pilosa L. (Asteraceae reduces intestinal injury from 5-fluorouracil-induced mucositis in mice

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    Paulo Henrique Marcelino de Ávila

    2015-01-01

    Full Text Available Gastrointestinal mucositis induced during cancer treatment is considered a serious dose-limiting side effect of chemotherapy and/or radiotherapy. Frequently, interruption of the cancer treatment due to this pathology leads to a reduction in cure rates, increase of treatment costs and decrease life quality of the patient. Natural products such as Bidens pilosa L. (Asteraceae, represent a potential alternative for the treatment of mucositis given its anti-inflammatory properties. In this study, B. pilosa glycolic extract was formulated (BPF with poloxamer, a mucoadhesive copolymer, was used for treatment of 5-fluorouracil (5-FU-induced mucositis in mice. As expected, animals only treated with 5-FU (200 mg/kg presented marked weight loss, reduction of intestinal villi, crypts and muscular layer, which was associated with severe disruption of crypts, edema, inflammatory infiltrate and vacuolization in the intestinal tissue, as compared to the control group and healthy animals only treated with BPF. On the other hand, the treatment of intestinal mucositis-bearing mice with BPF (75, 100 or 125 mg/kg managed to mitigate clinical and pathologic changes, noticeably at 100 mg/kg. This dose led to the restoration of intestinal proliferative activity through increasing Ki-67 levels; modulated the expression of Bax, Bcl2 and p53 apoptotic markers protecting intestinal cells from cell death. Moreover, this treatment regulated lipid peroxidation and inflammatory infiltration. No acute toxic effects were observed with this formulation. This work demonstrated that BPF was safe and effective against 5-FU-induced intestinal mucositis in mice. Additional studies are already in progress to further characterize the mechanisms involved in the protective effects of this technological formulation toward the development of a new medicine for the prevention and treatment of intestinal injury in patients undergoing chemotherapy/radiotherapy.

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

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    Yasushi Hamaya

    Full Text Available 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.

  7. Cost minimization analysis of capecitabine versus 5-fluorouracil-based treatment for gastric cancer patients in Hong Kong.

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    Zhou, Keary R; Cheng, Ashley; Ng, W T; Kwok, T Y; Yip, Elton Y P; Yao, Rosa; Leung, P Y; Lee, V W Y

    2017-05-01

    EOX (epirubicin, oxaliplatin, Xeloda; capecitabine) and FOLFOX4 (5-fluorouracil (5-FU), leucovorin, oxaliplatin) are the common chemotherapy regimens used in the treatment of advanced gastric cancer (aGC) in Hong Kong. This study aimed to compare the costs of these therapies for aGC patients from both the healthcare and societal perspectives. It should be noted that, while FOLFOX4 is routinely administered in an outpatient setting in North America and Europe, inpatient setting is adopted in Hong Kong instead, incurring hospitalization cost as a result. Fifty-eight patients were identified from the electronic records in two public tertiary hospitals, with 45 and 13 receiving EOX and FOLFOX4 regimens, respectively. Healthcare cost was direct medical costs including drugs, clinic follow-up, hospitalization, diagnostic laboratories, and radiographs. Societal cost refers to indirect costs such as patient time and travel costs. Cost items were further classified as "expected" or "unexpected". All cost data was expressed in US dollars. Patients in the EOX and FOLFOX4 arm received an average of 5.3 and 7.8 cycles of treatment, respectively. The capecitabine-based regimen group had a higher expected medication cost per cycle when compared to the 5-FU-based treatment group (US$290.3 vs US$66.9, p costs (US$76.9 vs US$1,269.2, p cost and total societal cost per patient was reduced by 67.2% (US$5,691.9 vs US$17,357.4, p full cycle regimen costs and net capecitabine or 5-FU/leucovorin costs still showed EOX to be less costly than FOLFOX4. The capecitabine-based regimen, EOX, was found to generate significant cost saving from both the healthcare and societal perspectives in regions in which FOLFOX4 is given in an inpatient setting.

  8. DNA repair pathways involved in repair of lesions induced by 5-fluorouracil and its active metabolite FdUMP.

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    Matuo, Renata; Sousa, Fabrício Garmus; Escargueil, Alexandre E; Soares, Daniele G; Grivicich, Ivana; Saffi, Jenifer; Larsen, Annette K; Henriques, João Antonio Pêgas

    2010-01-15

    5-Fluorouracil (5-FU) is an antitumor antimetabolite that can be converted into fluoronucleotides and FdUMP. Fluoronucleotides are incorporated into DNA and RNA, while FdUMP results in nucleotide pool imbalance. Saccharomyces cerevisiae is unable to convert 5-FU into FdUMP, making yeast a unique model system to study the cellular effects of 5-FU and FdUMP independently. A panel of repair-deficient yeast strains was used to identify the DNA repair pathways needed for repair of lesions generated by 5-FU or FdUMP. This included yeast deficient in base excision repair (BER), nucleotide excision repair (NER), translesion synthesis (TLS), mismatch repair (MMR), post-replication repair (PRR), homologous recombination (HR) and non-homologous end-joining (NHEJ). The results revealed an important role of BER, since BER-mutants (ntg1, ntg2, apn1, apn2) showed pronounced sensitivity to both 5-FU and FdUMP. MMR mutants also showed high sensitivity to both compounds. In contrast, deficiencies in NER, NHEJ and TLS repair had only minor influence on the sensitivity to FU and FdUMP. Interestingly, deficiencies in HR (rad52) and PPR (rad6, rad18) were associated with increased sensitivity to 5-FU, but not to FdUMP. Taken together, our study reveals an important contribution of DNA repair pathways on the sensitivity to 5-FU and its active metabolite FdUMP. Importantly, the repair mechanisms differed for the 2 antimetabolites since lesions induced by 5-FU were repaired by BER, MMR, HR and PRR, while only BER and MMR were required for repair of FdUMP-induced lesions.

  9. Chemistry of Secondary Metabolites (Production, Properties, Biological Activity, etc.: Solubility Study of the Interaction between Pamam G-3 Dendrimer and 5 Fluorouracil in Aqueous Solution

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    B. PALECZ

    2014-06-01

    Full Text Available Poly(amidoamine dendrimers (PAMAM are polymeric macromolecules that can find their use as carriers of small ligand molecules such as cosmetics and drugs. 5- Fluorouracil is a potent oncological drug, whose usage is limited because of its relatively high toxicity.The surface and internal layer groups in PAMAM dendrimer belonging to the third (G3 generation create an open-type structure, which facilitate small ligand molecules to bind with them.The formation equilibrium of PAMAM G3 dendrimer complex with an oncologic drug such as 5 fluorouracil (FU in water at room temperature was examined. Using the results of the drug solubility in dendrimer solutions, the maximal number of drug molecules in the dendrimer-drug complex was evaluated. Solubility results show that PAMAM G3 dendrimer can transfer tens 5 fluorouracil molecules in aqueous solution.This research work was funded from the Polish budget appropriations for science in the years 2013-2015, project number IP2012 022372.

  10. Natural polymer-stabilized multiple water-in-oil-in-water emulsions: a novel dermal drug delivery system for 5-fluorouracil.

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    Hoppel, Magdalena; Mahrhauser, Denise; Stallinger, Christina; Wagner, Florian; Wirth, Michael; Valenta, Claudia

    2014-05-01

    The aim of this study was to create multiple water-in-oil-in-water (W/O/W) emulsions with an increased long-term stability as skin delivery systems for the hydrophilic model drug 5-fluorouracil. Multiple W/O/W emulsions were prepared in a one-step emulsification process, and were characterized regarding particle size, microstructure and viscosity. In-vitro studies on porcine skin with Franz-type diffusion cells, tape stripping experiments and attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR) were performed. The addition of Solagum AX, a natural polymer mixture of acacia and xanthan gum, led to multiple W/O/W emulsions with a remarkably increased long-term stability in comparison to formulations without a thickener. The higher skin diffusion of 5-fluorouracil from the multiple emulsions compared with an O/W-macroemulsion could be explained by ATR-FTIR. Shifts to higher wave numbers and increase of peak areas of the asymmetric and symmetric CH2 stretching vibrations confirmed a transition of parts of the skin lipids from an ordered to a disordered state after impregnation of porcine skin with the multiple emulsions. Solagum AX is highly suitable for stabilization of the created multiple emulsions. Moreover, these formulations showed superiority over a simple O/W-macroemulsion regarding skin permeation and penetration of 5-fluorouracil. © 2013 Royal Pharmaceutical Society.

  11. The effect of a pre-anesthetic infusion of amino acids on body temperature, venous blood pH, glucose, creatinine, and lactate of healthy dogs during anesthesia.

    Science.gov (United States)

    Clark-Price, Stuart C; Dossin, Olivier; Ngwenyama, Thandeka R; O'Brien, Mauria A; McMichael, Maureen; Schaeffer, David J

    2015-05-01

    To evaluate the effect of preanesthetic, intravenous (IV) amino acids on body temperature of anesthetized healthy dogs. Randomized, experimental, crossover study. Eight mixed-breed dogs approximately 2 years of age weighing 20.7 ± 2.1 kg. Dogs received 10% amino acid solution (AA) or 0.9% saline (SA) IV at 5 mL kg(-1) over 60 minutes. Body temperature (BT) was recorded at 5 minute intervals during infusions. Dogs were then anesthetized with sevoflurane for 90 minutes. BT was recorded at 5 minute intervals during anesthesia. Jugular blood samples were analyzed for pH, glucose, creatinine, and lactate concentrations at baseline, after infusion, after anesthesia and after 24 hours. BT at conclusion of infusion decreased -0.34 ± 0.42 °C in group AA and -0.40 ± 0.38 °C in group SA and was not different between groups (p = 0.072). BT decreased 2.72 ± 0.37 °C in group AA and 2.88 ± 0.26 °C in group SA after anesthesia and was different between groups (p dogs, preanesthetic IV infusion of amino acids attenuated heat loss compared to controls, however, the amount attenuated may not be clinically useful. Further studies are warranted to determine if nutrient-induced thermogenesis is beneficial to dogs undergoing anesthesia. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  12. 5-Fluorouracil induces inflammation and oxidative stress in the major salivary glands affecting salivary flow and saliva composition.

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    Bomfin, Luana E; Braga, Cíntia M; Oliveira, Thais A; Martins, Conceição S; Foschetti, Danielle A; Santos, Ana A Q A; Costa, Deiziane V S; Leitão, Renata F C; Brito, Gerly A C

    2017-12-01

    This study aimed to elucidate the effect of 5-fluorouracil (5-FU) on the histological aspects of the major salivary glands, salivary flow and saliva composition using an established oral mucositis model in hamsters. Oral mucositis was induced by two intraperitoneal administrations of 5-FU in two consecutive days (60 and 40mg/kg), followed by cheek pouch mucosa scratch, on day 4. The Pilocarpine-stimulated salivary flow was measured 4 and 10days after the first 5-FU injection. Salivary glands were harvested for histopathological analysis, measurement of inflammatory cells, quantification of pro-inflammatory cytokines (TNF-α and IL-1β), investigation of cell death and cell proliferation. Oxidative stress and oxidative defense system were also investigated in the salivary gland tissues using MDA (malondialdehyde), nitrite, non-protein sulfhydryl groups (NP-SH), SOD (superoxide dismutase) and CAT (catalase). In addition, the CAT and lysozyme activities and the IgA and SOD levels were evaluated in the saliva samples. 5-FU significantly reduced the pilocarpine-stimulated salivary flow rate on the 4th experimental day, associated with an increase in the SOD levels in saliva. Recovery of the salivary flow and SOD were observed on day 10, when an increase in the saliva lysozyme levels was detected. In addition, 5-FU promoted vacuolization in parotid (P) and periductal edema in submandibular (SM) gland, combined with an increase in the inflammatory cells influx, mostly observed on the 4th day in SM gland and on 4th and 10th days in P. Oxidative stress was found mostly on day 10 in SM, SL and P glands, associated with release of proinflammatory cytokines, observed in SM and SL glands, but not in P. 5-FU induces an inflammatory response in the major salivary glands, most observed ten days after its first injection, which may contribute to the major salivary glands hypofunction, leading to alterations in the salivary flow rate and composition. Copyright © 2017 Elsevier Inc

  13. Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation.

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    Pangeni, Rudra; Choi, Sang Won; Jeon, Ok-Cheol; Byun, Youngro; Park, Jin Woo

    Oxaliplatin (OXA) is a third-generation cisplatin analog that has been approved as first-line chemotherapy in combination with 5-fluorouracil (5-FU) for the treatment of resectable and advanced colorectal cancer. However, the therapeutic efficacy of oral OXA and 5-FU is limited by their low bioavailability due to poor membrane permeability. The aim of the present study was to develop an oral delivery system for OXA and 5-FU. We constructed an ion-pairing complex of OXA with a deoxycholic acid derivative (N α -deoxycholyl-l-lysyl-methylester, DCK) (OXA/DCK) as a permeation enhancer. Next, we prepared multiple water-in-oil-in-water nanoemulsions incorporating OXA/DCK and 5-FU to enhance their oral absorption. To evaluate their membrane permeability, we assessed in vitro permeabilities of OXA/DCK and 5-FU through an artificial intestinal membrane and Caco-2 cell monolayer. Finally, oral bioavailability in rats and tumor growth inhibition in the colorectal adenocarcinoma cell (CT26)-bearing mouse model were investigated after oral administration of nanoemulsion containing OXA/DCK and 5-FU. The droplet size of the optimized nanoemulsion was 20.3±0.22 nm with a zeta potential of -4.65±1.68 mV. In vitro permeabilities of OXA/DCK and 5-FU from the nanoemulsion through a Caco-2 cell monolayer were 4.80- and 4.30-fold greater than those of OXA and 5-FU, respectively. The oral absorption of OXA/DCK and 5-FU from the nanoemulsion also increased significantly, and the resulting oral bioavailability values of OXA/DCK and 5-FU in the nanoemulsive system were 9.19- and 1.39-fold higher than those of free OXA and 5-FU, respectively. Furthermore, tumor growth in CT26 tumor-bearing mice given the oral OXA/DCK- and 5-FU-loaded nanoemulsion was maximally inhibited by 73.9%, 48.5%, and 38.1%, compared with tumor volumes in the control group and the oral OXA and 5-FU groups, respectively. These findings demonstrate the therapeutic potential of a nanoemulsion incorporating OXA/DCK and

  14. A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients

    Science.gov (United States)

    Honing, J.; Smit, J. K.; Muijs, C. T.; Burgerhof, J. G. M.; de Groot, J. W.; Paardekooper, G.; Muller, K.; Woutersen, D.; Legdeur, M. J. C.; Fiets, W. E.; Slot, A.; Beukema, J. C.; Plukker, J. Th. M.; Hospers, G. A. P.

    2014-01-01

    Background In esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens. Patients and methods This multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m2 and 1 g/m2) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m2). Results Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62–1.51]}, with a median survival of 16.1 (CI 11.8–20.5) and 13.8 months (CI 10.8–16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60–1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9–15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1–14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (≥grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001). Conclusions In this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for

  15. Cooperative effect of Bifidobacteria lipoteichoic acid combined with 5-fluorouracil on hepatoma-22 cells growth and apoptosis.

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    Guo, Bin; Xie, Ning; Wang, Yue

    2015-03-01

    To investigate the cooperative effect of Bifidobacteria lipoteichoic acid (BLTA) combined with 5-fluorouracil on tumor cells growth and apoptosis in mice bearing H22. Hepatoma-22 (H22) cells were cultured in RPMI1640. Establish tumor-bearing mice model of liver cancer by injecting intraperitoneally 1×10(6)/mL cells into the above-mentioned Balb/c mice. 5-FU alone, BLTA alone or BLTA in combination with 5-FU were used to treat tumor-bearing mice. The tumor size were observed and measured regularly. The growth-inhibiting rate (IR) of tumor was detected. Real-Time PCR and Western blot were used to detect Bcl-2, Bax and Caspase-3 expressions of mRNA and protein in tumor tissue of tumor-bearing mice. Detection of apoptotic cells in tumor tissue by HE staining analysis. Detection of the organ index was for evaluate the added-activity of immune organs in mouse. FCM was used to detect T subgroup ratio of spleen cells of tumor-bearing mice. Expression change of mRNA and proteins of Foxp3 and TIM-3 were detected by Real-Time PCR and Western blot in tumor-bearing mice tumor tissue. BLTA and 5-FU significantly inhibited the proliferation of tumor and induced obvious apoptosis, the combined effects were greater than those of the individual agents (P<0.01). The underlying molecular mechanism of apoptotic process could be up-regulation of Bax and down-regulation of Bcl-2 and Caspase-3. The HE staining indicated that combined treat could both induce tissue cells necrosis and increase immune cells infiltration. Organ index showed that BLTA can enhance the proliferation of immune organs. The ratio of CD4(+)CD25(+) Treg significantly decreased and CD4(+) T cell increased in BLTA and 5-FU group (P<0.01). Compared to NS group, mRNA and proteins expression of Foxp3 and TIM-3 down regulated in BLTA and 5-FU group (P<0.01). These results show that combined effects of Bifidobacteria lipoteichoic acid and 5-FU on H22 cells were superior to the individual. The combination did not only

  16. 5-Fluorouracil-induced RNA stress engages a TRAIL-DISC-dependent apoptosis axis facilitated by p53

    Science.gov (United States)

    Akpinar, Birce; Bracht, Ethiene V.; Reijnders, Dorin; Safarikova, Barbora; Jelinkova, Iva; Grandien, Alf; Vaculova, Alena Hyrslova; Zhivotovsky, Boris; Olsson, Magnus

    2015-01-01

    Despite recent advances in targeted therapeutics, administration of 5-fluorouracil (5-FU) remains a common clinical strategy for post-surgical treatment of solid tumors. Although it has been proposed that RNA metabolism is disturbed by 5-FU treatment, the key cytotoxic response is believed to be enzymatic inhibition of thymidylate synthase resulting in nucleotide pool disproportions. An operating p53 tumor suppressor signaling network is in many cases essential for the efficiency of chemotherapy, and malfunctions within this system remain a clinical obstacle. Since the fate of chemotherapy-insensitive tumor cells is rarely described, we performed a comparative analysis of 5-FU toxicity in p53-deficient cells and conclude that p53 acts as a facilitator rather than a gatekeeper of cell death. Although p53 can act as a regulator of several cellular stress responses, no rerouting of cell death mode was observed in absence of the tumor suppressor. Thus, the final death outcome of 5-FU-treated p53−/− cells is demonstrated to be caspase-dependent, but due to a slow pace, accumulation of mitochondrial reactive oxygen species contributes to necrotic characteristics. The oligomerization status of the p53 target gene DR5 is determined as a significant limiting factor for the initiation of caspase activity in an intracellular TRAIL-dependent manner. Using several experimental approaches, we further conclude that RNA- rather than DNA-related stress follows by caspase activation irrespectively of p53 status. A distinct 5-FU-induced stress mechanism is thereby functionally connected to a successive and discrete cell death signaling pathway. Finally, we provide evidence that silencing of PARP-1 function may be an approach to specifically target p53-deficient cells in 5-FU combinatorial treatment strategies. Together, our results disclose details of impaired cell death signaling engaged as a consequence of 5-FU chemotherapy. Obtained data will contribute to the comprehension of

  17. Comparison of plain ice and flavoured ice for preventing oral mucositis associated with the use of 5 fluorouracil.

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    Nikoletti, Sue; Hyde, Susan; Shaw, Thérèse; Myers, Helen; Kristjanson, Linda J

    2005-07-01

    The study aimed to compare the use of plain ice, flavoured ice and standard care, to evaluate the effect on mucositis and to determine patients' perceptions of the two forms of oral cryotherapy. Despite evidence that oral cryotherapy is useful in preventing mucositis in patients receiving 5-fluorouracil, concerns have been expressed about its clinical utility, due to potential side effects and negative perceptions. A randomized, controlled, crossover trial was conducted in the outpatient chemotherapy department of an acute care teaching hospital in Perth, Western Australia. Patients were randomized to receive each of three interventions across three cycles of chemotherapy: standard care alone; standard care plus plain ice; and standard care plus flavoured ice. Oral mucositis was assessed by nurses prior to each of the three chemotherapy cycles and 15 days after each intervention. Two assessment tools were used, the Oral Assessment Guide, and the Western Consortium Cancer Nursing Research Scale. Participants completed a questionnaire to determine their comfort and satisfaction with oral cryotherapy, as well as factors affecting compliance. Findings from 67 patients revealed that when participants used standard care alone, they were significantly more likely to experience symptoms of mucositis than when they used either plain or flavoured ice. Odds ratios were at least threefold higher for standard care alone, varying according to the instrument used. The two main concerns reported were the taste of flavoured ice and the time required to complete the cryotherapy interventions. Side effects such as nausea, sensitivity and headache were reported more frequently for flavoured ice (n = 11) compared with plain ice (n = 5) and standard care (n = 1). Both forms of oral cryotherapy were effective in reducing the severity of oral mucositis after chemotherapy and were more effective than standard care alone. Flavoured ice was associated with the highest frequency of side

  18. Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice.

    Science.gov (United States)

    Wu, Zhen-Qian; Han, Xiao-Dong; Wang, Yu; Yuan, Ke-Li; Jin, Zhi-Ming; Di, Jian-Zhong; Yan, Jun; Pan, Ye; Zhang, Pin; Huang, Xin-Yu; Wang, Zhi-Gang; Zheng, Qi

    2011-07-01

    The aim of this study was to investigate the relationship between changes in IL-1β expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine. Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200 mg/kg). IL-1Ra (1 mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1β induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining. The variation of IL-1β expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1β and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice. Our studies elucidate that IL-1β is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy

  19. Comparison of two low-dose calcium infusion schedules for localization of insulinomas by selective pancreatic arterial injection with hepatic venous sampling for insulin.

    Science.gov (United States)

    Braatvedt, G; Jennison, E; Holdaway, I M

    2014-01-01

    Localization of small insulinomas may be difficult. Selective pancreatic arterial injection of calcium with hepatic venous insulin measurement (SACST) has been used for this purpose, but can rarely cause hypoglycaemia. Two low-dose concentrations of calcium, 0·25 and 0·1 of the usual concentration used for the test, have been compared for sensitivity of localization and safety. Selective pancreatic arterial injection of calcium with hepatic venous insulin measurement was performed at calcium concentrations of 0·0025 (Protocol A) and 0·00625 (Protocol B) mEq calcium per kg. The standard concentration is 0·025 mEq/kg. Twenty one successive patients with biochemical evidence of insulinoma were studied. Using surgical localization as the gold standard, Protocol A had a sensitivity of 91% and Protocol B 75% for correct localization. The false-positive localization rate was 16%. No hypoglycaemia was observed. These results compare favourably with published data using the standard calcium concentration. Selective pancreatic arterial injection of calcium with hepatic venous insulin measurement was superior to localization by noninvasive imaging; in seven cases, SACST was correct when conventional imaging was negative (five) or false positive (two). Low concentrations of calcium are effective and safe when performing SACST for localization of insulinoma. © 2013 John Wiley & Sons Ltd.

  20. Optimization of health-care organization and perceived improvement of patient comfort by switching from intra-venous BU four-times-daily infusions to a once-daily administration scheme in adult hematopoietic stem cell recipients.

    Science.gov (United States)

    Xhaard, A; Rzepecki, P; Valcarcel, D; Santarone, S; Fürst, S; Serrano, D; De Angelis, G; Krüger, W; Scheid, C

    2014-04-01

    Previous studies have shown an equivalent pharmacokinetic profile between four-times-daily (4QD) and once-daily (QD) administration of intra-venous (IV) BU, without increased toxicity. We assess the impact of a switch in IV BU from a 4QD to a QD schedule, in terms of health-care organization, staff working conditions, quality of care dispensed and perceived patient comfort. Clinicians, nurses and pharmacists from nine allogeneic transplantation units in five European countries were interviewed face to face. Overall perception of QD versus 4QD BU was very positive. Both administration schemes were evaluated to be equally efficaciousZ. QD BU was perceived to be safer and more convenient. Clinicians and nurses perceived that patient comfort was improved, due to fewer complications associated with repeated infusions, and avoiding night infusions associated with stress, anxiety and decreased quality of sleep. Switching from 4QD to QD BU had a significant impact on health-care organization, with a better integration in the overall management and usual timelines in the pharmacies and transplantation units. Time spent to prepare and administer BU was significantly reduced, leading to potential financial savings that merit further assessment and would be of particular interest in the current economic climate.

  1. Protein fraction of Calotropis procera latex protects against 5-fluorouracil-induced oral mucositis associated with downregulation of pivotal pro-inflammatory mediators.

    Science.gov (United States)

    Freitas, Ana Paula F; Bitencourt, Flavio S; Brito, Gerly Anne C; de Alencar, Nylane Maria N; Ribeiro, Ronaldo A; Lima-Júnior, Roberto Cesar P; Ramos, Marcio V; Vale, Mariana L

    2012-10-01

    Oral mucositis is an important dose-limiting and costly side effect of cancer chemotherapy. Soluble proteins obtained of the latex of Calotropis procera have been extensively characterized as anti-inflammatory in different experimentally induced inflammatory conditions, including arthritis and sepsis. In this study, the phytomodulatory laticifer proteins (LP) were challenged to regress the inflammatory events associated with 5-fluorouracil-induced oral mucositis. We also evaluated the expression of pro-inflammatory cytokines and inducible enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Oral mucositis was induced in hamsters by two injections of 5-fluorouracil (5-FU; 60 and 40 mg/kg, i.p., on experimental days 1 and 2, respectively). LP (5 mg/kg, i.p.) was injected 24 h before and 24 h after mechanical trauma of the cheek pouches. A normal control group received only saline. On day 10, the animals were sacrificed, and the cheek pouches were excised for macroscopic and histopathological analysis, myeloperoxidase activity measurement, and immunohistochemical assessment of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), iNOS, and COX-2. LP significantly inhibited macroscopic histopathological scores and myeloperoxidase activity compared with the 5-FU control group. 5-Fluorouracil also induced marked immunostaining of TNF-α, IL-1β, iNOS, and COX-2 on inflamed conjunctive and epithelial tissue compared with the normal control group. Such damage was significantly inhibited (p < 0.05) by LP treatment compared with the 5-FU group. These findings demonstrate an anti-inflammatory effect of LP on 5-FU-induced oral mucositis. The protective mechanism appears to involve inhibition of the expression of iNOS, COX-2, TNF-α, and IL-1β.

  2. A polymeric prodrug of 5-fluorouracil-1-acetic acid using a multi-hydroxyl polyethylene glycol derivative as the drug carrier.

    Science.gov (United States)

    Li, Man; Liang, Zhen; Sun, Xun; Gong, Tao; Zhang, Zhirong

    2014-01-01

    Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, which limits the application of PEG for drug conjugation purposes. To increase the drug loading and prolong the retention time of 5-fluorouracil (5-Fu), a macromolecular prodrug of 5-Fu, 5-fluorouracil-1 acid-PAE derivative (5-FA-PAE) was synthesized and tested for the antitumor activity in vivo. PEG with a molecular weight of 38 kDa was selected to synthesize the multi-hydroxyl polyethylene glycol derivative (PAE) through an addition reaction. 5-fluorouracil-1 acetic acid (5-FA), a 5-Fu derivative was coupled with PEG derivatives via ester bond to form a macromolecular prodrug, 5-FA-PAE. The in vitro drug release, pharmacokinetics, in vivo distribution and antitumor effect of the prodrug were investigated, respectively. The PEG-based prodrug obtained in this study possessed an exceedingly high 5-FA loading efficiency of 10.58%, much higher than the maximum drug loading efficiency of unmodified PEG with the same molecular weight, which was 0.98% theoretically. Furthermore, 5-FA-PAE exhibited suitable sustained release in tumors. This study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives.

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

    Directory of Open Access Journals (Sweden)

    Kravik Katherine L

    2006-05-01

    Full Text Available Abstract 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

  4. Preparation of ethosomes and deformable liposomes encapsulated with 5-fluorouracil and their investigation of permeability and retention in hypertrophic scar.

    Science.gov (United States)

    Wo, Yan; Zhang, Zhen; Zhang, Yixin; Wang, Danru; Pu, Zheming; Su, Weijie; Qian, Yunliang; Li, Yunwu; Cui, Daxiang

    2011-09-01

    With the aim of comparing scar penetration efficiency and retention between ethosomes and deformable liposomes both encapsulated with 5-fluorouracil (5-FU), the 5-FU ethosomal suspensions (5-FU ES, 81.74 +/- 9.37 nm) and the 5-FU Deformable Liposomal Suspensions (5-FU DS, 73.7 +/- 9.45 nm) were prepared respectively by Touitou method and Cevc method, their sizes were determined by Particle Sizer System (PSS), and their entrapment Efficiency (EE) was detected by ultracentrifugation and microcolumn centrifugation. Their transdermal delivery experiments were done in hypertrophic scars in vitro. The permeated amount of 5-FU and retention contents of 5-FU were both calculated by High Performance Liquid Chromatography (HPLC). Fluorescence intensities of ES and DS labeled with Rodanmin 6GO (Rho) were measured by Laser Scanning Microscopy (LSM). The control groups such as the 5-FU and empty ethosomal vesicles (5-FU + EEV), the 5-FU and empty deformable liposomal vesicles (5-FU + EDV) and 5-FU PBS Solution (5-FU Sol) were set up. Results showed that, prepared 5-FU ES was 81.74 +/- 9.37 nm in size, 5-FU DS was 73.7 +/- 9.45 nm, EE of 5-FU ES was 10.95%, EE of 5-FU DS was 15.05%. Within 24 hours, in the group of 5-FU ES, the penetration amount of 5-FU in scar was 14.12 +/- 0.1 microg/mL/cm2, the retention contents of 5-FU was 10.74 +/- 1.17 microg/cm2, and the fluorescence intensity of Rho in hypertrophic scar tissues were 182 +/- 18.3; in the group of 5-FU DS: the penetration amount of 5-FU was 12.35 +/- 1.21 microg/mLcm2; the retention contents of 5-FU was 17.48 +/- 0.82 microg/cm2, and the fluorescence intensity of Rho was 241.45 +/- 7.63; there existed statistical difference between penetration amount in the group of 5-FU ES and that in the group of 5-FU DS as well as control groups (P < 0.05, P < 0.01), the penetration amount in the group of ES is markedly higher than DS group or control groups. Conversely, the retention contents of 5-FU and the fluorescence intensity of

  5. Chitosan-Coated Cinnamon/Oregano-Loaded Solid Lipid Nanoparticles to Augment 5-Fluorouracil Cytotoxicity for Colorectal Cancer: Extract Standardization, Nanoparticle Optimization, and Cytotoxicity Evaluation.

    Science.gov (United States)

    Kamel, Kamel M; Khalil, Islam A; Rateb, Mostafa E; Elgendy, Hosieny; Elhawary, Seham

    2017-09-13

    This study aimed to coat lipid-based nanocarriers with chitosan to encapsulate nutraceuticals, minimize opsonization, and facilitate passive-targeting. Phase one was concerned with standardization according to the World Health Organization. Qualitative analysis using liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS) investigated the active constituents, especially reported cytotoxic agents. Cinnamaldehyde and rosmarinic acid were selected to be quantified using high-performance liquid chromatography. Phase two was aimed to encapsulate both extracts in solid lipid nanoparticles (core) and chitosan (shell) to gain the advantages of both materials properties. The developed experimental model suggested an optimum formulation with 2% lipid, 2.3% surfactant, and 0.4% chitosan to achieve a particle size of 254.77 nm, polydispersity index of 0.28, zeta potential of +15.26, and entrapment efficiency percentage of 77.3% and 69.1% for cinnamon and oregano, respectively. Phase three was focused on the evaluation of cytotoxic activity unencapsulated/encapsulated cinnamon and oregano extracts with/without 5-fluorouracil on HCT-116 cells. This study confirmed the success of the suggested combination with 5-fluorouracil for treating human colon carcinoma with a low dose leading to decreasing side effects and allowing uninterrupted therapy.

  6. Quality by design case study 1: Design of 5-fluorouracil loaded lipid nanoparticles by the W/O/W double emulsion - Solvent evaporation method.

    Science.gov (United States)

    Amasya, Gulin; Badilli, Ulya; Aksu, Buket; Tarimci, Nilufer

    2016-03-10

    With Quality by Design (QbD), a systematic approach involving design and development of all production processes to achieve the final product with a predetermined quality, you work within a design space that determines the critical formulation and process parameters. Verification of the quality of the final product is no longer necessary. In the current study, the QbD approach was used in the preparation of lipid nanoparticle formulations to improve skin penetration of 5-Fluorouracil, a widely-used compound for treating non-melanoma skin cancer. 5-Fluorouracil-loaded lipid nanoparticles were prepared by the W/O/W double emulsion - solvent evaporation method. Artificial neural network software was used to evaluate the data obtained from the lipid nanoparticle formulations, to establish the design space, and to optimize the formulations. Two different artificial neural network models were developed. The limit values of the design space of the inputs and outputs obtained by both models were found to be within the knowledge space. The optimal formulations recommended by the models were prepared and the critical quality attributes belonging to those formulations were assigned. The experimental results remained within the design space limit values. Consequently, optimal formulations with the critical quality attributes determined to achieve the Quality Target Product Profile were successfully obtained within the design space by following the QbD steps. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Induction Chemotherapy With Gemcitabine, Oxaliplatin, and 5-Fluorouracil/Leucovorin Followed by Concomitant Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer: A Taiwan Cooperative Oncology Group Phase II Study

    Energy Technology Data Exchange (ETDEWEB)

    Ch' ang, Hui-Ju [National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan (China); Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, Taiwan (China); Lin, Yu-Lin [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Wang, Hsiu-Po [Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (China); Chiu, Yen-Feng [Institute of Public Health Sciences, National Health Research Institutes, Miaoli, Taiwan (China); Chang, Ming-Chu [Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (China); Hsu, Chih-Hung [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Tien, Yu-Wen [Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan (China); Chen, Jen-Shi [Department of Internal Medicine, Chang-Gung Memorial Hospital, Chang Gung University, College of Medicine, Tao-Yuan, Taiwan (China); Hsieh, Ruey-Kuen [Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan (China); Lin, Pin-Wen; Shan, Yan-Shen [Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan (China); Cheng, Ann-Lii [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Chang, Jang-Yang [National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan (China); Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan (China); Whang-Peng, Jacqueline [National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan (China); Cancer Center Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan (China); Hwang, Tsann-Long, E-mail: hwangtl@adm.cgmh.org.tw [Department of Surgery, Chang-Gung Memorial Hospital, Chang Gung University, College of Medicine, Tao-Yuan, Taiwan (China); and others

    2011-12-01

    Purpose: To evaluate the therapeutic efficacy of 3-month triplet induction chemotherapy (ICT) followed by concomitant chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer (LAPC). Patients and Methods: Chemonaieve patients with measurable, histologically confirmed LAPC were eligible. The ICT consisted of biweekly gemcitabine (800 mg/m{sup 2}) infusion at a fixed dose rate (10 mg/m{sup 2}/min), followed by 85 mg/m{sup 2} oxaliplatin and 48-h infusion of 5-fluorouracil/leucovorin (3000/150 mg/m{sup 2}) for 6 cycles. Patients without disease progression 4 weeks after ICT would receive weekly 400 mg/m{sup 2} gemcitabine and 5040 cGy radiation in 28 fractions. After CCRT, patients were subjected for surgical intervention and/or maintenance chemotherapy until progression or intolerable toxicity. Results: Between December 2004 and August 2008, 50 patients were enrolled. The best responses after ICT were partial response (PR) in 9, stable disease in 26, and progressive disease or not evaluable in 15. Among the former 35 patients, 2 had disease progression before CCRT, and 3 declined to have CCRT. Of the 30 patients receiving CCRT, an additional 4 and 1 patient(s) achieved PR at the end of CCRT and during maintenance chemotherapy, respectively. On intent-to-treat analysis, the overall best response was PR in 14 patients and stable disease in 21. The overall response rate and disease control rate were 28% (95% confidence interval [CI], 16.2-42.5%) and 70% (95% CI, 44.4-99.2%), respectively. The median time to progression and overall survival of the intent-to-treat population was 9.3 (95% CI, 5.8-12.8) months and 14.5 (95% CI, 11.9-17.1) months, respectively. One- and two-year survival rates were 68% (95% CI, 55.1-80.9%) and 20.6% (95% CI, 8.7-32.5%), respectively. Neutropenia was the most common Grade 3-4 toxicity of both ICT and CCRT, with a frequency of 28% and 26.7%, respectively. Significant sensory neuropathy occurred in 9 patients (18

  8. A phase II experience with neoadjuvant irinotecan (CPT-11, 5-fluorouracil (5-FU and leucovorin (LV for colorectal liver metastases

    Directory of Open Access Journals (Sweden)

    Bigam David

    2009-05-01

    Full Text Available Abstract Background Chemotherapy may improve survival in patients undergoing resection of colorectal liver metastases (CLM. Neoadjuvant chemotherapy may help identify patients with occult extrahepatic disease (averting unnecessary metastasectomy, and it provides in vivo chemosensitivity data. Methods A phase II trial was initiated in which patients with resectable CLM received CPT-11, 5-FU and LV for 12 weeks. Metastasectomy was performed unless extrahepatic disease appeared. Postoperatively, patients with stable or responsive disease received the same regimen for 12 weeks. Patients with progressive disease received either second-line chemotherapy or best supportive care. The primary endpoint was disease-free survival (DFS; secondary endpoints included overall survival (OS and safety. Results 35 patients were accrued. During preoperative chemotherapy, 16 patients (46% had grade 3/4 toxicities. Resection was not possible in 5 patients. One patient died of arrhythmia following surgery, and 1 patient had transient liver failure. During the postoperative treatment phase, 12 patients (55% had grade 3/4 toxicities. Deep venous thrombosis (DVT occurred in 11 patients (34% at various times during treatment. Of those who underwent resection, median DFS was 23.0 mo. and median OS has not been reached. The overall survival from time of diagnosis of liver metastases was 51.6 mo for the entire cohort. Conclusion A short course of chemotherapy prior to hepatic metastasectomy may serve to select candidates best suited for resection and it may also direct postoperative systemic treatment. Given the significant incidence of DVT, alternative systemic neoadjuvant regimens should be investigated, particularly those that avoid the use of a central venous line. Trial Registration ClinicalTrials.gov NCT00168155.

  9. Comparison of cisplatinum/paclitaxel with cisplatinum/5-fluorouracil as first-line therapy for nonsurgical locally advanced esophageal squamous cell carcinoma patients

    Directory of Open Access Journals (Sweden)

    Hu GF

    2016-07-01

    Full Text Available Guofang Hu,1 Zhehai Wang,2 Yuan Wang,1 Qingqing Zhang,1 Ning Tang,1 Jun Guo,2 Liyan Liu,2 Xiao Han2 1School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, 2Department of Oncology, Shandong Cancer Hospital, Shandong University, Jinan, Shandong, People’s Republic of China Background: To retrospectively evaluate the efficacy and toxicity of definitive concurrent chemoradiotherapy (dCRT with cisplatinum/paclitaxel versus cisplatinum/5-fluorouracil in patients with locally advanced esophageal squamous cell carcinoma (ESCC who received nonsurgical treatment. Methods: This study retrospectively evaluated 202 patients with locally advanced ESCC treated at Shandong Cancer Hospital between January 2009 and December 2013. All the patients initially received dCRT, including platinum and paclitaxel or 5-fluorouracil, with concurrent 1.8 or 2 Gy/fraction radiation (total dose, 54–60 Gy. The patient population was divided into two treatment groups: 105 patients who received the cisplatinum/paclitaxel regimen were allocated to group A, and 97 patients who received the cisplatinum/5-fluorouracil regimen were allocated to group B. We compared the progression-free survival (PFS and overall survival (OS by various clinical variables, including prior treatment characteristics, major toxicities (mainly in grade 3 and 4 hematological, and response to dCRT. We used the receiver operating curve analysis to determine the optimal cutoff value of clinical stage and radiation dose. The Kaplan–Meier method was used for survival comparison and Cox regression for multivariate analysis. Results: Median PFS and OS in group A were significantly better compared with group B (median PFS, 15.9 versus 13.0 months, P=0.016 and median OS, 33.9 versus 23.1 months, P=0.014, respectively. The 1- and 2-year survival rates of the two groups were 82.9% versus 76.3%, and 61.9% versus 47.6%, respectively. The complete response and response rate

  10. Skin tumor development after UV irradiation and photodynamic therapy is unaffected by short-term pretreatment with 5-fluorouracil, imiquimod and calcipotriol

    DEFF Research Database (Denmark)

    Bay, Christiane; Togsverd-Bo, Katrine; Lerche, Catharina M

    2016-01-01

    Background Photodynamic therapy (PDT) delays ultraviolet (UV) radiation-induced squamous cell carcinomas (SCCs) in hairless mice. Efficacy may be enhanced by combining PDT with antineoplastic or pro-differentiating agents. We investigated if pretreatment with 5-fluorouracil (5FU), imiquimod (IMIQ......) or calcipotriol (CAL) before PDT further delays tumor onset. Methods Hairless mice (n = 224) were exposed 3 times weekly to 3 standard erythema doses (SED) of UV radiation. Methyl-aminolevulinate (MAL)-PDT sessions were given on days 45 and 90 before SCC development. Three applications of topical 5FU, IMIQ or CAL...... were given before each PDT session. Fluorescence photography quantified protoporphyrin IX (PpIX) formation. Results PDT delayed UV-induced SCC development by 59 days (212 days UV-MAL-PDT vs. 153 days UV-control, P PDT did not further delay SCC onset...

  11. Urachal carcinoma with liver, lung, and brain metastases: benefit of a new combination chemotherapy (bevacizumab, 5-fluorouracil, irinotecan – case report

    Directory of Open Access Journals (Sweden)

    Dekoninck J

    2011-05-01

    Full Text Available J Dekoninck1, P Demetter2, Filip Geurs1, R De Loecker31Department of Medical Oncology, Regional Hospital Sint Maria, Halle, Belgium; 2Department of Pathology, Hopital Erasme – Université Libre de Bruxelles (ULB, Anderlecht, Belgium; 3Department of Laboratory, Regional Hospital Sint Maria, Halle, BelgiumAbstract: After failure of cisplatin-based chemotherapy for metastatic urachal carcinoma, a 16-year-old patient presents with diffuse liver-, lung-, and brain metastases. The K-ras mutation is present in the liver as well as in the primary resected specimen. The regimen was therefore changed to bevacizumab, 5-fluorouracil, and irinotecan. This led to a partial response which lasted 7 months.Keywords: K-ras mutation, urachal cancer, adenocarcinoma

  12. Complete radiographic remission with 5-fluorouracil and leucovorin after sorafenib failure in hepatocellular carcinoma: is there a role for chemotherapy after targeted agents?

    Science.gov (United States)

    Tan-Shalaby, Jocelyn

    2013-09-16

    A 57-year-old Caucasian man with a history of Child's class A hepatitis C, cirrhosis and progressive multifocal hepatocellular carcinoma was treated with sorafenib but progressed after 7 months of stable disease. At progression he was given salvage chemotherapy consisting of 5-fluorouracil and leucovorin and went into complete radiographic remission after 12 cycles of treatment. He did develop a portal vein thrombosis but nevertheless his hepatic lesions continued to resolve. Throughout his therapy α-fetoprotein (AFP) levels decreased only minimally. He did not seek retreatment after 14 cycles of chemotherapy and presented 3 months later with relapsed disease on CT scans with markedly elevated AFP levels. He received one more chemotherapy cycle but was unable to tolerate further treatment, succumbing to his disease 3 months thereafter, and a total of 29 months after he was deemed a sorafenib failure.

  13. Interaction between paliperidone extended release and TS-1(®), an oral anticancer drug containing a 5-fluorouracil derivative, in a schizophrenic patient.

    Science.gov (United States)

    Yasui-Furukori, Norio; Hashimoto, Kojiro; Kubo, Kazutoshi; Tomita, Tetsu

    2013-01-01

    Until now there has been no information available on drug interaction between paliperidone and TS-1(®), an oral anticancer drug containing a 5-fluorouracil derivative. The patient in the case presented here was a 39-year-old man with a 15-year history of schizophrenia. The patient's usual treatment of 2 mg/day of risperidone was changed to 3 mg/day of paliperidone extended release. He experienced worsening psychotic symptoms after switching from risperidone to paliperidone while he was also receiving TS-1. Retrospective analyses showed plasma concentration of paliperidone was consistently lower during the treatment with TS-1 than without TS-1. This case suggests there is drug interaction between paliperidone extended-release tablets and TS-1.

  14. Utility of initial induction chemotherapy with 5-fluorouracil, cisplatin, and docetaxel (DCF) for T4 esophageal cancer: a propensity score-matched analysis.

    Science.gov (United States)

    Makino, T; Yamasaki, M; Miyazaki, Y; Wada, N; Takahashi, T; Kurokawa, Y; Nakajima, K; Takiguchi, S; Mori, M; Doki, Y

    2017-11-28

    Although no consensus is available on the treatment of esophageal squamous cell carcinoma (ESCC) invading adjacent organs (T4), establishing effective induction treatments is crucial to altering an unresectable status and achieving curative resection. Here, we evaluated the efficacy of chemotherapy using 5-fluorouracil, cisplatin, and docetaxel (DCF) as the initial induction treatment for T4 ESCC. Fifty patients without distant metastasis who underwent initial induction chemotherapy using DCF for T4 ESCC were propensity score-matched with 50 patients who underwent radiotherapy concurrent with cisplatin and 5-fluorouracil (CRT). In the DCF group, 24 (48.0%) patients underwent surgery, achieving a 64% clinical response rate compared to 72.0% for induction CRT. CRT was also performed in another 24 (48.0%) patients in the DCF group in whom surgical resection was not indicated. The DCF group had significantly higher overall resectability than the CRT group (78.0% vs. 48.0%, P = 0.0017). The esophageal perforation rate during induction treatments was significantly lower in the DCF group than the CRT group (4.0% vs. 18.0%, P = 0.0205). Prognosis was significantly better in the DCF group than the CRT group (5-year cancer-specific survival 42.1% vs. 22.2%, P = 0.0146). Thus, induction DCF chemotherapy in patients with T4 ESCC reduced esophageal perforation and increased overall resectability, leading to better survival than CRT alone. Therefore, DCF chemotherapy may be an effective and safe option for initial induction treatment of T4 ESCC. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Irinotecan and 5-fluorouracil-co-loaded, hyaluronic acid-modified layer-by-layer nanoparticles for targeted gastric carcinoma therapy

    Directory of Open Access Journals (Sweden)

    Gao Z

    2017-09-01

    Full Text Available Zhuanglei Gao,1 Zhaoxia Li,2 Jieke Yan,3 Peilin Wang1 1Department of General Surgery, 2Department of Pediatrics, 3Department of Renal Transplantation, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China Abstract: For targeted gastric carcinoma therapy, hyaluronic acid (HA-modified layer-by-layer nanoparticles (NPs are applied for improving anticancer treatment efficacy and reducing toxicity and side effects. The aim of this study was to develop HA-modified NPs for the co-loading of irinotecan (IRN and 5-fluorouracil (5-FU. A novel polymer–chitosan (CH–HA hybrid formulation (HA–CH–IRN/5-FU NPs consisting of poly(D,L-lactide-co-glycolide (PLGA and IRN as the core, CH and 5-FU as a shell on the core and HA as the outmost layer was prepared. Its morphology, average size, zeta potential and drug encapsulation ability were evaluated. Human gastric carcinoma cells (MGC803 cells and cancer-bearing mice were used for the testing of in vitro cytotoxicity and in vivo antitumor efficiency of NPs. HA–CH–IRN/5-FU NPs displayed enhanced antitumor activity in vitro and in vivo than non-modified NPs, single drug-loaded NPs and drugs solutions. The results demonstrate that HA–CH–IRN/5-FU NPs can achieve impressive antitumor activity and the novel targeted drug delivery system offers a promising strategy for the treatment of gastric cancer. Keywords: gastric carcinoma, irinotecan, 5-fluorouracil, hyaluronic acid, layer-by-layer nanoparticles

  16. Concurrent cisplatin and 5-fluorouracil versus concurrent cisplatin and docetaxel with radiotherapy for esophageal squamous cell carcinoma: a propensity score-matched analysis

    Science.gov (United States)

    Hu, Yong-Hong; Guo, Xiaobo; Zhao, Lei; Liu, Hui; Liu, Shi-Liang; Luo, Li-Ling; Liu, Qing; Liu, Meng-Zhong

    2016-01-01

    The optimal concurrent chemotherapy regimen with radiotherapy for esophageal cancer is unknown. Here, we compared the survival outcomes and toxicity of definitive chemoradiotherapy with either cisplatin/5-fluorouracil (PF) or docetaxel/cisplatin (DP) in patients with unresectable esophageal squamous cell carcinoma (ESCC). In this study, we identified 317 patients with ESCC who received PF or DP concurrently with definitive radiotherapy. PF group patients received two cycles of cisplatin (60 mg/m2) and 5-fluorouracil (300 mg/m2) at 4-week intervals during radiotherapy. DP group patients received a concurrent three-weekly schedule of docetaxel (60 mg/m2) and cisplatin (80 mg/m2) or cisplatin (25 mg/m2) and docetaxel (25 mg/m2) weekly. The overall survival (OS) and progression-free survival (PFS) were compared using propensity score (−adjusted, −weighted, −stratified, and −matched) analyses. A sensitivity analysis was performed to examine the impact of unmeasured confounders. Inverse probability of treatment weighting for propensity score demonstrated an improvement in OS and PFS with DP group in comparison with PF group (hazard ratio, 0.700; 95% CI, 0.577-0.851) and similar results were achieved with propensity score matching and stratification. Grade 3-4 esophagitis was more common (16/102 vs. 4/102) and grade 3-4 thrombopenia and skin toxicity were less common (3/102 vs. 10/102; 7/102 vs. 19/102; respectively) in the PF group than the DP group. In conclusion, concurrent chemoradiotherapy with the DP regimen resulted in better OS and PFS compared to concurrent PF regimen with tolerable toxicities in ESCC patients. Prospective randomized trials are required to confirm the efficacy of the DP regimen. PMID:27183916

  17. Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer

    Science.gov (United States)

    Yokota, Tomoya; Kato, Ken; Hamamoto, Yasuo; Tsubosa, Yasuhiro; Ogawa, Hirofumi; Ito, Yoshinori; Hara, Hiroki; Ura, Takashi; Kojima, Takashi; Chin, Keisho; Hironaka, Shuichi; Kii, Takayuki; Kojima, Yasushi; Akutsu, Yasunori; Matsushita, Hisayuki; Kawakami, Kentaro; Mori, Keita; Nagai, Yushi; Asami, Chika; Kitagawa, Yuko

    2016-01-01

    Background: The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus. Methods: Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30–40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS). Results: From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy. Conclusions: Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus. PMID:27811857

  18. Effect of topical chamomile on immunohistochemical levels of IL-1β and TNF-α in 5-fluorouracil-induced oral mucositis in hamsters.

    Science.gov (United States)

    Curra, Marina; Martins, Marco Antonio T; Lauxen, Isabel S; Pellicioli, Ana Carolina A; Sant'Ana Filho, Manoel; Pavesi, Vanessa Christina S; Carrard, Vinicius C; Martins, Manoela D

    2013-02-01

    The aim of the present study was to evaluate the effect of topical chamomile and corticosteroid treatment on the profile of tissue cytokines (IL-1β and TNF-α) in 5-fluorouracil-induced oral mucositis in hamsters. Thirty-six hamsters were randomly separated into three groups (12 animals each): Group I--without treatment (control); Group II-treatment with chamomile (Ad-Muc(®)); and Group III--treatment with corticosteroid (betamethasone elixir- Celestone(®)). The animals received an intraperitoneal injection of 5--fluorouracil on Days 0 and 2. On Days 3 and 4, the buccal mucosa was scratched and therapy was initiated on Day 5. Three animals from each group were killed on Days 0, 5, 10, and 14 and the buccal mucosa was removed. The streptavidin-biotin complex method was used to delineate the in situ distribution, localization, and semiquantitative analysis of IL-1β and TNF-α. Data from the semiquantitative analysis of immunohistochemical staining were comparatively analyzed using the Kruskal-Wallis test, followed by Dunn's multiple comparisons test. The distribution and localization of IL-1β and TNF-α immunolabeling were similar. These proteins exhibited a diffuse pattern distributed throughout the connective tissue. The epithelium and adipose tissue were negative for both proteins. The semiquantitative analysis revealed that immunolabeling of IL-1β and TNF-α increased in all groups with the development of mucositis. On Day 10 (period of peak mucositis), the group treated with chamomile had lower scores for both pro-inflammatory cytokines. Treatment with topical chamomile reduced the tissue levels of IL-1β and TNF-α, thereby demonstrating anti-inflammatory action in oral mucositis in hamsters.

  19. Exposição de fibroblastos da cápsula de Tenon normal de portadores de pterígio ao 5-fluorouracil e à mitomicina C Exposure of normal Tenon's capsule fibroblasts from pterygium to 5-fluorouracil and mitomycin C

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    Magda Massae Hata Viveiros

    2007-02-01

    Full Text Available OBJETIVO: Avaliar a atividade proliferativa dos fibroblastos da cápsula de Tenon normal, proveniente de portadores de pterígios primários e recidivados. MÉTODOS: Foi realizado estudo prospectivo, aleatório, avaliando-se fragmentos da cápsula de Tenon normal, removidos de 20 portadores de pterígios primários e 21, recidivados. A taxa de proliferação foi avaliada em fibroblastos de terceira passagem, quando as culturas foram expostas a agentes antimitóticos: mitomicina C e 5-fluorouracil. Os dados obtidos foram submetidos à análise estatística. RESULTADOS: Dentre os 41 espécimes cultivados, apenas 1 de pterígio primário e 2 de recidivado proliferaram. Quando expostos a mitomicina C e ao 5-fluorouracil não houve diferença estatisticamente significativa quanto a inibição de proliferação celular. CONCLUSÃO: Desta forma, in vitro, ambos os antimitóticos estudados têm a mesma eficácia na inibição da proliferação sobre os fibroblastos de cápsulas de Tenon normal.PURPOSE: To evaluate the fibroblast proliferation activity of normal Tenon's capsule from primary and recurrent patients with pterygium. METHODS: A randomized prospective study was performed with 41 normal Tenon's capsule fragments from 21 primary and 20 recurrent patients with pterygium. The sample was collected from the inferior cul-de-sac. Proliferation rate from fibroblasts were evaluated after mitomycin C and 5-fluorouracil exposition. Data were submitted to statistical analysis. RESULTS: Of the 41 cultivated normal Tenon's capsules, only 1 from primary and 2 from recurrent pterygium patients proliferated. After antimitotic exposition, the proliferation rate was similar with both drugs. CONCLUSION: Mitomycin and 5-fluorouracil promote similar inhibition regarding proliferation of normal Tenon's fibroblast cultures.

  20. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial.

    NARCIS (Netherlands)

    Ducreux, M.; Cutsem, E. van; Laethem, J. van; Gress, T.M.; Jeziorski, K.; Rougier, P.; Wagener, T.; Anak, O.; Baron, B.; Nordlinger, B.

    2005-01-01

    Previous small phase II trials have demonstrated that the combination of 5-fluorouracil (5FU) and cisplatin(CDDP) could have clinical activity in metastatic biliary tract cancer. This randomised phase II trial was designed to assess the activity and safety of a high-dose infusional weekly 5FU alone

  1. Type I interferon receptor in peripheral blood mononuclear cells may predict response to intra-arterial 5-fluorouracil + interferon therapy for advanced hepatocellular carcinoma

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    Korenaga K

    2011-04-01

    Full Text Available Yasuyuki Tomiyama1, Naoko Yoshioka1, Yoshiaki Yanai2,3, Tomoya Kawase1, Sohji Nishina1, Yuichi Hara1, Koji Yoshida1, Keiko Korenaga1, Masaaki Korenaga1, Keisuke Hino11Department of Hepatology and Pancreatology, Kawasaki Medical University, Kurashiki, Japan; 2Institute of Fujisaki, Hayashibara Biochemical Lab Inc, Okayama, Japan; 3Pharmaceutical Marketing Division, Otsuka Pharmaceutical Co Ltd, Tokyo, JapanBackground: Type 1 interferon alpha receptor 2 (IFNAR2 in the liver has been reported to be a predictive factor for the response to intra-arterial 5-fluorouracil (5-FU + systemic interferon (IFN-alpha combination therapy in patients with advanced hepatocellular carcinoma. We tested whether IFNAR2 expression in peripheral blood mononuclear cells could predict the response to 5-FU + IFN.Methods: Predictive factors for survival and response to therapy were determined in 30 patients with advanced hepatocellular carcinoma who underwent treatment with 5-FU + IFN. IFNAR2 expression in peripheral blood mononuclear cells was measured in 11 of the 30 patients.Results: With a mean number of 4.2 courses of combination therapy, one patient (3% showed a complete response, eight (27% showed partial responses, 13 (43% had stable disease, and eight (27% showed progressive disease. The median survival time of responders (complete response/partial response was 12.7 months and that of nonresponders (stable disease/progressive disease was 7.5 months. The one-year and two-year cumulative survival rates of responders and nonresponders were 87/69% and 40/11%, respectively (P = 0.019. Multivariate analysis identified response to therapy (P = 0.037 as the sole independent determinant of survival. The expression level of IFNAR2 in peripheral blood mononuclear cells was significantly (P = 0.012 higher in responders (6.5 ± 2.4 than in nonresponders (2.4 ± 0.6, even though no clinical factors were identified as being associated with the response to the combination

  2. Clinical significance of the thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase mRNA expressions in hepatocellular carcinoma patients receiving 5-fluorouracil-based transarterial chemoembolization treatment

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    Zhao H

    2013-07-01

    Full Text Available Hongyun Zhao,1,* Yuanyuan Zhao,2,* Ying Guo,1 Yan Huang,2 Suxia Lin,3 Cong Xue,2 Fei Xu,2 Yang Zhang,1 Liping Zhao,2 Zhihuang Hu,2 Li Zhang1,2 1State Key Laboratory of Oncology in South China and National Anti-Cancer Drug Clinical Research Centre, 2State Key Laboratory of Oncology in South China and Department of Medical Oncology, 3Department of Pathological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China*These authors contributed equally to this workPurpose: To determine whether 5-fluorouracil (5-FU sensitivity is associated with the mRNA expressions of thymidylate synthase (TS, dihydropyrimidine dehydrogenase (DPD, and thymidine phosphorylase (TP in patients with hepatocellular carcinoma (HCC treated with 5-FU-based transarterial chemoembolization (TACE.Methods: Formalin-fixed, paraffin-embedded tumor specimens from 40 patients treated with 5-FU-based TACE were selected for the examination of TS, DPD, and TP expression level by a quantitative real-time reverse transcription- polymerase chain reaction (PCR technique. Patients were categorized into high and low expression groups according to the median expression level of each enzyme. Associations between the mRNA expression levels of TS, DPD, and TP and clinical parameters including treatment efficacies, clinicopathological factors, and prognosis were assessed.Results: High DPD expression was associated with worse treatment outcome, including intrahepatic disease progression rate (hazard ratio [HR] for high DPD versus low DPD, 2.212; 95% confidence interval [CI], 1.030–4.753; P = 0.042, extrahepatic disease progression rate (HR for high versus low DPD, 3.171; 95% CI, 1.003–10.023; P = 0.049, and progression-free survival (HR for high versus low DPD, 2.308; 95% CI, 1.102–4.836; P = 0.027. No correlation was found between the mRNA expression of TS/TP and treatment outcome.Conclusion: DPD mRNA expression level was negatively correlated with the clinical

  3. Transcriptional activation and cell cycle block are the keys for 5-fluorouracil induced up-regulation of human thymidylate synthase expression.

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    Alessio Ligabue

    Full Text Available BACKGROUND: 5-fluorouracil, a commonly used chemotherapeutic agent, up-regulates expression of human thymidylate synthase (hTS. Several different regulatory mechanisms have been proposed to mediate this up-regulation in distinct cell lines, but their specific contributions in a single cell line have not been investigated to date. We have established the relative contributions of these previously proposed regulatory mechanisms in the ovarian cancer cell line 2008 and the corresponding cisplatin-resistant and 5-FU cross-resistant-subline C13*. METHODOLOGY/PRINCIPAL FINDINGS: Using RNA polymerase II inhibitor DRB treated cell cultures, we showed that 70-80% of up-regulation of hTS results from transcriptional activation of TYMS mRNA. Moreover, we report that 5-FU compromises the cell cycle by blocking the 2008 and C13* cell lines in the S phase. As previous work has established that TYMS mRNA is synthesized in the S and G(1 phase and hTS is localized in the nuclei during S and G(2-M phase, the observed cell cycle changes are also expected to affect the intracellular regulation of hTS. Our data also suggest that the inhibition of the catalytic activity of hTS and the up-regulation of the hTS protein level are not causally linked, as the inactivated ternary complex, formed by hTS, deoxyuridine monophosphate and methylenetetrahydrofolate, was detected already 3 hours after 5-FU exposure, whereas substantial increase in global TS levels was detected only after 24 hours. CONCLUSIONS/SIGNIFICANCE: Altogether, our data indicate that constitutive TYMS mRNA transcription, cell cycle-induced hTS regulation and hTS enzyme stability are the three key mechanisms responsible for 5-fluorouracil induced up-regulation of human thymidylate synthase expression in the two ovarian cancer cell lines studied. As these three independent regulatory phenomena occur in a precise order, our work provides a feasible rationale for earlier observed synergistic combinations of 5

  4. Comparison of the short-term efficacy between docetaxel plus carboplatin and 5-fluorouracil plus carboplatin in locoregionally advanced nasopharyngeal carcinoma

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    Lv X

    2016-08-01

    Full Text Available Xing Lv,1,2,* Wei-Xiong Xia,1,2,* Liang-Ru Ke,1,2 Jing Yang,1,2 Wen-Zhe Qiu,1,2 Ya-Hui Yu,1,2 Hu Liang,1,2 Xin-Jun Huang,1,2 Guo-Yin Liu,1,2 Qi Zeng,1,2 Xiang Guo,1,2 Yan-Qun Xiang1,2 1Key Laboratory of Oncology in South China, 2Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Objective: Platinum-based chemotherapy in combination with radiotherapy is a standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma (NPC. This study aimed to investigate the long-term efficacy and tolerability of inductive chemotherapy with docetaxel plus carboplatin (TC or 5-fluorouracil plus carboplatin (FC followed by concurrent radiation therapy in patients with NPC. Methods: Patients (N=88 were randomized to receive TC or FC as inductive therapy followed by concurrent radiotherapy (60–70 Gy with two cycles of carboplatin (area under the curve =5 mg·h/L. Patients were followed up for 8 years. Primary end point was progression-free survival (PFS. Secondary end points included overall survival (OS, toxicity, tumor response, distant metastasis-free survival, and local recurrence-free survival. Results: At the end of the follow-up period, 31 patients died, 32 had disease progression, eleven had cancer recurrence, and 25 had distant metastasis. Overall, there was no difference between treatment groups with regard to response or survival. We found that following induction and concurrent chemoradiotherapy, the majority of patients showed a complete response (~96%–98% for induction therapy and 82%–84% for comprehensive therapy to both therapies. PFS and OS were also similar between groups. The rate of PFS was 63.6% for both FC and TC and that of OS was 65.9% and 63.5%, respectively. The overall incidence of grade 3–4 adverse events in the TC group (20.5% was higher than in the FC group (10.7%. Neutropenia and leukopenia

  5. Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

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    Chen D

    2013-10-01

    Full Text Available Dan Chen, Jue Cheng, Kai Yang, Yue Ma, Fang Yang Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China Background: Chronomodulated chemotherapy has emerged as a new therapy as a result of recent studies focusing on the biological clock. It has been demonstrated that combination chronomodulated chemotherapy of platinum-based drugs and 5-fluorouracil (5-Fu can significantly improve efficacy and reduce the incidence of adverse events in patients with metastatic colorectal cancer, as compared with conventional chemotherapy. However, the results may be different in different tumors. Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC is very difficult to treat, with an extremely unfavorable prognosis. So far, no report is available on chronomodulated chemotherapy for HNSCC. Methods: Retrospective analyses were made on 49 patients with local recurrent and/or metastatic HNSCC who underwent palliative treatments with paclitaxel, carboplatin, and 5-Fu. The patients were divided into a chronomodulated chemotherapy group (28 patients and a conventional chemotherapy group (21 patients according to their administration times. The two groups were compared for tumor objective response rate, overall survival (OS, progression-free survival (PFS, and the incidence of adverse events. Results: The tumor objective response rate and patients' OS were significantly higher and longer in the chronomodulated chemotherapy group than in the conventional chemotherapy group (71.43% versus 42.86%, respectively, P0.05. The global incidence of adverse events in the chronomodulated chemotherapy group was significantly lower than that in the conventional chemotherapy group (46.43% versus 76.19%, P<0.05, with significantly lower incidence of grade 3–4 adverse events (7.14% versus 33.33%, P<0.05. Conclusion: Chronomodulated chemotherapy with paclitaxel, carboplatin, and

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

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    Cheng M

    2013-10-01

    Full Text Available Mingrong Cheng,1,2,* Hongzhi Xu,3,* Yong Wang,4,* Houxiang Chen,5 Bing He,3 Xiaoyan Gao,6 Yingchun Li,2 Jiang Han,1 Zhiping Zhang1 1Department of General Surgery, 2Department of Endoscopy, Pudong New Area District Zhoupu Hospital, Shanghai, People’s Republic of China; 3Department of General Surgery, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, People’s Republic of China; 4School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, People’s Republic of China; 5Zhejiang Huafon Fiber Research Institute, Zhejiang Huafon Spandex Co, Ltd, Wenzhou, People’s Republic of China; 6Department of Plastic Surgery, Pudong New Area District Zhoupu Hospital, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: 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

  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

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    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. CF101, An Agonist to the A3 Adenosine Receptor, Enhances the Chemotherapeutic Effect of 5-Fluorouracil in a Colon Carcinoma Murine Model

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    Sara Bar-Yehuda

    2005-01-01

    Full Text Available NF-κB and the upstream kinase PKB/Akt are highly expressed in chemoresistance tumor cells and may hamper the apoptotic pathway. CF101, a specific agonist to the A3 adenosine receptor, inhibits the development of colon carcinoma growth in cell cultures and xenograft murine models. Because CF101 has been shown to downregulate PKB/Akt and NF-κB protein expression level, we presumed that its combination with chemotherapy will enhance the antitumor effect of the cytotoxic drug. In this study, we utilized 3-[4,5Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT and colony formation assays and a colon carcinoma xenograft model. It has been shown that a combined treatment of CF101 and 5-fluorouracil (5-FU enhanced the cytotoxic effect of the latter on HCT-116 human colon carcinoma growth. Downregulation of PKB/Akt, NF-κB, and cyclin D1, and upregulation of caspase-3 protein expression level were observed in cells and tumor lesions on treatment with a combination of CF101 and 5-FU. Moreover, in mice treated with the combined therapy, myelotoxicity was prevented as was evidenced by normal white blood cell and neutrophil counts. These results show that CF101 potentiates the cytotoxic effect of 5-FU, thus preventing drug resistance. The myeloprotective effect of CF101 suggests its development as an add-on treatment to 5-FU.

  9. Analysis of the Thymidylate Synthase Gene Structure in Colorectal Cancer Patients and Its Possible Relation with the 5-Fluorouracil Drug Response

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    A. Calascibetta

    2010-01-01

    Full Text Available Thymidylate synthase (TS catalyzes methylation of dUMP to dTMP and it is the target for the 5-Fluorouracil (5-FU activity. Barbour et al. showed that variant structural forms of TS in tumour cell lines confer resistance to fluoropyrimidines. We planned to perform the whole TS gene structure by means of sequencing techniques in human colorectal cancer (CRC samples to try to identify the presence of any possible TS variant form that could be responsible of fluoropyrimidines drug resistance and of the worse prognosis. We performed the TS-DNA gene sequence in 68 CRC from patients of A, B, and C Dukes' stages and different histological grade, but we did not find any mutation in the TS-DNA structure. In the future we intend to widen the TS structure analysis to the metastatic CRCs, because due to their higher genomic instability, they could present a TS variant form responsible of the fluoropyrimidines drug resistance and the worse prognosis.

  10. Prognostic and Predictive Value of p21-activated Kinase 6 Associated Support Vector Machine Classifier in Gastric Cancer Treated by 5-fluorouracil/Oxaliplatin Chemotherapy

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    Yuming Jiang

    2017-08-01

    Full Text Available To determine whether p21-activated Kinase (PAK 6 is a prognostic and predictive marker in gastric cancer (GC and to construct a classifier that can identify a subset of patients who are highly sensitive to 5-fluorouracil/oxaliplatin chemotherapy. We retrospectively analyzed the expression levels of PAK6, cyclooxygenase 2, p21WAF1, Ki-67, excision repair cross-complementing gene 1, and thymidylate synthase in 242 paraffin-embedded GC specimens of the training cohort by immunohistochemistry. Then, we used support vector machine (SVM–based methods to develop a predictive classifier for chemotherapy (chemotherapy score – CS-SVM classifier. Further validation was performed in an independent cohort of 279 patients. High PAK6 expression was associated with poor prognosis and increased chemoresistance to 5-FU/oxaliplatin chemotherapy. The CS-SVM classifier distinguished patients with stage II and III GC into low- and high-CS-SVM groups, with significant differences in the 5-year disease-free survival (DFS and overall survival (OS in chemotherapy patients. Moreover, chemotherapy significantly prolonged the DFS and OS of the high CS-SVM patients in the training and validation cohorts. In conclusion, PAK6 was an independent prognostic factor and increased chemoresistance. The CS-SVM classifier distinguished a subgroup of stage II and III patients who would highly benefit from chemotherapy, thus facilitating patient counseling and individualizing the management.

  11. Correlations between expression levels of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase, and efficacy of 5-fluorouracil-based chemotherapy for advanced colorectal cancer.

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    Bai, Wenqi; Wu, Yueqin; Zhang, Ping; Xi, Yanfeng

    2015-01-01

    The efficacy of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer (CRC) widely varies among patients; therefore, it is difficult to accurately predict chemotherapeutic responses. Some recent studies have found that key enzymes in the various metabolic pathways activated by 5-FU present potential predictors of treatment outcome. Of these enzymes, thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are known to play important roles in the efficacy of therapeutic agents. Here, we measured expression levels of TS, TP, and DPD in formalin-fixed, paraffin-embedded, CRC specimens and paracancerous tissue with normal mucosa by immunohistochemical and fluorescence real-time quantitative polymerase chain reaction techniques. We found no significant differences in TS, TP, and DPD expression levels between CRC specimens and paracancerous tissues (P > 0.05), although overall survival and the chemotherapeutic effect were relatively poor in CRC patients with relatively high expression levels of TS, TP, and DPD, as compared to those with comparatively low expression levels (P < 0.05). Therefore, TS, TP, and DPD mRNA levels appear to be suitable indicators of the efficacy of 5-FU-based chemotherapy and prognosis of CRC.

  12. Effect of Phyllanthus amarus Extract on 5-Fluorouracil-Induced Perturbations in Ribonucleotide and Deoxyribonucleotide Pools in HepG2 Cell Line

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    Jian-Ru Guo

    2016-09-01

    Full Text Available The aim of this study was to investigate the antitumor activities of Phyllanthus amarus (PHA and its potential of herb–drug interactions with 5-Fluorouracil (5-FU. Cell viability, ribonucleotides (RNs and deoxyribonucleotides (dRNs levels, cell cycle distribution, and expression of thymidylate synthase (TS and ribonucleotide reductase (RR proteins were measured with 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay, high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS method, flow cytometry and Western blot analysis, respectively. Our standardized PHA extract showed toxicity to HepG2 cells at high concentrations after 72 h exposure and induced G2/M cell cycle arrest. Combined use of 5-FU with PHA resulted in significant decreases in ATP, CTP, GTP, UTP and dTTP levels, while AMP, CMP, GMP and dUMP levels increased significantly compared with use of 5-FU alone. Further, PHA could increase the role of cell cycle arrest at S phase induced by 5-FU. Although PHA alone had no direct impact on TS and RR, PHA could change the levels of RNs and dRNs when combined with 5-FU. This may be due to cell cycle arrest or regulation of key enzyme steps in intracellular RNs and dRNs metabolism.

  13. A Type II Arabinogalactan from Anoectochilus formosanus for G-CSF Production in Macrophages and Leukopenia Improvement in CT26-Bearing Mice Treated with 5-Fluorouracil

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    Li-Chan Yang

    2013-01-01

    Full Text Available Anoectochilus formosanus is an herb well known in Asian countries. The polysaccharide isolated from A. formosanus consists of type II arabinogalactan (AGAF, with branched 3,6-Gal as the major moiety. In this study, AGAF was examined for the granulocyte colony-stimulating factor (G-CSF production and related protein expression in RAW 264.7 murine macrophages. The signaling pathway of G-CSF production involves AGAF and mitogen-activated protein kinases (MAPKs inhibitors and pattern-recognition receptor antibodies. AGAF was evaluated to ease the leukopenia in CT26-colon-cancer-bearing mice treated with 5-fluorouracil (5-FU. The results of this study showed that AGAF was a stimulant for Toll-like receptor 2 and Dectin-1 and that it induced G-CSF production, through p38 and ERK MAPK, and NF-κB pathways. In vivo examination showed that the oral administration of AGAF mitigated the side effects of leukopenia caused by 5-FU in colon-cancer-bearing mice. In conclusion, the botanic type II AGAF in this study was a potent G-CSF inducer in vivo and in vitro.

  14. Effect of viscous additives on the absorption and hepatic disposition of 5-fluorouracil (5-FU) after application to liver surface in rats.

    Science.gov (United States)

    Kodama, Yukinobu; Horishita, Miyuki; Fumoto, Shintaro; Mine, Toyoharu; Miyamoto, Hirotaka; Yoshikawa, Naoki; Hirata, Haruna; Sasaki, Hitoshi; Nakamura, Junzo; Nishida, Koyo

    2012-10-01

    Objectives  The aim was to study the effect of viscous additives on the absorption and hepatic disposition of 5-fluorouracil (5-FU) after application to the liver surface in rats. Methods  5-FU solution with or without viscous additives was applied to the rat liver surface with a cylindrical diffusion cell. Then, blood and the remaining solution in the diffusion cell were collected at selected times, followed by excision of the liver. The excised liver was divided into three sites and assayed for 5-FU content. Key findings  The absorption rate of 5-FU from the liver surface was decreased in the presence of carboxymethylcellulose sodium (CMC-Na) and polyvinyl alcohol (PVA) as compared with the control. The k(a) values of PVA 15% and CMC-Na 1% were reduced to about 80 and 67% of the control. The maximum plasma concentration of 5-FU was decreased by incorporation of viscous additives. The 5-FU concentration at the diffusion cell attachment site of the liver (site 1) plateaued at 180 min in the absence of viscous additives. On the other hand, the concentration of 5-FU at site 1 increased in a time-dependent manner until 360 min in the presence of viscous additives. Conclusion  Viscous additives might be useful for retaining drugs at their application site and controlling the rate of absorption from the liver surface. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  15. Synergy of Irofulven in combination with various anti-metabolites, enzyme inhibitors, and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil.

    Science.gov (United States)

    Kelner, Michael J; McMorris, Trevor C; Rojas, Rafael J; Estes, Leita A; Suthipinijtham, Pharnuk

    2008-10-01

    The novel agent Irofulven (HMAF, NSC 683863) has demonstrated significant antitumor activity against solid tumors in various xenograft models and human clinical trials. The antitumor potential of combining irofulven with 72 different anti-metabolite, enzyme inhibiting, and miscellaneous agents was investigated in this study. The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with these different agents. Irofulven in combination with select anti-metabolites, notably cytidine or adenine-derived agents, displayed strong synergistic activity in both in vitro and in vivo studies. Agents demonstrating strong synergistic interaction with irofulven included gemcitabine, cyclocytidine, cytarabine, fludarabine phosphate, cladribine, and 5-fluorouracil. Other anti-metabolites, enzyme inhibitors, and a variety of miscellaneous agents failed to interact beneficially when administered in combination with irofulven. The therapeutic activity of irofulven is enhanced considerably when irofulven is combined with select anti-metabolite agents, and further clinical evaluation of these combinations is warranted. The synergistic interaction with these combinations may stem from a variety of actions including inhibition of the nucleotide excision repair (NER) pathway, topoisomerase I activity, and caspase-dependent and independent induction of apoptosis.

  16. Debulking surgery followed by intraarterial 5-fluorouracil chemotherapy plus subcutaneous interferon alfa for massive hepatocellular carcinoma with multiple intrahepatic metastases: a pilot study.

    Science.gov (United States)

    Tanaka, K; Yabushita, Y; Nakagawa, K; Kumamoto, T; Matsuo, K; Taguri, M; Endo, I

    2013-12-01

    The prognosis in advanced hepatocellular carcinoma (HCC) with multiple intrahepatic metastases is extremely poor. Combination therapy with subcutaneous interferon (IFN) alfa and intraarterial 5-fluorouracil was reported to be effective against such advanced HCC. We describe results of debulking surgery followed by combination therapy with IFN alfa and 5-FU for massive HCC with multiple intrahepatic metastases. In 27 HCC patients with massive tumors and multiple intrahepatic metastases, we performed combination therapy with IFN alfa and 5-FU after maximal liver tumor resection. Mean patient age was 63.3 years. Including intrahepatic metastases, tumors numbered 5 or more in 17 patients (63%). Portal or hepatic vein branches were invaded in 22 (81%). The mean maximum tumor diameter was 102 mm. Among 24 patients whose results were analyzed, an objective response by residual intrahepatic metastases was observed in 13 (54%; complete response in 12, and partial response in 1). Overall 1-, 3-, and 5-year survival was 73.2%, 38.7%, and 38.7%, respectively; 1-, 3-, and 5-year progression-free rates were 38.2%, 22.3%, and 22.3%. Debulking surgery followed by IFN alfa and 5-FU combination chemotherapy offers possibility of long-term survival despite massive HCC with multiple intrahepatic metastases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Synthesis and characterization of silane coated magnetic nanoparticles/glycidylmethacrylate-grafted-maleated cyclodextrin composite hydrogel as a drug carrier for the controlled delivery of 5-fluorouracil.

    Science.gov (United States)

    Anirudhan, Thayyath S; Divya, Peethambaran L; Nima, Jayachandran

    2015-10-01

    A novel drug delivery system (DDS), 3-methacryloxypropyl trimethoxy silane coated magnetic nanoparticles polymerized with glycidylmethacrylate-grafted-maleated cyclodextrin (MPTMS-MNP-poly-(GMA-g-MACD)) was prepared in the presence of ethyleneglycoldimethacrylate as cross-linker and a,a'-azobisisobutyronitrile as initiator and characterized by means of SEM, FT-IR, XRD, DLS, VSM and TEM. The encapsulation efficiency (EE) and drug loading efficiency (DLE) of the DDS were tested using various formulations of DDS. The DDS showed activity against gram positive and negative bacteria. The cytotoxicity studies were also performed using MCF-7 (human breast carcinoma) cells and found that the drug carrier is biocompatible and it shows sustained and controlled release of drug to the targeted site. The drug release mechanism was found to obey non-Fickian diffusion (n=0.709) method where polymer relaxation and drug diffusion played important roles in drug release. In this DDS, advantages of core magnetic nanoparticles and host-guest interactions of β-CD were combined for the controlled delivery of 5-Fluorouracil (5-FU) to maintain the therapeutic index of the drug. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Low molecular weight procyanidins from grape seeds enhance the impact of 5-Fluorouracil chemotherapy on Caco-2 human colon cancer cells.

    Science.gov (United States)

    Cheah, Ker Y; Howarth, Gordon S; Bindon, Keren A; Kennedy, James A; Bastian, Susan E P

    2014-01-01

    Grape seed procyanidins (PC) are flavan-3-ol oligomers and polymers known for their biological activity in the gut. Grape seed extract (GSE) have been reported to reduce intestinal injury in a rat model of mucositis. We sought to investigate effects of purified PC fractions differing in mean degree of polymerization (mDP) combined with 5-Fluorouracil (5-FU) chemotherapy on the viability of colon cancer cells (Caco-2). SixPC fractions (F1-F6) were isolated from Cabernet Sauvignon seeds at two ripeness stages: pre-veraison unripe (immature) and ripe (mature), utilizing step gradient, low-pressure chromatography on a Sephadex LH-20 resin. Fractions were tested on Caco-2 cells, alone and in combination with 5-FU. Eluted fractions were characterized by phloroglucinolysis and gel permeation chromatography. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) (MTT) assay. All isolated fractions significantly reduced Caco-2 cell viability compared to the control (PCaco-2 cells. When combined with 5-FU, immature fractions F1-F3 enhanced the cell toxicity effects of 5-FU by 27-73% (PCaco-2 cells (PCaco-2 cells (PCaco-2 cells, but also surpassed standard 5-FU chemotherapy as an anti-cancer agent.The bioactivity of PC is therefore attributed primarily to lower molecular weight PCs.

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

    Science.gov (United States)

    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. Copyright © 2015. Published by Elsevier B.V.

  20. Simultaneous Integrated Boost Using Intensity-Modulated Radiotherapy Compared With Conventional Radiotherapy in Patients Treated With Concurrent Carboplatin and 5-Fluorouracil for Locally Advanced Oropharyngeal Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Clavel, Sebastien, E-mail: sebastien.clavel@umontreal.ca [Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); Nguyen, David H.A.; Fortin, Bernard [Department of Radiation Oncology, Hopital Maisonneuve-Rosemont, Montreal, QC (Canada); Despres, Philippe [Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); Khaouam, Nader [Department of Radiation Oncology, Hopital Maisonneuve-Rosemont, Montreal, QC (Canada); Donath, David [Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); Soulieres, Denis [Department of Medical Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); Guertin, Louis [Department of Head and Neck Surgery, Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); Nguyen-Tan, Phuc Felix [Department of Radiation Oncology, Hopital Maisonneuve-Rosemont, Montreal, QC (Canada)

    2012-02-01

    Purpose: To compare, in a retrospective study, the toxicity and efficacy of simultaneous integrated boost using intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT) in patients treated with concomitant carboplatin and 5-fluorouracil for locally advanced oropharyngeal cancer. Methods and Materials: Between January 2000 and December 2007, 249 patients were treated with definitive chemoradiation. One hundred patients had 70 Gy in 33 fractions using IMRT, and 149 received CRT at 70 Gy in 35 fractions. Overall survival, disease-free survival, and locoregional control were estimated using the Kaplan-Meier method. Results: Median follow-up was 42 months. Three-year actuarial rates for locoregional control, disease-free survival, and overall survival were 95.1% vs. 84.4% (p = 0.005), 85.3% vs. 69.3% (p = 0.001), and 92.1% vs. 75.2% (p < 0.001) for IMRT and CRT, respectively. The benefit of the radiotherapy regimen on outcomes was also observed with a Cox multivariate analysis. Intensity-modulated radiotherapy was associated with less acute dermatitis and less xerostomia at 6, 12, 24, and 36 months. Conclusions: This study suggests that simultaneous integrated boost using IMRT is associated with favorable locoregional control and survival rates with less xerostomia and acute dermatitis than CRT when both are given concurrently with chemotherapy.

  1. Photo-Fenton and Fenton-like processes for the treatment of the antineoplastic drug 5-fluorouracil under simulated solar radiation.

    Science.gov (United States)

    Koltsakidou, Α; Antonopoulou, M; Sykiotou, M; Εvgenidou, Ε; Konstantinou, I; Lambropoulou, D A

    2017-02-01

    In the present study, photo-Fenton and Fenton-like processes were investigated for the degradation and mineralization of the antineoplastic drug 5-fluorouracil (5-FU). For the optimization of photo-Fenton treatment under simulated solar light (SSL) radiation, the effects of several operating parameters (i.e., 5-FU concentration, Fe3+, and oxidant concentration) on the treatment efficiency were studied. According to the results, SSL/[Fe(C2Ο4)3]3-/Η2Ο2 process was the most efficient, since faster degradation of 5-FU and higher mineralization percentages were achieved. All the applied processes followed quite similar transformation routes which include defluorination-hydroxylation as well as pyrimidine ring opening, as demonstrated by the transformation products identified by high resolution mass spectrometry analysis. The toxicity of the treated solutions was evaluated using the Microtox assay. In general, low toxicity was recorded for the initial solution and the solution at the end of the photocatalytic treatment, while an increase in the overall toxicity was observed only at the first stages of SSL/Fe3+/Η2Ο2 and SSL/Fe3+/S2O82- processes.

  2. Construction of METHFR shRNA/5-fluorouracil co-loaded folate-targeted chitosan polymeric nanoparticles and its anti-carcinoma effect on gastric cells growth

    Energy Technology Data Exchange (ETDEWEB)

    Xin, Lin, E-mail: xiinlin@163.com; Fan, Ji-Chang; Le, Yi-Guan; Zeng, Fei; Cheng, Hua; Hu, Xiao-yun; Cao, Jia-Qing [The Second Affiliated Hospital of Nanchang University, Department of General Surgery (China)

    2016-05-15

    PEGylated and folate-targeted chitosan polymeric nanoparticles (FPNs) for the treatment of gastric carcinoma were prepared successfully. OQC-anchored folate conjugates were synthesized and used in assembling FPNs nano-system for enhancing intracellular uptake against folate receptor overexpressing cancer cells. The results indicated that folate-targeted chitosan polymeric nanoparticles (CPNs) can reverse drug-resistant SGC-7901 cells of 5-fluorouracil (5-FU) compared with non-targeted CPNs. Increased therapeutic efficiency of 5-FU/METHFR shRNA co-loaded PNs were also tested in SGC-7901 cells and compaed with 5-FU or METHFR shRNA in solution, which was associated with increased cell inhibition function for single drug group and synergistic effects of 5-FU and METHFR shRNA at 2.0 µg/mL FPNs concentration. In addition, the cell accumulation levels of 5-FU in SGC-7901 cells was time dependent for these nanoparticles. FPNs (effective diameter: 83.2 ± 1.1 nm; polydispersity index: 0.193) could significantly boost cellular accumulation of 5-FU and overcome the drug efflux mechanism of MDR than 5-FU-loaded NPNs and 5-FU in solution. In conclusion, ligand-targeted PNs can be used as a potentially effective drug delivery system.

  3. Optimization of the tissue source, malignancy, and initial substrate of tumor cell-derived matrices to increase cancer cell chemoresistance against 5-fluorouracil.

    Science.gov (United States)

    Hoshiba, Takashi; Tanaka, Masaru

    2015-02-13

    The low chemoresistance of in vitro cancer cells inhibits the development of new anti-cancer drugs. Thus, development of a new in vitro culture system is required to increase the chemoresistance of in vitro cancer cells. Tumor cell-derived matrices have been reported to increase the chemoresistance of in vitro cancer cells. However, it remains unclear how tissue sources and the malignancy of cells used for the preparation of matrices affect the chemoresistance of tumor cell-derived matrices. Moreover, it remains unclear how the initial substrates used for the preparation of matrices affect the chemoresistance. In this study, we compared the effects of tissue sources and the malignancy of tumor cells, as well as the effect of the initial substrates on chemoresistance against 5-fluorouracil (5-FU). The chemoresistance of breast and colon cancer cells against 5-FU increased on matrices prepared with cells derived from the corresponding original tissues with higher malignancy. Moreover, the chemoresistance against 5-FU was altered on matrices prepared using different initial substrates that exhibited different characteristics of protein adsorption. Taken together, these results indicated that the appropriate selection of tissue sources, malignancy of tumor cells, and initial substrates used for matrix preparation is important for the preparation of tumor cell-derived matrices for chemoresistance assays. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Decellularized matrices as in vitro models of extracellular matrix in tumor tissues at different malignant levels: Mechanism of 5-fluorouracil resistance in colorectal tumor cells.

    Science.gov (United States)

    Hoshiba, Takashi; Tanaka, Masaru

    2016-11-01

    Chemoresistance is a major barrier for tumor chemotherapy. It is well-known that chemoresistance increases with tumor progression. Chemoresistance is altered by both genetic mutations and the alteration of extracellular microenvironment. Particularly, the extracellular matrix (ECM) is remodeled during tumor progression. Therefore, ECM remodeling is expected to cause the acquisition of chemoresistance in highly malignant tumor tissue. Here, we prepared cultured cell-derived decellularized matrices that mimic native ECM in tumor tissues at different stages of malignancy, and 5-fluorouracil (5-FU) resistance was compared among these matrices. 5-FU resistance of colorectal tumor cells increased on the matrices derived from highly malignant tumor HT-29 cells, although the resistance did not increase on the matrices derived from low malignant tumor SW480 cells and normal CCD-841-CoN cells. The resistance on HT-29 cell-derived matrices increased through the activation of Akt and the upregulation of ABCB1 and ABCC1 without cell growth promotion, suggesting that ECM remodeling plays important roles in the acquisition of chemoresistance during tumor progression. It is expected that our decellularized matrices, or "staged tumorigenesis-mimicking matrices", will become preferred cell culture substrates for in vitro analysis of comprehensive ECM roles in chemoresistance and the screening and pharmacokinetic analysis of anti-cancer drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Effects of Supernatants from Escherichia coli Nissle 1917 and Faecalibacterium prausnitzii on Intestinal Epithelial Cells and a Rat Model of 5-Fluorouracil-Induced Mucositis.

    Science.gov (United States)

    Wang, Hanru; Jatmiko, Yoga D; Bastian, Susan E P; Mashtoub, Suzanne; Howarth, Gordon S

    2017-01-01

    Faecalibacterium prausnitzii (Fp) and Escherichia coli Nissle 1917 (EcN) are probiotics, which have been reported to ameliorate certain gastrointestinal disorders. We evaluated the effects of supernatants (SN) derived from Fp and EcN on 5-fluorouracil (5-FU)-treated intestinal cells and in a rat model of mucositis. In vitro: IEC-6, Caco-2, and T-84 cells were analyzed for viability and monolayer permeability. In vivo: Female dark agouti rats were gavaged with Fp or EcN SN and injected intraperitoneally with saline (control) or 5-FU to induce mucositis. Rats were euthanized and intestinal tissues collected for myeloperoxidase assay and histological analyses. In vitro: Caco-2 cell viability was further reduced when treated with Fp SN + 5-FU compared to 5-FU controls. In both Caco-2 and T-84 cells, Fp SN partially prevented the decrease in transepithelial electrical resistance (TER) caused by 5-FU administration. In vivo: 5-FU-injected rats administered Fp SN or EcN SN partly prevented body weight loss and normalized water intake compared to 5-FU controls. These results suggest a growth inhibitory mechanism of Fp SN action on transformed epithelial cells that could be mediated by effects on tight junctions. Factors derived from Fp SN and EcN SN could have a role in reducing the severity of intestinal mucositis.

  6. Prospective non-randomized study of preoperative concurrent platinum plus 5-fluorouracil-based chemoradiotherapy with or without paclitaxel in esophageal cancer patients: long-term follow-up.

    Science.gov (United States)

    Zemanova, M; Petruzelka, L; Pazdro, A; Kralova, D; Smejkal, M; Pazdrova, G; Honova, H

    2010-02-01

    Combined modality treatment for esophageal carcinoma seems to improve survival over surgery alone. Different combinations of cytotoxic drugs have been studied to improve antitumor efficacy and limit the toxicity of chemoradiotherapy (CRT) with inconsistent results. We present a prospective study of neoadjuvant CRT with or without paclitaxel in chemotherapy schedule. One hundred seven patients (93 males, 14 females), median age 59 years (range 44-76), with operable esophageal cancer were enrolled. They received the following neoadjuvant therapy: Carboplatin, area under curve (AUC) = 6, intravenously on days 1 and 22, 5-fluorouracil (5-FU), 200 mg/m(2)/day, continuous infusion on days 1 to 42, radiation therapy 45 grays/25fractions/5 weeks beginning on day 1. Forty-four patients (41%) were furthermore non-randomly assigned to paclitaxel 200 mg/m(2)/3 h intravenously on days 1 and 22. Nutritional support from the beginning of the treatment was offered to all patients. Surgery was done within 4-8 weeks after completion of CRT, if feasible. All patients were evaluated for grade 3 plus 4 toxicities: leukopenia (28%), neutropenia (30%), anemia (6%), thrombocytopenia (31%), febrile neutropenia (6%), esophagitis (24%), nausea and vomiting (7%), pneumotoxicity (8%). Seventy-eight patients (73%) had surgery and 63 of them were completely resected. Twenty-two patients (20%) achieved pathological complete remission, and additional 20 (19%) had node-negative and esophageal wall-positive residual disease. There were 10 surgery-related deaths, mostly due to pulmonary insufficiency. Twenty-nine patients were not resected, 15 for early progression, 14 for medical reasons or patient refusal. After a median follow-up of 52 months (range 27-80), median survival of 18.0 months and 1-, 2-, 3- and 5-year survival of 56.7, 37.5, 27.0 and 21% was observed in the whole group of 107 patients. Addition of paclitaxel to carboplatin and continual infusion of FU significantly increased

  7. [Venous ulcer].

    Science.gov (United States)

    Böhler, Kornelia

    2016-06-01

    Venous disorders causing a permanent increase in venous pressure are by far the most frequent reason for ulcers of the lower extremity. With a prevalence of 1 % in the general population rising to 4 % in the elderly over 80 and its chronic character, 1 % of healthcare budgets of the western world are spent on treatment of venous ulcers. A thorough investigation of the underlying venous disorder is the prerequisite for a differenciated therapy. This should comprise elimination of venous reflux as well as local wound management. Chronic ulcers can successfully be treated by shave therapy and split skin grafting. Compression therapy is a basic measure not only in venous ulcer treatment but also in prevention of ulcer recurrence. Differential diagnosis which have to be considered are arterial ulcers, vasculitis and neoplasms.

  8. Evaluation of methyl methanesulfonate, 2,6-diaminotoluene and 5-fluorouracil: Part of the Japanese center for the validation of alternative methods (JaCVAM) international validation study of the in vivo rat alkaline comet assay.

    Science.gov (United States)

    Plappert-Helbig, Ulla; Junker-Walker, Ursula; Martus, Hans-Joerg

    2015-07-01

    As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), we examined methyl methanesulfonate, 2,6-diaminotoluene, and 5-fluorouracil under coded test conditions. Rats were treated orally with the maximum tolerated dose (MTD) and two additional descending doses of the respective compounds. In the MMS treated groups liver and stomach showed significantly elevated DNA damage at each dose level and a significant dose-response relationship. 2,6-diaminotoluene induced significantly elevated DNA damage in the liver at each dose and a statistically significant dose-response relationship whereas no DNA damage was obtained in the stomach. 5-fluorouracil did not induce DNA damage in either liver or stomach. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. A comparative study of the safety and efficacy effect of 5-fluorouracil or mitomycin C mounted biological delivery membranes in a rabbit model of glaucoma filtration surgery

    Directory of Open Access Journals (Sweden)

    Wu ZH

    2013-03-01

    Full Text Available Zhihong Wu,1 Shuning Li,2 Ningli Wang,2 Wanshun Liu,3 Wen Liu3 1General Hospital of Armed Police Forces, Beijing, People’s Republic of China; 2Beijing Tongren Eye Center, Capital Medical University, Beijing, People’s Republic of China 3Ocean University of China, Qingdao, People’s Republic of China Purpose: To investigate the potential usage of biological delivery membranes containing mitomycin C (MMC or 5-fluorouracil (5-FU in the construction of glaucoma-filtering blebs, and to evaluate their safety and efficacy. Methods: Chitosan was selected as the biological membrane carrier to prepare sustained-released membranes. Twelve micrograms of 5-FU or MMC was covalently conjugated onto the membranes by solvent volatilization. Rabbits underwent glaucoma filtration surgery and were randomly allocated into one of the four treatment regimens: glaucoma filtration operation with no implantation of chitosan membrane group (as control, drug-free chitosan membrane implantation group (blank/placebo group, membrane containing 5-FU treatment group (5-FU group, and membrane containing MMC treatment group (MMC group. Each group consisted of 12 rabbits. Intraocular pressure (IOP was measured and evaluated over a 28-day period follow-up preoperatively, then after surgery on days 1, 3, 5, 7, 14, 21, and 28 by Tono-Pen. The aqueous humor was analyzed in each experimental and control groups at days 4, 6, 8, 10, 12, 14, 16, and 20 after operation. Bleb survival and anterior segment were examined with a slit lamp microscope and photographed simultaneously. Two rabbits from each group were killed on day 28 and eight eye samples obtained for histopathological study. Corneas and lenses were examined by transmission and scanning electron microscopy. Results: Both 5-FU and MMC significantly prolonged bleb survival compared with control groups. The filtering bleb’s survival period was significantly more prolonged in the MMC and 5-FU groups (maintained 14 days than the

  10. Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy.

    Directory of Open Access Journals (Sweden)

    Pornthip Chaisawang

    Full Text Available The chemotherapy drug, 5-fluorouracil (5-FU, has been reported to cause cognitive impairments in cancer patients. The drug also reduces cell proliferation and survival in the brain. Asiatic acid (AA is a triterpene compound found in Centella asiatica that can protect against reduction of neurogenesis in the hippocampus and memory deficits induced by valproic acid (VPA. In the present study, we investigated the preventive effects of AA on the deficits in spatial working memory and cell proliferation and survival caused by 5-FU chemotherapy in a rat model. Male Sprague Dawley rats received 5-FU (5 i.v. injections, 25 mg/kg on day 8, 11, 14, 17 and 20 of the study. This was co-administered with AA (30 mg/kg, oral gavage tube either 20 days before receiving 5-FU (preventive, after receiving 5-FU (recovery, or for the entire period of the experiment (throughout. Spatial working memory was determined using the novel object location (NOL test and hippocampal cell proliferation and survival of dividing cells were quantified using immunohistochemistry. Rats in the 5-FU alone and recovery groups showed memory deficits in the NOL test and reductions in cell proliferation and cell survival in the subgranular zone (SGZ of the hippocampal dentate gyrus. Rats in the control, AA alone, and both preventive and throughout co-administration groups, however, did not exhibit these characteristics. The results showed that 5-FU chemotherapy impaired memory and reduced cell proliferation and cell survival in the SGZ of the hippocampal dentate gyrus. However, these impairments in the animals receiving 5-FU chemotherapy were restored to control levels when AA was co-administered before and during 5-FU treatment. These data demonstrate that AA can prevent the spatial working memory and hippocampal neurogenesis impairments caused by 5-FU chemotherapy.

  11. Multicenter Phase 2 Study of Cisplatin and 5-Fluorouracil With Concurrent Radiation Therapy as an Organ Preservation Approach in Patients With Squamous Cell Carcinoma of the Cervical Esophagus

    Energy Technology Data Exchange (ETDEWEB)

    Zenda, Sadamoto, E-mail: szenda@east.ncc.go.jp [Department of Radiation Oncology, National Cancer Center Hospital East, Chiba (Japan); Kojima, Takashi [Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba (Japan); Kato, Ken [Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo (Japan); Izumi, Sachiko [Department of Radiation Oncology, Tokyo Women' s Medical University, Tokyo (Japan); Ozawa, Taijiro [Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Aichi (Japan); Kiyota, Naomi [Department of Medical Oncology and Hematology, Kobe University Hospital, Hyogo (Japan); Katada, Chikatoshi [Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara (Japan); Tsushima, Takahiro [Department of Gastrointestinal Endoscopy and Oncology, Shizuoka Cancer Center Hospital, Shizuoka (Japan); Ito, Yoshinori [Division of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Akimoto, Tetsuo [Department of Radiation Oncology, National Cancer Center Hospital East, Chiba (Japan); Hasegawa, Yasuhisa [Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Aichi (Japan); Kanamaru, Miyuki [Department of Radiation Oncology, National Cancer Center Hospital East, Chiba (Japan); Daiko, Hiroyuki [Department of Surgery, National Cancer Center Hospital East, Chiba (Japan)

    2016-12-01

    Purpose: To clarify, in a multicenter, single-arm, phase 2 study (UMIN Clinical Trials Registry no. UMIN000001439), the clinical profile of chemoradiotherapy (CRT) for cervical esophageal cancer. Patients and Methods: Patients with operable cervical esophageal cancer, excluding candidates for endoscopic resection, were enrolled. Protocol treatment consisted of CRT and adjuvant chemotherapy (CT). First, patients received concurrent CRT with 5-fluorouracil (5-FU) plus cisplatin (CDDP). Chemotherapy consisted of 5-FU at 700 mg/m{sup 2} intravenous on days 1 to 4 and CDDP at 70 mg/m{sup 2} intravenous on day 1, repeated every 4 weeks for 2 cycles. Radiation therapy consisted of 60 Gy in 30 fractions. After completion of CRT, 2 additional cycles of CT with 5-FU (800 mg/m{sup 2}, days 1-5) and CDDP (80 mg/m{sup 2}, day 1) were repeated at a 4-week interval. The primary endpoint was 3-year overall survival. Results: Thirty patients were enrolled across 8 institutions in Japan, consisting of 26 men and 4 women with a median age of 64.5 years (range, 50-75 years). No grade 4 hematologic toxicity was seen in the CRT phase, and 1 grade 4 thrombocytopenia was seen in the CT phase. Grade 3 nonhematologic acute toxicities in the CRT phase were nausea (10%), mucositis (13.3%), and dysphagia (13.3%). No treatment-related death in either phase occurred. Overall complete response rate was 73%, and 3-year overall and laryngectomy-free survival were 66.5% and 52.5%, respectively. Regarding T4 disease, 3-year overall and laryngectomy-free survival were 58.3% and 38.5%, respectively. Conclusions: This study, the first prospective study for cervical esophageal cancer, showed that CRT has sufficient efficacy and safety for use as an alternative to surgery for these patients.

  12. Thymidylate synthase polymorphism in sporadic colorectal and gastric cancer in Tunisian population: a predictive role in 5-fluorouracil based chemotherapy treatment.

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    Baroudi, Olfa; Baroudi, Thouraya; Omrane, Ines; Moussa, Amel; Mezlini, Amel; Ayari, Hajer; Guermazi, Sami; Bahloul, Abdesslem; Bouzaienne, Hassen; Uhrhammer, Nancy; Bignon, Yves Jean; El-Gaaied, Amel Benammar; Bougatef, Karim

    2014-02-01

    In our study, we investigate the possible association of thymidylate synthase polymorphism, 28 bp tandem repeat in 5'-UTR (transcription enhancer element) with susceptibility of colorectal and gastric cancer in Tunisian population. Because thymidylate synthase provides an effective prediction of chemotherapy treatment based on 5-fluorouracil, our interest in this study was focused on finding an eventual interaction between thymidylate synthase polymorphism and treatment of sporadic colorectal and gastric cancer. Whole blood was collected into EDTA tube, after centrifugation for 15 min, the buffy coat was isolated, and genotyping of TS 5'-UTR polymorphism was carried by polymerase chain reaction method using appropriate primers. Determination of the different genotypes was done directly on the stained agarose gel. Our finding showed that the 5'tandem repeat polymorphism of the thymidylate synthase gene is associated with risk of colorectal cancer; thus, LL (3R/3R) genotype is significantly high in patients with colorectal cancer compared to controls (P = 0.002; OR 2.7; 95 % CI 1.4-5.2). In addition, we found a positive association between SL (2R/3R) genotype in the thymidylate synthase 5'-UTR and gastric cancer risk (P = 0.015; OR 4.46; 95 % CI 1.08-19.64). Furthermore, we found a correlation of thymidylate synthase polymorphism with the fluorouracil-based therapy regimes and also with preoperatory radiation in patients with colorectal cancer. Thymidylate synthase is associated with risk of colorectal cancer but not with gastric cancer; however, heterozygous SL (2R/3R) polymorphism is associated with risk of gastric cancer; moreover, the 5' tandem repeat polymorphism of thymidylate synthase gene was an independent predictor of the clinical treatment.

  13. Long noncoding RNA XIST is a prognostic factor in colorectal cancer and inhibits 5-fluorouracil-induced cell cytotoxicity through promoting thymidylate synthase expression.

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    Xiao, Yang; Yurievich, Usenko Alexander; Yosypovych, Smorzhevskyi Valentyn

    2017-10-10

    A major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to 5-fluorouracil (5FU)-based treatment. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical regulators in chemoresistance. By using the next generation HiSeq sequencing assay, we identified lncRNAs showing differential expression levels in 5FU resistant and non-resistant CRC patients. RT-qPCR was then performed for validation in tissues and serum samples, and lncRNA XIST was verified to be up-regulated in non-responding patients and have considerable diagnostic potential to identify responding patients from non-responding patients. In addition, increased serum XIST level was associated with poor response and lower survival rate in CRC patients receiving 5FU-based treatment. Subsequently, the 5FU resistant (5FU-R) cell lines were established, and lncRNA XIST was significantly up-regulated HT29 5FU-R and HCT116 5FU-R cells. Furthermore, knockdown of XIST reversed 5FU resistance while enhanced XIST could restrained the 5FU-induced cell cytotoxcity in both CRC cell lines. Western blotting and immunofluorescence analysis indicated that XIST promoted the expression of thymidylate synthase, a critical 5FU-targetd enzyme. In conclusion, our integrated approach demonstrates that increased expression of lncRNA XIST3 in CRC confers a potent poor therapeutic efficacy, and that lncRNA XIST participated in 5FU resistance through promoting the expression of thymidylate synthase. Thus, specific silence oflncRNA XIST could be a future direction to develop a novel therapeutic strategy to overcome 5FU resistance of CRC patients.

  14. Dual sphingosine kinase inhibitor SKI-II enhances sensitivity to 5-fluorouracil in hepatocellular carcinoma cells via suppression of osteopontin and FAK/IGF-1R signalling.

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    Grbčić, Petra; Tomljanović, Ivana; Klobučar, Marko; Kraljević Pavelić, Sandra; Lučin, Ksenija; Sedić, Mirela

    2017-06-10

    Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths globally. Although 5-Fluorouracil (5-FU) is used as the first choice treatment for advanced HCC, it exerts poor efficacy and is associated with acquired and intrinsic resistance. Sphingosine kinases (Sphk) 1 and 2 play tumour-promoting roles in different cancer types including HCC and thus represent promising pharmacological targets. In the present study, we have investigated for the first time the anticancer efficacy and underlying molecular mechanisms of combined administration of 5-FU and dual Sphk1/Sphk2 inhibitor SKI-II (4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol) in HepG2 hepatocellular carcinoma cells. Here, we report that co-administration of 5-FU and SKI-II at low sub-toxic concentrations of 20 μM and 5 μM, respectively, synergistically inhibit cell proliferation, markedly reduce cell migration and the clonogenic survival, and increase apoptosis induction in HepG2 cells. Additional Western blot analyses have shown that possible mechanisms underlying enhanced sensitivity to 5-FU induced by dual Sphk 1/2 inhibition could include abrogation of FAK-regulated IGF-1R activity and down-regulation of osteopontin expression culminating in the inhibition of NF-κB activity and its downstream signalling mediated by sirtuin 1 and p38 MAPK. Our results clearly show that pharmacological blockade of both Sphk isoforms represents a promising strategy to boost the anti-tumour efficacy of 5-FU and provide a rationale for further in vivo studies into the possible use of SKI-II inhibitor as an adjunct to 5-FU treatment in HCC. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Effects of 5-fluorouracil in nuclear and cellular morphology, proliferation, cell cycle, apoptosis, cytoskeletal and caveolar distribution in primary cultures of smooth muscle cells.

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    Marcelo de Carvalho Filgueiras

    Full Text Available Colon cancer is one of the most prevalent types of cancer in the world and is one of the leading causes of cancer death. The anti-metabolite 5- fluorouracil (5-FU is widely used in the treatment of patients with colon cancer and other cancer types. 5-FU-based chemotherapy has been shown to be very efficient in the improvement of overall survival of the patients and for the eradication of the disease. Unfortunately, common side effects of 5-FU include severe alterations in the motility of the gastrointestinal tissues. Nevertheless, the molecular and cellular effects of 5-FU in smooth muscle cells are poorly understood. Primary smooth muscle cell cultures are an important tool for studies of the biological consequences of 5-FU at the cellular level. The avian gizzard is one of the most robust organs of smooth muscle cells. Here we studied the molecular and cellular effects of the chemotherapic drug 5-FU in a primary culture of chick gizzard smooth muscle cells. We found that treatment of smooth muscle cells with 5-FU inhibits cell proliferation by the arrest of cells in the G1 phase of cell cycle and induce apoptosis. 5-FU induced a decrease in the percentage of histone H3-positive cells. Treatment of cells with 5-FU induced changes in cellular and nuclear morphology, a decrease in the number of stress fibers and a major decrease in the number of caveolin-3 positive cells. Our results suggest that the disorganization of the actin cytoskeleton and the reduction of caveolin-3 expression could explain the alterations in contractility observed in patients treated with 5-FU. These findings might have an impact in the understanding of the cellular effects of 5-FU in smooth muscle tissues and might help the improvement of new therapeutic protocols for the treatment of colon cancer.

  16. Radiochemotherapy including cisplatin alone versus cisplatin + 5-fluorouracil for locally advanced unresectable stage IV squamous cell carcinoma of the head and neck

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    Tribius, Silke; Kilic, Yasemin [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany); Kronemann, Stefanie [Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Schroeder, Ursula [Dept. of Head and Neck Surgery, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Hakim, Samer [Dept. of Oro-Maxillo-Facial Surgery, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Schild, Steven E. [Dept. of Radiation Oncology, Mayo Clinic, Scottsdale, AZ (United States); Rades, Dirk [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany); Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany)

    2009-10-15

    Background and purpose: the optimal radiochemotherapy regimen for advanced head-and-neck cancer is still debated. This nonrandomized study compares two cisplatin-based radiochemotherapy regimens in 128 patients with locally advanced unresectable stage IV squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: concurrent chemotherapy consisted of either two courses cisplatin (20 mg/m{sup 2}/d1-5 + 29-33; n = 54) or two courses cisplatin (20 mg/m{sup 2}/d1-5 + 29-33) + 5-fluorouracil (5-FU; 600 mg/m{sup 2}/d1-5 + 29-33; n = 74). Results: at least one grade 3 toxicity occurred in 25 of 54 patients (46%) receiving cisplatin alone and in 52 of 74 patients (70%) receiving cisplatin + 5-FU. The latter regimen was particularly associated with increased rates of mucositis (p = 0.027) and acute skin toxicity (p = 0.001). Seven of 54 (13%) and 20 of 74 patients (27%) received only one chemotherapy course due to treatment-related acute toxicity. Late toxicity in terms of xerostomia, neck fibrosis, skin toxicity, and lymphedema was not significantly different. The 2-year locoregional control rates were 67% after cisplatin alone and 52% after cisplatin + 5-FU (p = 0.35). The metastases-free survival rates were 79% and 69%, respectively (p = 0.65), and the overall survival rates 70% and 51%, respectively (p = 0.10). On multivariate analysis, outcome was significantly associated with performance status, T-category, N-category, hemoglobin level prior to radiotherapy, and radiotherapy break > 1 week. Conclusion: two courses of fractionated cisplatin (20 mg/m{sup 2}/day) alone appear preferable, as this regimen resulted in similar outcome and late toxicity as two courses of cisplatin + 5-FU, but in significantly less acute toxicity. (orig.)

  17. Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways.

    Science.gov (United States)

    Gao, Yue; Xiao, Xiangsheng; Zhang, Changlin; Yu, Wendan; Guo, Wei; Zhang, Zhifeng; Li, Zhenglin; Feng, Xu; Hao, Jiaojiao; Zhang, Kefang; Xiao, Bingyi; Chen, Miao; Huang, Wenlin; Xiong, Shunbin; Wu, Xiaojun; Deng, Wuguo

    2017-03-01

    5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in colon cancer treatment, but has a narrow therapeutic index limited by its toxicity. Melatonin exerts antitumor activity in various cancers, but it has never been combined with 5-FU as an anticolon cancer treatment to improve the chemotherapeutic effect of 5-FU. In this study, we assessed such combinational use in colon cancer and investigated whether melatonin could synergize the antitumor effect of 5-FU. We found that melatonin significantly enhanced the 5-FU-mediated inhibition of cell proliferation, colony formation, cell migration and invasion in colon cancer cells. We also found that melatonin synergized with 5-FU to promote the activation of the caspase/PARP-dependent apoptosis pathway and induce cell cycle arrest. Further mechanism study demonstrated that melatonin synergized the antitumor effect of 5-FU by targeting the PI3K/AKT and NF-κB/inducible nitric oxide synthase (iNOS) signaling. Melatonin in combination with 5-FU markedly suppressed the phosphorylation of PI3K, AKT, IKKα, IκBα, and p65 proteins, promoted the translocation of NF-κB p50/p65 from the nuclei to cytoplasm, abrogated their binding to the iNOS promoter, and thereby enhanced the inhibition of iNOS signaling. In addition, pretreatment with a PI3K- or iNOS-specific inhibitor synergized the antitumor effects of 5-FU and melatonin. Finally, we verified in a xenograft mouse model that melatonin and 5-FU exerted synergistic antitumor effect by inhibiting the AKT and iNOS signaling pathways. Collectively, our study demonstrated that melatonin synergized the chemotherapeutic effect of 5-FU in colon cancer through simultaneous suppression of multiple signaling pathways. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Polymorphisms of MTHFR C677T and A1298C associated with survival in patients with colorectal cancer treated with 5-fluorouracil-based chemotherapy.

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    Yeh, Chih-Ching; Lai, Ching-Yu; Chang, Shih-Ni; Hsieh, Ling-Ling; Tang, Reiping; Sung, Fung-Chang; Lin, Yi-Kuei

    2017-06-01

    This study examined the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and survival of patients with colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)-based chemotherapy in Taiwan. We genotyped MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) for 498 CRC patients treated with 5-FU-based chemotherapy after receiving surgery. Survival analyses on MTHFR polymorphisms were performed using log-rank test and Kaplan-Meier curve. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MTHFR genotypes and survival. Overall survival (OS) was significantly longer in CRC patients with MTHFR 677 CT+TT genotypes compared with those with 677 CC genotype (HR 0.77; 95% CI 0.60-0.98). Although the MTHFR A1298C polymorphism was not associated with OS in CRC, this polymorphism was associated with significantly shorter OS in rectal cancer. Among rectal cancer patients, OS was shorter for patients with AC+CC genotypes than for those with the AA genotype (HR 1.95; 95% CI 1.35-2.83). In haplotype analysis, better OS was found for colon cancer patients carrying the MTHFR 677T-1298A haplotype (HR 0.73; 95% CI 0.55-0.97), but worse survival was linked to rectal cancer patients carrying the MTHFR 677C-1298C haplotype (HR 1.53; 95% CI 1.08-2.18). Our findings suggest that MTHFR genotypes provide prognostic information for CRC patients treated with 5-FU-based chemotherapy.

  19. Live and heat-killed Lactobacillus rhamnosus GG upregulate gene expression of pro-inflammatory cytokines in 5-fluorouracil-pretreated Caco-2 cells.

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    Fang, Shiuh-Bin; Shih, Hsin-Yu; Huang, Chih-Hung; Li, Li-Ting; Chen, Chia-Chun; Fang, Hsu-Wei

    2014-06-01

    This study investigates whether post-chemotherapeutic use of live and heat-killed Lactobacillus rhamnosus GG can modulate the expression of three pro-inflammatory cytokines in 5-fluorouracil (5-FU)-induced intestinal mucositis in vitro. Live L. rhamnosus GG and heat-killed L. rhamnosus GG were observed using scanning electron microscopy. To establish the duration required for optimal expression of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and interleukin-12 (IL-12), 5 μM of 5-FU was selected to treat 10-day-old Caco-2 cells for 4, 6, 8, and 24 h. Caco-2 cells were treated with 5-FU (5 μM) for 4 h, followed by the administration of live L. rhamnosus GG (multiplicity of infection = 25), and heat-killed L. rhamnosus GG for 2 and 4 h. Finally, total cellular RNA was isolated to quantify mRNA expression of TNF-α, MCP-1, and IL-12 using real-time PCR. The results demonstrated that heat-killed L. rhamnosus GG remained structurally intact with elongation. A biphasic upregulated expression of TNF-α, MCP-1, and IL-12 was observed in 5-FU-treated Caco-2 cells at 4 and 24 h. Compared to non-L. rhamnosus GG controls in 5-FU-pretreated Caco-2 cells, a 2-h treatment of heat-killed L. rhamnosus GG significantly upregulated the MCP-1 expression (p GG treatments lasting 4 h upregulated the TNF-α and MCP-1 expression (p GG upregulated the IL-12 expression (p GG can upregulate the gene expression of 5-FU-induced pro-inflammatory cytokines in Caco-2 cells. Human intestinal epithelium may be vulnerable to the post-chemotherapeutic use of L. rhamnosus GG in 5-FU-induced mucositis that requires further in vivo studies for clarification.

  20. Uptake of 5-fluorouracil (5-FU) in peritoneal metastases in relation to the route of drug administration and tumour debulking surgery. an autoradiographic study in the rat.

    Science.gov (United States)

    Mahteme, H; Larsson, B; Sundin, A; Khamis, H; Graf, W

    2004-01-01

    Patients with peritoneal metastases from colorectal cancer have a poor prognosis. Aggressive treatment by debulking surgery and intraperitoneal (i.p.) chemotherapy has been suggested as an alternative therapy. However, the drug penetrance into the tumour in relation to the administration route and surgical reduction of the tumour is not well known. We compared locoregional administration with intravenous (i.v.) injection. Thirty-four in-bred rats with peritoneal metastases were randomly allocated into eight groups and injected with 14C-labelled 5-fluorouracil (5-FU) either through the i.v. or i.p. route, with or without a preceding tumour debulking, and were sacrificed after 2 or 8 h. Tumour radioactivity was visualised by autoradiography and quantified by a computer-based image analysis. After 8 h, 19 debulked and i.p.-injected tumours had a higher drug uptake, 63.2+/-28 (mean+/-standard deviation (SD)) kBq/g than 62 native i.p.-injected tumours (32.8+/-14) or 22 debulked and i.v.-injected tumours (18.5+/-18, P=0.002). After 8 h, 9 small tumours (/=median 571 pixels), 16 debulked and i.p.-injected tumours had a higher radioactivity (drug uptake) (150.7+/-63) at 2 h than 49 i.p.-injected native tumours (48.5+/-59) or 11 reduced and i.v.-injected tumours (19.9+/-13, P=0.03). At 8 h, 10 debulked and i.p.-injected tumours had a higher drug uptake (50.3+/-24) than 33 native and i.p.-injected (30.8+/-10) or 14 debulked and i.v.-injected tumours (16.0+/-19, P=0.001). These results indicate that a debulking procedure and locoregional treatment of peritoneal metastases is associated with an increased level of 5-FU in the tumours.

  1. The Effect of Analogues of 1α,25-Dihydroxyvitamin D2 on the Regrowth and Gene Expression of Human Colon Cancer Cells Refractory to 5-Fluorouracil

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    Jacek Neska

    2016-06-01

    Full Text Available This study aimed to evaluate the capacity of hypocalcemic analogues of 1α,25-dihydroxyvitamin D2 (1,25D2 and 1α,25-dihydroxyvitamin D3 (1,25D3 to inhibit regrowth and regulate the stemness-related gene expression in colon cancer cells undergoing renewal after exposure to 5-fluorouracil (5-FU. All of the tested analogues of 1,25D2 equally potently decreased the clonogenicity and the proliferative activity of HT-29 cells which survived the exposure to 5-FU, but differently regulated gene expression of these cells during their renewal. 1,25D2 and analogues (PRI-1907 and PRI-1917, as well as 1,25D3 and analogue PRI-2191, decreased the relative expression level of several stemness-related genes, such as NANOG, OCT3/4, PROM1, SOX2, ALDHA1, CXCR4, in HT-29/5-FU cells during their renewal, in comparison to untreated HT-29/5-FU cells. The other 1,25D2 analogues (PRI-1906 and PRI-1916 were not capable of downregulating the expression of these stemness-related genes as the analogues PRI-1907 and PRI-1917 did. All of the tested vitamin D analogues upregulated CDH1, the gene encoding E-cadherin associated with epithelial phenotype. Out of the series of analogues studied, side-chain branched analogues of 1,25D2 (PRI-1907, PRI-1917 and the analogue of 1,25D3 (PRI-2191 might be used to target cancer cells with stem-like phenotypes that survive conventional chemotherapy.

  2. Synthesis of F16 conjugated with 5-fluorouracil and biophysical investigation of its interaction with bovine serum albumin by a spectroscopic and molecular modeling approach.

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    Xiang, Chen; Li, Dong-Wei; Qi, Zu-De; Jiang, Feng-Lei; Ge, Yu-Shu; Liu, Yi

    2013-01-01

    5-Fluorouracil (5-FU) has been widely used as a chemotherapy agent in the treatment of many types of solid tumors. Investigation of its antimetabolites led to the development of an entire class of fluorinated pyrimidines. However, the toxicity profile associated with 5-FU is significant and includes diarrhea, mucositis, hand-foot syndrome and myelosuppression. In aiming at reducing of the side effects of 5-FU, we have designed and synthesized delocalized lipophilic cations (DLCs) as a vehicle for the delivery of 5-FU. DLCs accumulate selectively in the mitochondria of cancer cells because of the high mitochondrial transmembrane potential (ΔΨm). Many DLCs exhibited anti-cancer efficacy and were explored as potential anti-cancer drugs based on their selective accumulation in the mitochondria of cancer cells. F16, the DLC we used as a vehicle, is a small molecule that selectively inhibits tumor cell growth and dissipates mitochondrial membrane potential. The binding of the conjugate F16-5-FU to bovine serum albumin (BSA) was investigated using spectroscopic and molecular modeling approaches. Fluorescence quenching constants were determined using the Stern-Volmer equation to provide a measure of the binding affinity between F16-5-FU and BSA. The activation energy of the interaction between F16-5-FU and BSA was calculated and the unusually high value was discussed in terms of the special structural block indicated by the molecular modeling approach. Molecular modeling showed that F16-5-FU binds to human serum albumin in site II, which is consistent with the results of site-competitive replacement experiments. It is suggested that hydrophobic and polar forces played important roles in the binding reaction, in accordance with the results of thermodynamic experiments. Copyright © 2012 John Wiley & Sons, Ltd.

  3. Ocular surface and tear film abnormalities in women under adjuvant chemotherapy for breast cancer with the 5-Fluorouracil, Epirubicin and Cyclophosphamide (FEC) regimen.

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    Karamitsos, A; Kokkas, V; Goulas, A; Paraskevopoulos, P; Gougoulias, K; Karampatakis, V; Boboridis, K

    2013-04-01

    To study possible ocular surface and lacrimal drainage changes in women being on adjuvant chemotherapy with 5-Fluorouracil 600 mg/m2, Epirubicin 60-90 mg/m(2), Cyclophosphamide 600 mg/m(2) (FEC) regimen for breast cancer. Sixty one consecutive women with early stage breast cancer (median age 58 years - interquartile range 22) were included in this study. They all underwent mastectomy followed by 6 cycles of tri-weekly administration of FEC regimen and were free of ocular surface, eyelid and tear film symptomatic disease at baseline. None of them had pre- or coexisting treatment with other chemotherapeutic agent or radiotherapy. Slit lamp examination of the ocular surface, Schirmer test I (without topical anesthesia) and tears Break up Time test (BUT) were performed before the initiation of treatment and immediately after the third therapeutic cycle. From 61 women 39.34% had significant conjunctival hyperemia, 41.0% lid margin abnormalities, 4.92% blepharitis, 6.56% madarosis, 3.28% punctate epithelial keratopathy and 4.92% oedema of the lower punctum mucosal opening after three chemotherapeutic cycles. Mean BUT measures were found lower after the third chemotherapeutic cycle (p=0.001) but mean Schirmer test I values were higher after the third chemotherapeutic cycle (p=0.001). Women on chemotherapy with FEC regimen are more susceptible to develop ocular surface and tear film alterations, within the first three cycles of chemotherapy for breast cancer, and thus, prompt ophthalmological evaluation may be proven beneficial for early diagnosis and management of the induced ocular disease.

  4. miR-1290 Is a Biomarker in DNA-Mismatch-Repair-Deficient Colon Cancer and Promotes Resistance to 5-Fluorouracil by Directly Targeting hMSH2

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    Ling Ye

    2017-06-01

    Full Text Available 5-Fluorouracil (5FU-based adjuvant therapy is the first-line therapy for treating stage II and III colon cancer after surgery. However, its therapeutic efficacy is limited because of chemoresistance, especially in deficient mismatch repair (dMMR colon cancer. Here, we first used laser capture microdissection to obtain purified cells from four dMMR and four proficient mismatch repair (pMMR colon cancer tissues. Second, microRNA (miRNA microarray chips were used to identify miRNAs that are differentially expressed between these two classes of tumors. Third, we analyzed their differential expression by qRT-PCR in a panel of 5-FU-resistant colon cancer cell lines. We identified that miR-1290 was one of the most upregulated miRNAs in both dMMR colon cancer tissues and 5-FU-resistant cells. We also found that miR-1290 was positively correlated with dMMR status and predicted poor prognosis in stage II and III colon cancer patients who received 5-FU-based chemotherapy. Furthermore, we demonstrated that inhibition of the expression of miR-1290 enhanced sensitivity to 5-FU treatment in vitro and in tumor xenografts in vivo by direct targeting hMSH2. Our study indicates that miR-1290 may become a promising biomarker of dMMR colon cancer and predicts the prognosis of stage II and III patients who receive 5-FU-based adjuvant therapy.

  5. Demonstration in vitro of inhibition in normal rat tissues yet stimulation in Jensen sarcoma cells of 5-fluorouracil anabolism by purine nucleosides

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    Beltz, R.E.; Haddad-Zackrison, L.

    1986-05-01

    It has been shown previously that the ability of tumor cells to anabolize 5-fluorouracil (FUra) to nucleotides can often be enhanced by exposing the cells to various purine nucleosides. Increases in FUra cytotoxicity have been observed to accompany this enhancement. In the present study the effects of purine nucleosides on FUra anabolism in rat tumor cells and in normal rat tissues sensitive to FUra were compared. Pieces of small intestine (SI), bone marrow suspensions (BM) and Jensen tumor cells were incubated in culture medium at 37/sup 0/ for 1 hr in the presence (or absence) of a selected purine nucleoside, then (2-/sup 14/C)FUra was added and the incubation was continued for another hr. Incorporation of radioactivity into the trichloroacetic acid-insoluble fraction in each case was determined as a measure of FUra anabolism. Inosine, adenosine and N/sup 6/-methyl-adenosine, 1 mM, stimulated FUra incorporation into the acid-insoluble fraction 2-3 fold in the tumor cells but inhibited this incorporation 59-70% in SI and 31-70% in BM. Attempts to further suppress FUra anabolism in the normal tissues resulted in a maximal inhibition of 92% in SI, using 1 mM alloxanthine, and a maximal inhibition of 84% in BM, employing combined 1 mM alloxanthine and 1 mM 5-aminoimidazole-4-carbox-amide ribonucleoside. These data suggest ways of selectively altering FUra anabolism in normal tissue and in tumor tissue of the tumor-bearing rat to improve the therapeutic index of FUra.

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

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    Kaya Yoshida

    Full Text Available 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.

  7. Clinical, biochemical and histological study of the effect of antimicrobial photodynamic therapy on oral mucositis induced by 5-fluorouracil in hamsters.

    Science.gov (United States)

    Cruz, Érika de Paula da; Campos, Luana; Pereira, Filipi da Silva; Magliano, Gabriela Campos; Benites, Bernar Monteiro; Arana-Chavez, Victor Elias; Ballester, Rafael Yagüe; Simões, Alyne

    2015-06-01

    Oral mucositis (OM) is a debilitating side effect of chemotherapy, which can be relieved by phototherapy. Antimicrobial photodynamic therapy (aPDT) may be used for the treatment of OM, when infection is present. However, there are no studies showing that aPDT affects tissue repair process when used in the treatment of lesions caused by OM. This work aims to evaluate the effect of aPDT in healing OM induced by 5-Fluorouracil (5-FU). Two hundred forty-five hamsters were divided into two groups, control (C) and experimental, which were subdivided into 4 subgroups (Ch, ChP, ChL, aPDT). C group received only the vehicle of chemotherapy and anesthesia, whereas all animals of the experimental groups received anesthesia and chemotherapy agent 5-FU to induce OM. Ch group received no OM treatment; ChP group received an application of methylene blue (MB) 0.01%; ChL received irradiation with low-power-laser (LPL-660 nm/120 J /cm(2)/40 mW/4.4 J per point); and aPDT received MB and LPL irradiation. OM Clinical severity were daily assessed by a blinded examiner. The animals were sacrificed after 5, 7 and 10 days of experiment and their oral mucosa were removed for biochemical (enzymatic activity of SOD and catalase) and histological analyzes (light microscopy). After statistical analysis was performed, results showed that aPDT reduced the severity of OM on the tenth day of the experiment, when compared to the initial OM score (p < 0.05), as well as increased keratinization with organized collagen deposition in the lamina propria. In conclusion, aPDT can be safely used in animals with infected OM because it does not affect lesion-repairing processes. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Long-term results of radiotherapy combined with nedaplatin and 5-fluorouracil for postoperative loco-regional recurrent esophageal cancer: update on a phase II study.

    Science.gov (United States)

    Jingu, Keiichi; Matsushita, Haruo; Takeda, Ken; Umezawa, Rei; Takahashi, Chiaki; Sugawara, Toshiyuki; Kubozono, Masaki; Abe, Keiko; Tanabe, Takaya; Shirata, Yuko; Yamamoto, Takaya; Ishikawa, Youjirou; Nemoto, Kenji

    2012-11-22

    In 2006, we reported the effectiveness of chemoradiotherapy for postoperative recurrent esophageal cancer with a median observation period of 18 months. The purpose of the present study was to update the results of radiotherapy combined with nedaplatin and 5-fluorouracil (5-FU) for postoperative loco-regional recurrent esophageal cancer. Between 2000 and 2004, we performed a phase II study on treatment of postoperative loco-regional recurrent esophageal cancer with radiotherapy (60 Gy/30 fractions/6 weeks) combined with chemotherapy consisting of two cycles of nedaplatin (70 mg/m2/2 h) and 5-FU (500 mg/m2/24 h for 5 days).The primary endpoint was overall survival rate, and the secondary endpoints were progression-free survival rate, irradiated-field control rate and chronic toxicity. A total of 30 patients were enrolled in this study. The regimen was completed in 76.7% of the patients. The median observation period for survivors was 72.0 months. The 5-year overall survival rate was 27.0% with a median survival period of 21.0 months. The 5-year progression-free survival rate and irradiated-field control rate were 25.1% and 71.5%, respectively. Grade 3 or higher late toxicity was observed in only one patient. Two long-term survivors had gastric tube cancer more than 5 years after chemoradiotherapy.Pretreatment performance status, pattern of recurrence (worse for patients with anastomotic recurrence) and number of recurrent lesions (worse for patients with multiple recurrent lesions) were statistically significant prognostic factors for overall survival. Radiotherapy combined with nedaplatin and 5-FU is a safe and effective salvage treatment for postoperative loco-regional recurrent esophageal cancer. However, the prognosis of patients with multiple regional recurrence or anastomotic recurrence is very poor.

  9. Long-term bresults of radiotherapy combined with nedaplatin and 5-fluorouracil for postoperative loco-regional recurrent esophageal cancer: update on a phase II study

    Science.gov (United States)

    2012-01-01

    Background In 2006, we reported the effectiveness of chemoradiotherapy for postoperative recurrent esophageal cancer with a median observation period of 18 months. The purpose of the present study was to update the results of radiotherapy combined with nedaplatin and 5-fluorouracil (5-FU) for postoperative loco-regional recurrent esophageal cancer. Methods Between 2000 and 2004, we performed a phase II study on treatment of postoperative loco-regional recurrent esophageal cancer with radiotherapy (60 Gy/30 fractions/6 weeks) combined with chemotherapy consisting of two cycles of nedaplatin (70 mg/m2/2 h) and 5-FU (500 mg/m2/24 h for 5 days). The primary endpoint was overall survival rate, and the secondary endpoints were progression-free survival rate, irradiated-field control rate and chronic toxicity. Results A total of 30 patients were enrolled in this study. The regimen was completed in 76.7% of the patients. The median observation period for survivors was 72.0 months. The 5-year overall survival rate was 27.0% with a median survival period of 21.0 months. The 5-year progression-free survival rate and irradiated-field control rate were 25.1% and 71.5%, respectively. Grade 3 or higher late toxicity was observed in only one patient. Two long-term survivors had gastric tube cancer more than 5 years after chemoradiotherapy. Pretreatment performance status, pattern of recurrence (worse for patients with anastomotic recurrence) and number of recurrent lesions (worse for patients with multiple recurrent lesions) were statistically significant prognostic factors for overall survival. Conclusions Radiotherapy combined with nedaplatin and 5-FU is a safe and effective salvage treatment for postoperative loco-regional recurrent esophageal cancer. However, the prognosis of patients with multiple regional recurrence or anastomotic recurrence is very poor. PMID:23171077

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

    Energy Technology Data Exchange (ETDEWEB)

    Simonetti, S., E-mail: ssimonet@uns.edu.ar [Universidad Nacional del Sur (UNS)—Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca (Argentina); Universidad Tecnológica Nacional (UTN), Bahía Blanca (Argentina); Compañy, A. Díaz [Comisión de Investigaciones Científicas (CIC), Buenos Aires (Argentina); Pronsato, E.; Juan, A.; Brizuela, G. [Universidad Nacional del Sur (UNS)—Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca (Argentina); Lam, A. [Instituto de Ciencia y Tecnología de Materiales (IMRE), Universidad de La Habana (Cuba)

    2015-12-30

    Graphical abstract: - Highlights: • Favorable energies results in optimum four adsorption geometries. • Silanols are partially weakening and establish H-bonds with polar groups of 5-FU drug. • Dispersion forces approach the 5-FU molecule toward the surface. • Electron exchange is presented after adsorption. • H-bonds stabilize the molecule playing significant role in the adsorption mechanism. - Abstract: 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 SiO{sub 2} (1 1 1) surface is reflected by the elevated number of hydrogen bonds that play a significant role in the adsorption mechanisms.

  11. Effects of low-level laser therapy on collagen expression and neutrophil infiltrate in 5-fluorouracil-induced oral mucositis in hamsters.

    Science.gov (United States)

    Lopes, Nilza Nelly Fontana; Plapler, Hélio; Lalla, Rajesh V; Chavantes, Maria Cristina; Yoshimura, Elisabeth Mateus; da Silva, Marco Antonio Bastos; Alves, Maria Teresa Seixas

    2010-08-01

    Several studies have suggested that low-level laser therapy (LLLT) can ameliorate oral mucositis; however, the mechanisms involved are not well understood. The aim of this study was to investigate the mechanisms of action of LLLT on chemotherapy-induced oral mucositis, as related to effects on collagen expression and inflammation. A hamster cheek pouch model of oral mucositis was used with all animals receiving intraperitoneal 5-fluorouracil, followed by surface irritation. Animals were randomly allocated into three groups, and treated with an InGaAIP diode laser at a wavelength of 660 nm and output power of 35 or 100 mW laser, or no laser. Clinical severity of mucositis was assessed at four time-points by a blinded examiner. Buccal pouch tissue was harvested from a subgroup of animals in each group at four time-points. Collagen was qualitatively and quantitatively evaluated after picrosirius staining. The density of the neutrophil infiltrate was also scored. Peak clinical severity of mucositis was reduced in the 35 mW laser group as compared to the 100 mW and control groups. The reduced peak clinical severity of mucositis in the 35 mW laser group was accompanied by a decrease in the number of neutrophils and an increase in the proportion of mature collagen as compared to the other two groups. The total quantity of collagen was significantly higher in the control (no laser) group at the day 11 time-point, as compared to the 35 mW laser group, consistent with a more prolonged inflammatory response in the control group. This study supports two mechanisms of action for LLLT in reducing mucositis severity. The increase in collagen organization in response to the 35 mW laser indicates that LLLT promotes wound healing. In addition, LLLT also appears to have an anti-inflammatory effect, as evidenced by the reduction in neutrophil infiltrate. (c) 2010 Wiley-Liss, Inc.

  12. Cyclooxygenase-2 and vascular endothelial growth factor expression in 5-fluorouracil-induced oral mucositis in hamsters: evaluation of two low-intensity laser protocols.

    Science.gov (United States)

    Lopes, Nilza Nelly Fontana; Plapler, Hélio; Chavantes, Maria Cristina; Lalla, Rajesh V; Yoshimura, Elisabeth Mateus; Alves, Maria Teresa Seixas

    2009-11-01

    The aim of this study was to investigate the mechanisms whereby low-intensity laser therapy may affect the severity of oral mucositis. A hamster cheek pouch model of oral mucositis was used with all animals receiving intraperitoneal 5-fluorouracil followed by surface irritation. Animals were randomly allocated into three groups and treated with a 35 mW laser, 100 mW laser, or no laser. Clinical severity of mucositis was assessed at four time-points by a blinded examiner. Buccal pouch tissue was harvested from a subgroup of animals in each group at four time-points. This tissue was used for immunohistochemistry for cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and factor VIII (marker of microvessel density) and the resulting staining was quantified. Peak severity of mucositis was reduced in the 35 mW laser group as compared to the 100 mW laser and control groups. This reduced peak clinical severity of mucositis in the 35 mW laser group was accompanied by a significantly lower level of COX-2 staining. The 100 mW laser did not have an effect on the severity of clinical mucositis, but was associated with a decrease in VEGF levels at the later time-points, as compared to the other groups. There was no clear relationship of VEGF levels or microvessel density to clinical mucositis severity. The tissue response to laser therapy appears to vary by dose. Low-intensity laser therapy appears to reduce the severity of mucositis, at least in part, by reducing COX-2 levels and associated inhibition of the inflammatory response.

  13. Comparative study of transfersomes, liposomes, and niosomes for topical delivery of 5-fluorouracil to skin cancer cells: preparation, characterization, in-vitro release, and cytotoxicity analysis.

    Science.gov (United States)

    Alvi, Iqrar Ali; Madan, Jitender; Kaushik, Dinesh; Sardana, Satish; Pandey, Ravi Shankar; Ali, Asgar

    2011-09-01

    Topical 5-fluorouracil (5-FU) is used for the treatment of actinic keratosis and nonmelanoma skin cancer. Unfortunately, 5-FU per se shows a poor percutaneous permeation, thus reducing its anticancer effectiveness after topical administration. Therefore, we have constructed transfersomes, liposomes, and niosomes of 5-FU for topical applications in this investigation. Transfersomes were prepared by the solvent evaporation method, whereas liposomes and niosomes were constructed by reverse-phase evaporation method. The nanovesicles were characterized for particle size, shape, zeta potential, viscosity, entrapment efficiency, deformability, in-vitro permeation release, and kinetics and retention. Cytotoxicity study was carried out on HaCaT cells. Transfersomes (153.2 ± 10.3 nm), liposomes (120.3 ± 9.8 nm), and niosomes (250.4 ± 8.6 nm) were produced with a maximum entrapment efficiency of 82.4 ± 4.8, 45.4 ± 3.3, and 43.4 ± 3.2%, respectively. Moreover, transmission electron microscopy and atomic force microscopy assure the smooth and spherical shape of nanovesicles. Skin permeation and retention showed better permeability and retention than the nonvesiculized dosage form. The IC50 value of transfersomes (1.02 μmol/l), liposomes (6.83 μmol/l), and niosomes (9.91 μmol/l) was found to be far less than 5-FU (15.89 μmol/l) at 72 h. 5-FU-loaded transfersomes were found to be most cytotoxic on the HaCaT cell line in comparison with liposomes and niosomes. We concluded that vesiculization of 5-FU not only improves the topical delivery, but also enhances the cytotoxic effect of 5-FU. We have presented here a viable formulation of 5-FU for the management of actinic keratosis and nonmelanoma skin carcinoma.

  14. Association of Ozone with 5-Fluorouracil and Cisplatin in Regulation of Human Colon Cancer Cell Viability: In Vitro Anti-Inflammatory Properties of Ozone in Colon Cancer Cells Exposed to Lipopolysaccharides

    Directory of Open Access Journals (Sweden)

    V. Simonetti

    2017-01-01

    Full Text Available Introduction. Ozone therapy is an effective medical treatment for different diseases like mucositis, psoriasis, acute pain, neurovascular diseases, and cancer. The aim of this study is based on the association of different ozone concentration with 5-fluorouracil and cisplatin in human colon cancer cell (HT29 cell line in order to investigate possible anticancer synergistic effects. Methods. HT29 cells were incubated with ozone at different concentration ranging from 10 up to 50 μg/ml at different incubation time alone or in combination with cisplatin and 5-fluorouracil. Cell viability was performed by using a modified MTT method. Anti-inflammatory studies were conducted incubating HT29 with or without 20, 30, or 50 μg/ml of ozone before exposure to lipopolysaccharides. Results. Ozone alone has a time and concentration dependent cytotoxicity against HT29 cells (IC50 at 24 h: 30 μg/ml. Association of ozone with drugs increases cytotoxicity by 15–20%. Preincubation of ozone at 50 μg/ml decreases IL-8, IL-6, and IL-1β production by 50, 56, and 70%, respectively, compared to untreated cells. Conclusion. These results indicated that ozone could be useful in colon cancer management in combination with 5-fluorouracil and cisplatin with significant inhibition of cytokines having a central role in colon cancer cell survival and chemoresistance.

  15. Tumor thickness and adnexal extension of superficial basal cell carcinoma (sBCC) as determinants of treatment failure for methylaminolevulinate (MAL)-photodynamic therapy (PDT), imiquimod, and 5-fluorouracil (FU).

    Science.gov (United States)

    Roozeboom, Marieke H; van Kleef, Lotte; Arits, Aimee H M M; Mosterd, Klara; Winnepenninckx, Veronique J L; van Marion, Arienne M W; Nelemans, Patty J; Kelleners-Smeets, Nicole W J

    2015-07-01

    Noninvasive treatments are frequently used in treatment of superficial basal cell carcinoma (sBCC) because of better cosmetic results, lower costs, and less burden on health care services when compared with surgical excision. However, probability of treatment failure is higher after noninvasive therapies and may depend on histologic tumor characteristics. We sought to investigate whether tumor thickness and adnexal extension are determinants of treatment failure in sBCC treated with topical methylaminolevulinate-photodynamic therapy, imiquimod, or 5-fluorouracil. Data were derived from a randomized controlled trial on the effectiveness of methylaminolevulinate photodynamic therapy, imiquimod, and 5-fluorouracil for treatment of sBCC (ISRCTN79701845). For tumors with treatment failure (n = 112) and a randomly selected control group of tumors without treatment failure (n = 224) data on tumor thickness and adnexal extension were retrospectively collected. Treatment failure was defined as a clinically and histologically persistent or recurrent tumor within 1-year posttreatment. Tumor thickness of included patients ranged from 0.2 to 1.0 mm. Tumor thickness and adnexal extension of sBCC were not significantly associated with treatment failure of methylaminolevulinate photodynamic therapy, imiquimod, or 5-fluorouracil. Follow-up period of 1 year is a limitation. There seems to be no need to determine tumor thickness or adnexal extension in sBCC before treatment. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  16. Comparative study in swines' vocal cords healing after excision of fragment with CO2 laser with mitomycin and 5-fluorouracil postoperative topical application Estudo comparado da cicatrização da prega vocal de suínos após exérese de fragmento com laser de CO2 e aplicação tópica pós-operatória de mitomicina e 5-fluorouracil

    Directory of Open Access Journals (Sweden)

    Eduardo Baptistella

    2009-02-01

    Full Text Available PURPOSE: To evaluate the deposition of collagen fibers at pig's vocal folds after topical use of mitomycin or 5-fluorouracil, when partial exeresis of mucosa layer had been promoted by CO2 laser. METHODS: There were used 18 Larger white pigs which were anesthetized and submitted to mucosa fragment's exeresis, bilaterally, at its free border. The animals were divided into 3 groups, each one with 6 animals: control group, without topical drug application; mitomycin group; and 5-fluorouracil group. After 30 days, the animals were subjected to euthanasia, and samples of the vocal folds were collected and stained by picrosirius red technique with polarization for quantification of total collagen deposition. RESULTS: In control group, the mean rate of right vocal fold's collagen deposition at submucosa consisted in a 3428.66 micrometers area. There was found an area whose size had, in average, 2196.36 micrometers, in mitomycin group, and 2269.19 micrometers, in 5-fluorouracil group. CONCLUSION: Mitomycin and 5-fluorouracil had promoted beneficial change in vocal fold's cicatrization with less collagen deposition, but there was no significant statistically difference when they were compared between themselves.OBJETIVO: Avaliar a deposição das fibras de colágeno total em pregas vocais suínas após o uso tópico de mitomicina ou 5-fluorouracil nas exéreses parciais de mucosa com laser de CO2. MÉTODOS: Foram utilizados 18 porcos da raça Larger white anestesiados e submetidos à exérese de fragmento de mucosa de borda livre da prega vocal direita e prega vocal esquerda. Os animais foram divididos em 3 grupos com 6 animais cada: grupo controle, sem aplicação de medicação tópica; grupo mitomicina, com uso tópico dessa substância; grupo 5-fluorouracil, uso tópico. Após 30 dias do experimento os animais foram submetidos à eutanásia, coletadas amostras das pregas vocais e coradas pela técnica do picrosirius red com polarização para a

  17. Anticancer activity of an extract from needles and twigs of Taxus cuspidata and its synergistic effect as a cocktail with 5-fluorouracil

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    Shang Weihu

    2011-12-01

    Full Text Available Abstract Background Botanical medicines are increasingly combined with chemotherapeutics as anticancer drug cocktails. This study aimed to assess the chemotherapeutic potential of an extract of Taxus cuspidata (TC needles and twigs produced by artificial cuttage and its co-effects as a cocktail with 5-fluorouracil (5-FU. Methods Components of TC extract were identified by HPLC fingerprinting. Cytotoxicity analysis was performed by MTT assay or ATP assay. Apoptosis studies were analyzed by H & E, PI, TUNEL staining, as well as Annexin V/PI assay. Cell cycle analysis was performed by flow cytometry. 5-FU concentrations in rat plasma were determined by HPLC and the pharmacokinetic parameters were estimated using 3p87 software. Synergistic efficacy was subjected to median effect analysis with the mutually nonexclusive model using Calcusyn1 software. The significance of differences between values was estimated by using a one-way ANOVA. Results TC extract reached inhibition rates of 70-90% in different human cancer cell lines (HL-60, BGC-823, KB, Bel-7402, and HeLa but only 5-7% in normal mouse T/B lymphocytes, demonstrating the broad-spectrum anticancer activity and low toxicity to normal cells of TC extract in vitro. TC extract inhibited cancer cell growth by inducing apoptosis and G2/M cell cycle arrest. Most interestingly, TC extract and 5-FU, combined as a cocktail, synergistically inhibited the growth of cancer cells in vitro, with Combination Index values (CI ranging from 0.90 to 0.26 at different effect levels from IC50 to IC90 in MCF-7 cells, CI ranging from 0.93 to 0.13 for IC40 to IC90 in PC-3M-1E8 cells, and CI TC extract did not affect the pharmacokinetics of 5-FU in rats. Conclusions The combinational use of the TC extract with 5-FU displays strong cytotoxic synergy in cancer cells and low cytotoxicity in normal cells. These findings suggest that this cocktail may have a potential role in cancer treatment.

  18. Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model.

    Science.gov (United States)

    Britten, C D; Hilsenbeck, S G; Eckhardt, S G; Marty, J; Mangold, G; MacDonald, J R; Rowinsky, E K; Von Hoff, D D; Weitman, S

    1999-03-01

    6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the toxin illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotoxicity in a variety of solid tumors in vivo, including the refractory HT29 human colon cancer xenograft. In this study, the potential application of MGI-114 in the treatment of colon cancer was further explored by evaluating the activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluorouracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated with either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination with CPT-11 or 5FU. MGI-114 was administered at doses of 3.5 and 7 mg/kg i.p. daily on days 1 through 5, and CPT-11 and 5FU were administered at doses of 50 and 100 mg/kg i.p. on days 1, 12, and 19. In the single agent studies, MGI-114, CPT-11, and 5FU all resulted in decreased final tumor weights compared with vehicle-treated controls (P<0.05), but only MGI-114 at 7 mg/kg produced partial responses. When MGI-114 at 3.5 mg/kg was combined with CPT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P< or =0.001). Also, administration of the low-dose combination (MGI-114 at 35 mg/kg and CPT-11 at 50 mg/kg) resulted in final tumor weights similar to those achieved after administration of high-dose MGI-114 as a single agent. Moreover, the combination of MGI-114 and CPT-11 produced partial responses in nearly all of the animals, with some animals achieving complete responses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results suggest enhanced activity when MGI-114 is combined with CPT-11, and clinical trials to further evaluate this combination regimen are planned.

  19. A Randomized Phase 2 Study of Neoadjuvant Chemoradiaton Therapy With 5-Fluorouracil/Leucovorin or Irinotecan/S-1 in Patients With Locally Advanced Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Minkyu; Shin, Sang Joon [Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Koom, Woong Sub [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Jung, Inkyung [Department of Biostatistics, Yonsei University College of Medicine, Seoul (Korea, Republic of); Keum, Ki Chang [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Hur, Hyuk; Min, Byung Soh; Baik, Seung Hyuk; Kim, Nam Kyu [Department of Surgery, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Hoguen [Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lim, Joon Seok [Department of Radiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Hong, Sung Pil; Kim, Tae Il [Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Roh, Jae Kyung [Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Park, Young Suk [Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Ahn, Joong Bae, E-mail: vvswm513@yuhs.ac [Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2015-12-01

    Purpose: The purpose of this study was to evaluate the rate of pathologic complete response (pCR) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation therapy (CRT) with leucovorin (FL) versus irinotecan/S-1 (IS). Methods and Materials: Patients with resectable LARC (clinical stage T3/4, lymph node positive, or both) were randomly assigned to receive preoperative radiation (45-50.4 Gy in 25 to 28 daily fractions) and concomitant chemotherapy either with a bolus injection of FL (400 mg/m{sup 2}/day 5-fluorouracil and 20 mg/m{sup 2}/day leucovorin) for 3 consecutive days every 4 weeks for 2 cycles (FL group) or with 40 mg/m{sup 2} irinotecan on days 1, 8, 15, 22, and 29, and 35 mg/m{sup 2} S-1 twice on the day of irradiation (IS group). Curative surgery was performed approximately 4 to 8 weeks after the completion of CRT. The postoperative chemotherapy regimen was FL with a primary endpoint of a pCR rate evaluation. Results: One hundred forty-two eligible patients were randomly assigned, and the median follow-up duration was 43.8 months (95% confidence interval, 40.8-46.8 months). One hundred thirty-three patients (93.7%) of 142 underwent total mesorectal excision; pCR was achieved in 11 (16.7%) of 66 patients in the FL group and 17 (25.8%) of 67 patients in the IS group (P=.246). When good responders were defined as patients with Mandard grades 1 and 2, the rate of good responders was significantly higher in the IS group than in the FL group (54.6% vs 36.4%, respectively, P=.036). The preoperative rates of grade 3 and 4 toxicities were higher in the IS group (7.0%) than in the FL group (1.4%, P=.095). The 3-year disease-free survival was not significantly different between the 2 groups (79.7% vs 76.6%, respectively, P=.896). Conclusions: IS-based preoperative CRT did not increase pCR rate, but it did increase acute toxicities compared with standard 5-FU treatment. Therefore, further investigation is needed.

  20. Feasibility and Efficacy of Induction Docetaxel, Cisplatin, and 5-Fluorouracil Chemotherapy Combined With Cisplatin Concurrent Chemoradiotherapy for Nonmetastatic Stage IV Head-and-Neck Squamous Cell Carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Prestwich, Robin J., E-mail: Robin.Prestwich@leedsth.nhs.uk [Department of Clinical Oncology, St. James' s Institute of Oncology, Leeds (United Kingdom); Oeksuez, Didem Colpan; Dyker, Karen; Coyle, Catherine; Sen, Mehmet [Department of Clinical Oncology, St. James' s Institute of Oncology, Leeds (United Kingdom)

    2011-11-15

    Purpose: To report the experience of treating selected fit patients with locally advanced head-and-neck squamous cell carcinoma with three cycles of induction TPF (docetaxel 75 mg/m{sup 2}, cisplatin 75 mg/m{sup 2}, 5-fluorouracil 750 mg/m{sup 2}, Days 2-5) followed by concurrent three-weekly bolus cisplatin 100 mg/m{sup 2} chemoradiotherapy. Methods and Materials: Between March 2006 and February 2010, 66 patients with nonmetastatic Stage IV head-and-neck squamous cell carcinoma were treated in a single institution with three cycles of induction TPF, followed by radical radiotherapy with concurrent cisplatin 100 mg/m{sup 2}. Results: Median age was 54 years (range, 33-69 years). Median follow-up was 21 months (range, 4-55 months). During TPF, Grade 3 toxicity occurred in 18 patients (27%), dose modifications in 10 (15%), delays in 3 (5%), and unplanned admissions in 6 (9%); a clinical tumor response was documented in 60 patients (91%). Median time from the final cycle of TPF to commencing radiotherapy was 22 days. Sixty-two patients (94%) received radical radiotherapy, and all completed treatment with no delays {>=}3 days. One, two, and three cycles of concurrent cisplatin were delivered to 18 patients (29%), 38 patients (61%), and 3 patients (5%), respectively. Ninety-two percent of patients received enteral feeding; median weight loss during treatment was 7%. Forty-two patients (68%) had unplanned admissions with no on-treatment deaths. Three unrelated deaths occurred after treatment. At 1 year after treatment, 21% of patients without disease progression remained gastrostomy dependent. Of 58 assessable patients, 50 (86%) achieved a complete response after treatment. One- and 2-year progression-free survival, cause-specific survival, and overall survival were 88%, 92%, and 86% and 80%, 85%, and 80%, respectively. Conclusion: The combination of induction TPF with concurrent cisplatin chemoradiotherapy in patients with locally advanced head and neck squamous cell

  1. Low molecular weight procyanidins from grape seeds enhance the impact of 5-Fluorouracil chemotherapy on Caco-2 human colon cancer cells.

    Directory of Open Access Journals (Sweden)

    Ker Y Cheah

    Full Text Available OBJECTIVE: Grape seed procyanidins (PC are flavan-3-ol oligomers and polymers known for their biological activity in the gut. Grape seed extract (GSE have been reported to reduce intestinal injury in a rat model of mucositis. We sought to investigate effects of purified PC fractions differing in mean degree of polymerization (mDP combined with 5-Fluorouracil (5-FU chemotherapy on the viability of colon cancer cells (Caco-2. DESIGN: SixPC fractions (F1-F6 were isolated from Cabernet Sauvignon seeds at two ripeness stages: pre-veraison unripe (immature and ripe (mature, utilizing step gradient, low-pressure chromatography on a Sephadex LH-20 resin. Fractions were tested on Caco-2 cells, alone and in combination with 5-FU. Eluted fractions were characterized by phloroglucinolysis and gel permeation chromatography. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2yl-2,5-diphenyl-tetrazolium bromide (MTT assay. RESULTS: All isolated fractions significantly reduced Caco-2 cell viability compared to the control (P<0.05, but F2 and F3 (mDP 2-6 were the most active fractions (immature F2 = 32% mDP 2.4, F3 = 35% mDP 5.8 and mature F2 = 13% mDP 3.6 and F3 = 17% mDP 5.9; percentage of viable cells remaining on Caco-2 cells. When combined with 5-FU, immature fractions F1-F3 enhanced the cell toxicity effects of 5-FU by 27-73% (P<0.05. Mature seed PC fractions (F1-F4 significantly enhanced the toxicity of 5-FU by 60-83% against Caco-2 cells (P<0.05. Moreover, some fractions alone were more potent at decreasing viability in Caco-2 cells (P<0.05; immature fractions = 65-68% and mature fractions = 83-87% compared to 5-FU alone (37%. CONCLUSIONS: PCs of mDP 2-6 (immature F1-F3 and mature F1 and F4not only enhanced the impact of 5-FU in killing Caco-2 cells, but also surpassed standard 5-FU chemotherapy as an anti-cancer agent.The bioactivity of PC is therefore attributed primarily to lower molecular weight PCs.

  2. Reactivating p53 and Inducing Tumor Apoptosis (RITA Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin

    Directory of Open Access Journals (Sweden)

    Armin Wiegering

    2017-04-01

    Full Text Available Colorectal carcinoma (CRC is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n = 9 including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n = 5 with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC50< 3.0 μmol/l were identified within established (4/9 and primary patient-derived (2/5 CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number

  3. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

    Science.gov (United States)

    Ajani, J A; Abramov, M; Bondarenko, I; Shparyk, Y; Gorbunova, V; Hontsa, A; Otchenash, N; Alsina, M; Lazarev, S; Feliu, J; Elme, A; Esko, V; Abdalla, K; Verma, U; Benedetti, F; Aoyama, T; Mizuguchi, H; Makris, L; Rosati, G

    2017-09-01

    The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in

  4. Venous Ulcers

    Science.gov (United States)

    Caprini, J.A.; Partsch, H.; Simman, R.

    2013-01-01

    Venous leg ulcers are the most frequent form of wounds seen in patients. This article presents an overview on some practical aspects concerning diagnosis, differential diagnosis and treatment. Duplex ultrasound investigations are essential to ascertain the diagnosis of the underlying venous pathology and to treat venous refluxes. Differential diagnosis includes mainly other vascular lesions (arterial, microcirculatory causes), hematologic and metabolic diseases, trauma, infection, malignancies. Patients with superficial venous incompetence may benefit from endovenous or surgical reflux abolition diagnosed by Duplex ultrasound. The most important basic component of the management is compression therapy, for which we prefer materials with low elasticity applied with high initial pressure (short-stretch bandages and Velcro-strap devices). Local treatment should be simple, absorbing and not sticky dressings keeping adequate moisture balance after debridement of necrotic tissue and biofilms are preferred. After the ulcer is healed compression therapy should be continued in order to prevent recurrence. PMID:26236636

  5. [Continuous-infusion ketamine].

    Science.gov (United States)

    Mancini, P G; Caggese, G; Di Fabio, A; Di Nino, G F; Cocchi, V

    1980-08-01

    An investigation was made of the employment of ketamin as the sole anaesthetic in general surgery, using continuous infusion of a 1% solution for both induction and maintenance in 118 cases. ECG was monitored and arterial pressure was measured invasively. Central venous pressure was also determined in 10 cases. Changes in serum enzyme values during and after surgery were examined in 35 patients. Blood samples were withdrawn before induction, after the return to consciousness, and 24 hr after the operation. Side-effects were common, but slight. Five patients suffered from nightmares, but these were persons with marked imaginative activity and a melancholic nature. Cardiocirculatory function was satisfactory. In particular, peripheral perfusion was excellent in all cases.

  6. A rare case of zolendronate infusion complication leading to glaucoma filtration surgery

    Directory of Open Access Journals (Sweden)

    Khan A

    2011-08-01

    Full Text Available A Khan1, G Lascaratos1, T Rane-Malcolm2, R Sanders21Princess Alexandra Eye Pavilion, Edinburgh, 2Department of Ophthalmology, Queen Margaret Hospital, Dunfermline, Fife, UKAbstract: Zolendronic acid is a nitrogenous biphosphonate commonly used as an intravenous infusion for the management of Paget’s disease, osteoporosis, and hypercalcemia of malignancy. We report a rare and challenging complication of zolendronate infusion: unilateral acute anterior uveitis followed by persistently raised intraocular pressure despite being on four different classes of antiglaucoma medication. The challenge was that the patient required topical steroid to treat her uveitis in the background of known glaucoma with corresponding steroid response. She eventually underwent a left phacotrabeculectomy augmented with 5-fluorouracil. Four weeks postoperatively she developed an encapsulated bleb and underwent needling with 5-fluorouracil. This case highlights the importance of having a high index of suspicion for anterior uveitis in patients with a red and painful eye after initiating biphosphonate therapy. Caution should also be exercised when prescribing biphosponates to glaucoma patients.Keywords: biphosponates, anterior uveitis, intraocular pressure

  7. Design of Infusion Schemes for Neuroreceptor Imaging

    DEFF Research Database (Denmark)

    Feng, Ling; Svarer, Claus; Madsen, Karine

    2016-01-01

    for bolus infusion (BI) or programmed infusion (PI) experiments. Steady-state quantitative measurements can be made with one short scan and venous blood samples. The GABAA receptor ligand [(11)C]Flumazenil (FMZ) was chosen for this purpose, as it lacks a suitable reference region. Methods. Five bolus [(11)C...... state was attained within 40 min, which was 8 min earlier than the optimal BI (B/I ratio = 55 min). Conclusions. The system can design both BI and PI schemes to attain steady state rapidly. For example, subjects can be [(11)C]FMZ-PET scanned after 40 min of tracer infusion for 40 min with venous...

  8. 1,3-Bis(2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of resveratrol on 5-fluorouracil sensitive/resistant colon cancer cells.

    Science.gov (United States)

    Das, Dipon; Preet, Ranjan; Mohapatra, Purusottam; Satapathy, Shakti Ranjan; Kundu, Chanakya Nath

    2013-11-14

    To study the mechanism of 5-fluorouracil (5-FU) resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment. We established and characterized a 5-FU resistance (5-FU-R) cell line derived from continuous exposure (25 μmol/L) to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells. The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting, respectively, after treatment with Resveratrol (Res) and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU). Apoptosis and cell cycle arrest was measured by 4',6'-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis, respectively. The extent of DNA damage was measured by the Comet assay. We measured the visible changes in the DNA damage/repair cascade by Western blotting. The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner. Combined application of BCNU and Res caused more apoptosis in 5-FU sensitive cells in comparison to individual treatment. In addition, the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells. We established a 5-FU resistance cell line (5-FU-R) from 5-FU-sensitive HCT-116 (mismatch repair deficient) cells that was not resistant to other chemotherapeutic agents (e.g., BCNU, Res) except 5-FU. The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay. There was no significant cell death noted in 5-FU-R cells in comparison to 5-FU sensitive cells after 5-FU treatment. This resistant cell line overexpressed anti-apoptotic [e.g., AKT, nuclear factor κB, FLICE-like inhibitory protein), DNA repair (e.g., DNA polymerase beta (POL-β), DNA polymerase eta (POLH), protein

  9. Central venous line complications and tip detection

    Directory of Open Access Journals (Sweden)

    Ameneh Rezaee Gheshlaghi

    2015-06-01

    Full Text Available Central venous line is one of a creative instrument that saves human’s life in critical medical situation. Central venous line access is frequently involved in the disease management. It is used for rapid fluid therapy, transvenous pacemakers, infusion of some medications, hemodialysis or plasmapheresis and etc. Most of the emergency departments have some staffs that are trained for central venous line insertion but related complications occur during central venous line placement.Central venous line might have some complications and complication follow-up should be considered. Thromboembolism and infection are two important medical complications. Arterial puncture, hematoma, pneumothorax and hemothorax are mechanical Central venous line complications. Chest X-ray and some other techniques should be used for detecting these complications.Central venous line tip misplace is a considerable problem for emergency department staffs, previously chest X-ray has been used for central venous line misplace detection. In some recent studies, contrast-enhanced ultrasonography and intravascular electrocardiography have been used for central venous line misplace.

  10. EMJH medium with 5-fluorouracil and nalidixic acid associated with serial dilution technique used to recover Leptospira spp from experimentally contaminated bovine semen Meio de EMJH com 5-fluorouracil e ácido nalidíxico associado a técnica das diluições seriadas usados para recuperar Leptospira spp do sêmen bovino experimentalmente contaminado

    Directory of Open Access Journals (Sweden)

    Fabiana Miraglia

    2009-03-01

    Full Text Available Bovine semen experimentally contaminated with Leptospira santarosai serovar Guaricura was submitted to the modified EMJH medium with 5-fluorouracil (300mg/L and nalidixic acid (20mg/L, named as "selective medium" and using the serial dilution technique, in order to evaluate the percentage of recovery of the added microorganism. The selective EMJH medium was found with higher percentage of recovery of leptospiras and minor losses of samples due to contamination with opportunistic microorganisms than the non-selective EMJH medium: 151/376 (40.0% of positive growth; and 38/376 (10.0% contamination and 58/376 (15% and 129/376 (34.0%, respectively. These results were statistically significant (pSêmen bovino experimentalmente contaminado com a estirpe Leptospira santarosai Sorovar Guaricura foi utilizado para verificar a porcentagem de recuperação de leptospiras, utilizando o meio de EMJH com 5-fluorouracil (300 mg/L e ácido nalidíxico (20 mg/L, denominado "meio seletivo", associado à técnica das diluições seriadas. O meio seletivo EMJH foi encontrado com porcentagem de recuperação mais elevada e com menos perda de amostras devido à contaminação com microorganismos oportunistas quando comparado com o meio EMJH não seletivo, que foram encontrados, respectivamente, com 151/376 (40.0% de crescimento positivo e 38/376 (10.0% de contaminação, 58/376 (15% e 129/376 (34.0%. Estes resultados foram estatíticamente significantes (p<0, 0001; Fisher. Diferenças foram encontradas quando as freqüências de leptospiras recuperadas foram comparadas com a técnica de diluição seriada (10-1 a 10-4 e entre os meios seletivo e não-seletivo, em diferentes níveis de diluição. À diluição de 1/10, as porcentagens encontradas foram (0%, 0/80 e (38%, 30/80; à diluição 1/100, (3%, 2/80 e (49%, 39/80; e à diluição 1/1000, (25%, 20/80 e (50%, 40/80, respectivamente. A porcentagem de recuperação de leptospiras foi diretamente proporcional

  11. Changes in thymidylate synthase mRNA in blood leukocytes from patients with colorectal cancer after bolus administration of 5-fluorouracil

    DEFF Research Database (Denmark)

    Ehrnrooth, E; Sørensen, B; Poulsen, J H

    2000-01-01

    target enzyme, thymidylate synthase (TS) mRNA, in blood leukocytes before and after courses 1 and 3 in 21 patients with colorectal cancer. TS mRNA expression was quantified using an RT-PCR assay with an internal RNA standard. Median TS mRNA expression decreased significantly 30 min after course no. 1 (p....... The present results indicate that TS mRNA in blood leukocytes may be an early indicator of an RNA damaging effect after i.v. bolus infusion of 5-FU....

  12. A phase II study of 5-fluorouracil, leucovorin, adriamycin, and cisplatin (FLAP) for metastatic gastric and gastroesophageal junction adenocarcinoma. A Penn Cancer Clinical Trial Group and Roswell Park Cancer Institute Community Oncology Research Program Trial.

    Science.gov (United States)

    Vaughn, D J; Meropol, N J; Holroyde, C; Mintzer, D; Nuamah, I; Armstead, B; Douglass, H O; Haller, D G

    1997-06-01

    A Phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil, leucovorin, Adriamycin, and cisplatin combination chemotherapy (FLAP) in patients with previously untreated advanced gastric and gastroesophageal (GE) junction adenocarcinoma. Forty-two consecutive patients were enrolled to received FLAP in this multi-institutional trial. Response, toxicity, and survival data were noted. Fifteen of 42 (36%) patients demonstrated objective responses, with two complete responses (5%) and 13 partial responses (31%). The median time to disease progression was 17 weeks, and the overall survival duration was 30 weeks. Myelosuppression was significant, requiring dose modifications, but there were no treatment-related deaths. FLAP is an active regimen in the treatment of advanced gastric and GE junction adenocarcinoma. We are presently using this regimen in the neoadjuvant setting in patients with gastric and GE junction cancers.

  13. Urachal Carcinoma with Choroidal, Lung, Lymph Node, Adrenal, Mammary, and Bone Metastases and Peritoneal Carcinomatosis Showing Partial Response after Chemotherapy Treatment with a Modified Docetaxel, Cisplatin and 5-Fluorouracil Regimen

    Directory of Open Access Journals (Sweden)

    Kathleen Dekeister

    2016-04-01

    Full Text Available Urachal carcinoma (UC is a rare tumor mainly affecting middle-aged males. Metastases occur most frequently in lymph nodes and the lungs. There are no standard adjuvant and metastatic treatments. We report the case of a 36-year-old female with UC treated with partial cystectomy who relapsed 3 years after surgery with left choroidal, lung, mediastinal lymph node, right adrenal, mammary, and bone metastases as well as peritoneal carcinomatosis. She obtained a partial response after 10 cycles of chemotherapy with a modified docetaxel, cisplatin and 5-fluorouracil (mTPF regimen. This is the first report on the use of the mTPF regimen in UC and on the existence of choroidal, adrenal, and mammary metastases.

  14. Platelet recruitment to venous stent thrombi.

    Science.gov (United States)

    McBane, Robert D; Karnicki, Krzysztof; Wysokinski, Waldemar E

    2013-11-01

    Thrombosis following venous stent placement is a morbid clinical outcome. Whether to target platelets or coagulation factors for venous stent thromboprophylaxis remains unclear. We sought to determine whether integrin α(IIb)β3 antagonism with lamifiban would inhibit platelet recruitment to venous stent thrombosis. Anti-thrombotic efficacy was compared between venous and arterial circulations. Pigs received either lamifiban (0.2 mg/kg bolus plus 0.2 mg/kg/h infusion; n = 6) or saline (n = 12). Carotid arteries were crush injured and then harvested 30 min later to provide an assessment of antithrombotic efficacy in the arterial circulation. Iliac venous stents were then deployed and thrombi allowed to propagate for 2 h before harvesting. Platelet deposition was measured by scintillation detection of autologous (111)In-platelets. Venous thrombi were quantified by weight and compared to platelet, Von Willebrand factor (VWF) and fibrinogen content. Arterial platelet deposition (×10(6)/cm(2)) was reduced >80% by lamifiban (398 ± 437) compared to controls (1,540 ± 883; p thrombi occurs in part through the integrin α(IIb)β3 receptor. Unlike arterial thrombosis, inhibition of this receptor is insufficient to prevent venous stent thrombosis.

  15. Jugular Venous Catheterization: A Case of Knotting

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    E. Erkılıç

    2015-01-01

    Full Text Available A 79-year-old woman, diagnosed for cancer of the ovary, had a central catheter that was placed with difficulty through the right internal jugular vein intraoperatively. After oophorectomy, it was realized that the catheter was knotted. Thus, the central venous catheter was removed successfully using a traction technique in the operating room. Central venous catheter use may result in various complications, although it has been used as an invasive method for hemodynamic monitoring and fluid and drug infusion. Here, we present catheter knotting in a case with solutions for this complication, under literature review.

  16. Forearm metabolism during infusion of adrenaline

    DEFF Research Database (Denmark)

    Simonsen, L; Stefl, B; Bülow, J

    2000-01-01

    Human skeletal muscle metabolism is often investigated by measurements of substrate fluxes across the forearm. To evaluate whether the two forearms give the same metabolic information, nine healthy subjects were studied in the fasted state and during infusion of adrenaline. Both arms were...... catheterized in a cubital vein in the retrograde direction. A femoral artery was catheterized for blood sampling, and a femoral vein for infusion of adrenaline. Forearm blood flow was measured by venous occlusion strain-gauge plethysmography. Forearm subcutaneous adipose tissue blood flow was measured...... by the local 133Xe washout method. Metabolic fluxes were calculated as the product of forearm blood flow and a-v differences of metabolite concentrations. After baseline measurements, adrenaline was infused at a rate of 0.3 nmol kg-1 min-1. No difference in the metabolic information obtained in the fasting...

  17. Concomitant bid radiotherapy with cisplatin and 5-fluorouracil in unresectable carcinoma of the pharynx: 10 year's experience at the Centre Antoine Lacassagne; Radiotherapie bifractionnee et chimiotherapie par cisplatine et 5-fluoro-uracile concomitantes dans les carcinomes epidermoides localement evolues non resecables du pharynx: dix ans d'experience au centre Antoine Lacassagne

    Energy Technology Data Exchange (ETDEWEB)

    Magne, N.; Pivot, X.; Marcy, P.Y.; Chauvel, P.; Courdi, A.; Dassonville, O.; Possonnet, G.; Vallicioni, J.; Ettore, F.; Falewee, M.N.; Milano, G.; Santini, J.; Lagrange, J.L.; Schneider, M.; Demard, F.; Bensadoun, R.J. [Centre Antoine-Lacassagne, 06 - Nice (France)

    2001-08-01

    Patients suffering from locally advanced unresectable squamous cell carcinoma of the oropharynx and hypopharynx treated with radiotherapy alone have a poor prognosis. More than 70% of patients die within 5 years mainly due to local recurrences. The aim of this study was to evaluate retrospectively the Antoine Lacassagne Cancer Center's experience in a treatment by concomitant bid radiotherapy and chemotherapy. Evaluation was based on analysis of the toxicity, the response rates, the survival, and the clinical prognostic factors. From 1992 to 2000, 92 consecutive patients were treated in our single institution. All of them had stage IV, unresectable squamous cell carcinoma of the pharynx and they received continuous bid radiotherapy (two daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal internal between fractions). Total radiotherapy dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Two or three chemotherapy courses of cisplatin (CP)-5-fluorouracil (5FU) were given during radiotherapy at 21 -day intervals (third not delivered after the end of the radiotherapy). CP dose was 100 mg/m{sup 2} (day 1) and 5-FU was given as 6-day continuous infusion (750 mg/m{sup 2}/day at 1. course; 430 mg/m{sup 2}/day at 2. and 3. courses). Special attention was paid to supportive care, particularly in terms of enteral nutrition and mucositis prevention by low-level laser energy. Acute toxicity was marked and included WHO grade III/IV mucositis (89%, 16% of them being grade IV), WHO grade III dermatitis (72%) and grade III/IV neutropenia (61%). This toxicity was significant but manageable with optimised supportive care, and never led to interruption of treatment for more than 1 week, although there were two toxic deaths. Complete global response rate at 6 months was 74%. Overall global survival at 1 and 3 years was 72% and 50% respectively, with a median follow-up of 17 months. Prognostic factors for overall were the Karnofsky index (71% survival at 3

  18. Placement of an implantable central venous access device

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Hoon; Lee, Young Suk [Dan Kook Univ., Seoul (Korea, Republic of). Hospital

    1998-03-01

    To evaluate the efficacy and safety of placement of a central venous catheter with infusion port into the superior vena cava. Central venous catheters with a infusion port were implanted in 21 patients (M:F=4:17, age range:15-63, mean age: 41) diagnosed as suffering from breast cancer (n=9), lymphoma (n=7), thymoma (n=2) rhabdomyosarcoma(n=2) and rectal cancer (n=1). The per(n=9), lymphoma(n=7), thymoma (n=2) rhabdomyosarcoma (n=2) and rectal cancer (n=1). The peripheral portion of the subclavian vein was punctured under fluoroscopic guidance during injection of contrast media at the site of the ipsilateral peripheral vein (20 cases) and under ultrasonographic guidance (1 case). 9.6F central venous catheters placed in the superior vena cava via the subclavian vein and the connected infusion ports were implanted in the subcutaneous pocket near the puncture site of the right anterosuperior chest wall. Radiologic placement under fluoroscopic guidance of a central venous catheter with a infusion port is easy, safe and useful for patients requiring long-term venous access. (author). 21 refs., 2 figs.

  19. Pleural and Pericardiac Effusion as a Complication of Properly Placed Umbilical Venous Catheter.

    Science.gov (United States)

    Unal, Sezin; Arifoglu, Ilter; Celik, Istemi Han; Yilmaz, Osman; Bas, Ahmet Yagmur; Demirel, Nihal

    2017-01-01

    Pleural and pericardial effusions are extremely rare complications of umbilical venous catheterization in newborns. A preterm male infant weighing 850g, with insertion of an umbilical venous catheter (UVC) developed massive right pleural and pericardial effusions. The position of catheter tip was verified by chest radiography and echocardiography. The effusions were drained by thoracentesis and pericardiocentesis without complication, and were biochemically similar as total parenteral infusion which infused through catheter.

  20. Phase II trial of carboplatin (c) and 5-fluorouracil (5-fu) chemotherapy given on outpatient basis combined with radiotherapy (rt) for the treatment of patients with locally advanced epidermoid esophageal cancer; Estudo prospectivo (fase II) do uso combinado de quimioterapia (5-fluorouracil e carboplatina) e radioterapia no tratamento do carcinoma espinocelular de esofago

    Energy Technology Data Exchange (ETDEWEB)

    Scalabrini Neto, Antonio Orlando [Minas Gerais Univ., Belo Horizonte, MG (Brazil). Hospital das Clinicas; Murad, Andre Marcio [Minas Gerais Univ., Belo Horizonte, MG (Brazil). Faculdade de Medicina. Dept. de Clinica Medica; Rocha, Paulo Roberto Savassi [Minas Gerais Univ., Belo Horizonte, MG (Brazil). Faculdade de Medicina. Dept. de Cirurgia

    2004-07-01

    Purpose: To determine the safety and efficacy of C and 5-FU on outpatient basis and concurrent radiotherapy for locally advanced epidermoid esophageal cancer. Methods and Patients: Patients (N=27) received: [Carboplatin: AUC 5 on day 1 and 5-FU: 750 mg/m{sup 2}/day on days 1-4 (4-hour infusion)] on outpatient basis 28/28 days for three cycles and RT: [2.0 Gy/day (total dose - 60 Gy)]. Results: Overall response in 20 (74%) patients. Median overall survival was feasible with a high rate of CRs and good tolerability. (author)

  1. Non-return valves do not prevent backflow and bacterial contamination of intravenous infusions

    NARCIS (Netherlands)

    Ellger, B.; Kiski, D.; Diem, E.; van den Heuvel, I.; Freise, H.; Van Aken, H.; Hinder, F.; Friedrich, A. W.

    Non-return valves (NRVs) are designed to avoid backflow of infusion fluid against the designated direction of flow (DDF) when more than one infusion is delivered via one venous access. We tested in vitro whether NRVs reliably prevent flow against the DDF at clinically relevant low flow rates. Since

  2. Central Venous Catheter-Related Hydrothorax

    Directory of Open Access Journals (Sweden)

    Se Hun Kim

    2015-11-01

    Full Text Available This report describes a case of 88-year-old women who developed central venous catheter-related bilateral hydrothorax, in which left pleural effusion, while right pleural effusion was being drained. The drainage prevented accumulation of fluid in the right pleural space, indicating that there was neither extravasation of infusion fluid nor connection between the two pleural cavities. The only explanation for bilateral hydrothorax in this case is lymphatic connections. Although vascular injuries by central venous catheter can cause catheter-related hydrothorax, it is most likely that the positioning of the tip of central venous catheter within the lymphatic duct opening in the right sub-clavian-jugular confluence or superior vena cava causes the catheter-related hydrothorax. Pericardial effusion can also result from retrograde lymphatic flow through the pulmonary lymphatic chains.

  3. Pediatric central venous access devices: nursing interventions

    Directory of Open Access Journals (Sweden)

    Duffy EA

    2017-05-01

    Full Text Available Elizabeth A Duffy, Kathryn N Nelson Department of Health Behavior and Biological Sciences, The University of Michigan School of Nursing, Ann Arbor, MI, USA Abstract: A central venous catheter (CVC is an indwelling catheter that provides permanent or temporary stable venous access for both acute and chronically ill pediatric patients. These catheters provide stable venous access that can be used for a variety of medical purposes including drawing blood, hemodynamic monitoring, infusion of intravenous medications, infusion of intravenous fluids, chemotherapy, blood products, and parenteral nutrition. Each day, nurses access and care for CVCs in infants, children, and adolescents; the precision of this care can prevent life-threatening complications. The purpose of this review and the case study is to highlight the importance and components of evidence-based nursing practice in pediatric CVC care. A historical perspective of CVC care is provided in conjunction with current national initiatives to improve patient outcomes for children with CVCs. Infection prevention, clinical practice guidelines, quality improvement, and evidence-based care bundles are discussed. Keywords: pediatric nursing, central venous catheters, central line-associated bloodstream infection, care bundles, pediatric case study 

  4. Synthesis of 5-Fluorouracil conjugated LaF{sub 3}:Tb{sup 3+}/PEG-COOH nanoparticles and its studies on the interaction with bovine serum albumin: spectroscopic approach

    Energy Technology Data Exchange (ETDEWEB)

    Mangaiyarkarasi, Rajendiran; Chinnathambi, Shanmugavel; Aruna, Prakasarao; Ganesan, Singaravelu, E-mail: sganesan@annauniv.edu, E-mail: ganesansingaravelu@gmail.com [Anna University, Department of Medical Physics (India)

    2015-03-15

    The luminescent lanthanide-doped nanoparticles have gathered considerable attention in many fields especially in biomedicine. In this work, the lanthanum fluoride-doped terbium nanoparticles (LaF{sub 3}:Tb{sup 3+} NPs) via simple chemical precipitation method has been synthesized and functionalized with polyethylene glycol. The size and the shape of the nanoparticles are confirmed using X-ray diffraction and transmission electron microscopy. The conjugation of 5-Fluorouracil (5-FU) and thus synthesized nanoparticles (NPs) were confirmed using various spectroscopic methods such as UV–Visible spectroscopy, fluorescence steady state, and excited state spectroscopy studies. The enhancement in fluorescence emission (λ = 543 nm) of drug-conjugated nanoparticles confirms the Vander Waals force of attraction due to F–F bonding between the drug and the nanoparticles. Further, the effects of 5FU-NPs in carrier protein were investigated using bovine serum albumin as a protein model. The 5FU–LaF{sub 3}:Tb{sup 3+} nanoparticles binding is illustrated with binding constant and number of binding sites. The structural change of bovine serum albumin has been studied using circular dichroism and Fourier transform infrared spectroscopy analysis.

  5. Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G₂ Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells.

    Science.gov (United States)

    Akiyama, Makoto; Sowa, Yoshihiro; Taniguchi, Tomoyuki; Watanabe, Motoki; Yogosawa, Shingo; Kitawaki, Jo; Sakai, Toshiyuki

    2017-09-21

    Ovarian cancer is the most lethal disease among gynecological malignancies. More effective therapy is required to counter high recurrence rates and chemotherapy resistance. We investigated the efficacy and molecular mechanisms of three combined treatments (TCTs)-a novel histone deacetylase (HDAC) inhibitor OBP-801/YM753, 5-fluorouracil (5-FU), and paclitaxel (PTX)-in human ovarian cancer SKOV-3 and OVCAR-3 cells. The inhibition of cell growth was stronger with TCTs than with each single agent and with two combined treatments. The TCTs significantly induce G2 phase arrest in both cell lines. We then analyzed the molecular mechanisms and found that the TCTs increased the phosphorylation of p38 (Thr180/Tyr182), decreased the expression of CDC25C, and increased the phosphorylation of CDC2 (Tyr15), an inactive form of CDC2. To examine the responsibilities of the p38 pathway for G2 phase arrest induced by the TCTs, we employed the p38 inhibitor SB203580. SB203580 inhibited G2 phase arrest, suppression of CDC25C, and phosphorylation of CDC2 (Tyr15) induced by the TCTs. These results suggest that the TCTs can induce G2 phase arrest through activation of the p38 signaling pathway. We therefore believe that this combination is promising as a novel therapeutic strategy against ovarian cancer.

  6. Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial.

    LENUS (Irish Health Repository)

    Curran, Desmond

    2009-09-01

    PURPOSE: The quality of life (QL) of advanced gastric cancer patients receiving irinotecan, folinic acid and 5-fluorouracil (5-FU) (IF arm) or cisplatin with 5-FU (CF arm) is presented. METHODS: Patients with measurable or evaluable advanced gastric cancer received IF weekly for 6\\/7 weeks or CF q4 weeks. QL was assessed using the EORTC QLQ-C30 at baseline, subsequently every 8 weeks until progression and thereafter every 3 months until death. The QL data were analysed using several statistical methods including summary measures and pattern-mixture modelling. RESULTS: A total of 333 patients were randomised and treated (IF 170, CF 163). The time-to-progression for IF and CF was 5.0 and 4.2 months (P = 0.088), respectively. The overall compliance rates for QL questionnaire completion were 60 and 56% in the IF and CF arms, respectively. Significant treatment differences were observed for the physical functioning scale (P = 0.024), nausea\\\\vomiting (P = 0.001) and EQ-5D thermometer (P = 0.020) in favour of the IF treatment arm. CONCLUSION: There was a trend in favour of IF over CF in time-to-progression. The IF group also demonstrated a better safety profile than CF and a better QL on a number of multi-item scales, suggesting that IF offers an alternative first-line platinum-free treatment option for advanced gastric cancer.

  7. Delayed complications in colo-rectal carcinoma treated by combination radiotherapy and 5-fluorouracil: Eastern Cooperative Oncology Group (E. C. O. G. ) pilot study. [/sup 60/Co-teletherapy

    Energy Technology Data Exchange (ETDEWEB)

    Danjoux, C.E.; Catton, G.E.

    1979-03-01

    From June 1976 to Dec 1977, 24 patients with residual, or recurrent, inoperable rectal carcinoma, were treated by a split-course irradiation and 5-FU. All patients received /sup 60/Co pelvic irradiation, with AP--PA opposed fields. The dose was delivered in 3 courses of 2000 rad in 2 weeks, with 2 weeks rest between each course. 5 Fluorouracil (5-FU)-(500 mg/m/sup 2/), was administered I.V., on the first 3 days of each course of irradiation. The acute reaction was minimal, and was not predictive of the late serious complications which occurred in 7/24 (29%), of our patients, 2/10 with minimal, and 5/14 with bulky pelvic disease. The median follow-up was 12 months--(range 4 to 26 months). The onset of serious complications occurred about 8 months following treatment, and consisted of bowel stenosis, necrosis, fistula formation, and subcutaneous fibrosis. In 5 of 7 patients, predisposing factors accounted for such complications. We believe this to be the first report of such an observation of delayed complications in the absence of serious early reaction with combined chemoradiotherapy. The safety of multimodality therapy cannot be predicted by how well it is tolerated initially.

  8. SEP enhanced the antitumor activity of 5-fluorouracil by up-regulating NKG2D/MICA and reversed immune suppression via inhibiting ROS and caspase-3 in mice.

    Science.gov (United States)

    Ke, Mengyun; Wang, Hui; Zhou, Yiran; Li, Jingwen; Liu, Yang; Zhang, Min; Dou, Jie; Xi, Tao; Shen, Baiyong; Zhou, Changlin

    2016-08-02

    Chemotherapy and immunotherapy are the main remedies used in cancer treatment. Because immunotherapy can not only reduce the toxicity of chemotherapeutics but also enhance antitumor effects in vivo, combining these two therapies is a trend that continues to gain more attention in clinic. SEP, a polysaccharide isolated from Strongylocentrotus nudus egg, has been reported to display antitumor activity by stimulating immune cells, including NK and T cells, via TLR2 and TLR4. In the present study, the synergistic effect between SEP and 5-fluorouracil (5-FU), a traditional cytotoxic drug, in vitro and in vivo was investigated. The results obtained indicated that SEP alone stimulated NK-92 cytotoxicity and coordinated with 5-FU to augment the cytotoxicity of NK-92 cells against HepG-2 or A549 cells in vitro. SEP promoted NK-92 activity by stimulating NKG2D and its downstream DAP10/PI3K/Erk signaling pathway. Additionally, 5-FU could increase MICA expression on HepG-2 or A549 cells and prevent membrane MICA from shedding as soluble MICA, which were abrogated in the tumor cells transfected with ADAM 10 overexpression plasmid. Moreover, in H22- or Lewis lung cancer (LLC)-bearing mouse models, SEP reversed 5-FU-induced atrophy and apoptosis in both the spleen and bone marrow in vivo by suppressing ROS generation and caspase-3 activation. All of these results highlight the potential for the combination of SEP and 5-FU in cancer therapy in the future.

  9. Docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy alone in stage III-IV unresectable head and neck cancer. Results of a randomized phase II study

    Energy Technology Data Exchange (ETDEWEB)

    Takacsi-Nagy, Zoltan; Polgar, Csaba; Major, Tibor; Fodor, Janos [National Institute of Oncology, Center of Radiotherapy, Budapest (Hungary); Hitre, Erika [National Institute of Oncology, Department of Chemotherapy and Clinical Pharmacology, Budapest (Hungary); Remenar, Eva; Kasler, Miklos [National Institute of Oncology, Department of Head and Neck and Maxillofacial Surgery, Budapest (Hungary); Oberna, Ferenc [Bacs-Kiskun County Hospital, Department of Oral, Maxillofacial and Head and Neck Surgery, Kecskemet (Hungary); Goedeny, Maria [National Institute of Oncology, Department of Radiology, Budapest (Hungary)

    2015-08-15

    Concurrent chemoradiotherapy (CRT) is the standard treatment for advanced head and neck squamous cell carcinoma. In this phase II randomized study, the efficacy and toxicity of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy (ICT) followed by concurrent CRT was compared with those after standard CRT alone in patients with locally advanced, unresectable head and neck cancer. Between January 2007 and June 2009, 66 patients with advanced (stage III or IV) unresectable squamous cell carcinoma of the head and neck (oral cavity, oropharynx, hypopharynx, and larynx) were randomly assigned to two groups: one receiving two cycles of docetaxel, cisplatin, and 5-fluorouracil ICT followed by CRT with three cycles of cisplatin and one treated by CRT alone. Response rate, local tumor control (LTC), locoregional tumor control (LRTC), overall survival (OS), progression-free survival (PFS), and toxicity results were assessed. Three patients from the ICT + CRT group did not appear at the first treatment, so a total of 63 patients were evaluated in the study (30 ICT + CRT group and 33 CRT group). Three patients died of febrile neutropenia after ICT. The median follow-up time for surviving patients was 63 months (range 53-82 months). The rate of radiologic complete response was 63 % following ICT + CRT, whereas 70 % after CRT alone. There were no significant differences in the 3-year rates of LTC (56 vs. 57 %), LRTC (42 vs. 50 %), OS (43 vs. 55 %), and PFS (41 vs. 50 %) in the ICT + CRT group and in the CRT group, respectively. The rate of grade 3-4 neutropenia was significantly higher in the ICT + CRT group than in the CRT group (37 and 12 %; p = 0.024). Late toxicity (grade 2 or 3 xerostomia) developed in 59 and 42 % in the ICT + CRT and CRT groups, respectively. The addition of ICT to CRT did not show any advantage in our phase II trial, while the incidence of adverse events increased. The three deaths as a consequence of ICT call attention to the importance of

  10. A simultaneous determination method for 5-fluorouracil and its metabolites in human plasma with linear range adjusted by in-source collision-induced dissociation using hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry.

    Science.gov (United States)

    Ishii, Hideaki; Shimada, Miki; Yamaguchi, Hiroaki; Mano, Nariyasu

    2016-11-01

    We applied a new technique for quantitative linear range shift using in-source collision-induced dissociation (CID) to complex biological fluids to demonstrate its utility. The technique was used in a simultaneous quantitative determination method of 5-fluorouracil (5-FU), an anticancer drug for various solid tumors, and its metabolites in human plasma by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). To control adverse effects after administration of 5-FU, it is important to monitor the plasma concentration of 5-FU and its metabolites; however, no simultaneous determination method has yet been reported because of vastly different physical and chemical properties of compounds. We developed a new analytical method for simultaneously determining 5-FU and its metabolites in human plasma by LC/ESI-MS/MS coupled with the technique for quantitative linear range shift using in-source CID. Hydrophilic interaction liquid chromatography using a stationary phase with zwitterionic functional groups, phosphorylcholine, was suitable for separation of 5-FU from its nucleoside and interfering endogenous materials. The addition of glycerin into acetonitrile-rich eluent after LC separation improved the ESI-MS response of high polar analytes. Based on the validation results, linear range shifts by in-source CID is the reliable technique even with complex biological samples such as plasma. Copyright © 2016 John Wiley & Sons Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  11. Central venous catheter - flushing

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000157.htm Central venous catheter - flushing To use the sharing features on this page, please enable JavaScript. You have a central venous catheter. This is a tube that goes into a ...

  12. Study on molecular structure, spectroscopic properties (FTIR and UV-Vis), NBO, QTAIM, HOMO-LUMO energies and docking studies of 5-fluorouracil, a substance used to treat cancer.

    Science.gov (United States)

    Almeida, Michell O; Barros, Daiane A S; Araujo, Sheila C; Faria, Sergio H D M; Maltarollo, Vinicius G; Honorio, Kathia M

    2017-09-05

    Cancer cells can expand to other parts of body through blood system and nodes from a mechanism known as metastasis. Due to the large annual growth of cancer cases, various biological targets have been studied and related to this disorder. A very interesting target related to cancer is human epidermal growth factor receptor 2 (HER2). In this study, we analyzed the main intermolecular interactions between a drug used in the cancer treatment (5-fluorouracil) and HER2. Molecular modeling methods were also employed to assess the molecular structure, spectroscopic properties (FTIR and UV-Vis), NBO, QTAIM and HOMO-LUMO energies of 5-FU. From the docking simulations it was possible to analyze the interactions that occur between some residues in the binding site of HER2 and 5-FU. To validate the choice of basis set that was used in the NBO and QTAIM analyses, theoretical calculations were performed to obtain FT-IR and UV/Vis spectra, and the theoretical results are consistent with the experimental data, showing that the basis set chosen is suitable. For the maximum λ from the theoretical calculation (254.89nm) of UV/Vis, the electronic transition from HOMO to LUMO occurs at 4.89eV. From NBO analyses, we observed interactions between Asp863 and 5-FU, i.e. the orbitals with high transfer of electrons are LP O15 (donor NBO) and BD* (π) N1-H10 (acceptor NBO), being that the value of this interaction is 7.72kcal/mol. Results from QTAIM indicate one main intermolecular H bond, which is necessary to stabilize the complex formed between the ligands and the biological target. Therefore, this study allowed a careful evaluation on the main structural, spectroscopic and electronic properties involved in the interaction between 5-FU and HER2, an important biological complex related to the cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Aptamer and 5-fluorouracil dual-loading Ag2S quantum dots used as a sensitive label-free probe for near-infrared photoluminescence turn-on detection of CA125 antigen.

    Science.gov (United States)

    Jin, Hui; Gui, Rijun; Gong, Jun; Huang, Wenxue

    2017-06-15

    In this article, Ag 2 S quantum dots (QDs) were prepared by a facile aqueous synthesis method, using thiourea as a new sulfur precursor. Based on electrostatic interactions, 5-fluorouracil (5-Fu) was combined with the aptamer of CA125 antigen to fabricate aptamer/5-Fu complex. The surface of as-prepared Ag 2 S QDs was modified with polyethylenimine, followed by combination with the aptamer/5-Fu complex to form Ag 2 S QDs/aptamer/5-Fu hybrids. During the combination of Ag 2 S QDs with aptamer/5-Fu complex, near-infrared (NIR) photoluminescence (PL) of QDs (peaked at 850nm) was markedly reduced under excitation at 625nm, attributed to photo-induced electron transfer from QDs to 5-Fu. However, the addition of CA125 induced obvious NIR PL recovery, which was ascribed to the strong binding affinity of CA125 with its aptamer, and the separation of aptamer/5-Fu complex from the surface of QDs. Hence, the Ag 2 S QDs/aptamer/5-Fu hybrids were developed as a novel NIR PL turn-on probe of CA125. In the concentration range of [CA125] from 0.1 to 10 6 ngmL -1 , there were a good linear relationship between NIR PL intensities of Ag 2 S QDs and Log[CA125], and a low limit of detection of 0.07ngmL -1 . Experimental results revealed the highly selective and sensitive NIR PL responses of this probe to CA125, over other potential interferences. In real human body fluids, this probe also exhibited superior analytical performance, together with high detection recoveries. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Study on molecular structure, spectroscopic properties (FTIR and UV-Vis), NBO, QTAIM, HOMO-LUMO energies and docking studies of 5-fluorouracil, a substance used to treat cancer

    Science.gov (United States)

    Almeida, Michell O.; Barros, Daiane A. S.; Araujo, Sheila C.; Faria, Sergio H. D. M.; Maltarollo, Vinicius G.; Honorio, Kathia M.

    2017-09-01

    Cancer cells can expand to other parts of body through blood system and nodes from a mechanism known as metastasis. Due to the large annual growth of cancer cases, various biological targets have been studied and related to this disorder. A very interesting target related to cancer is human epidermal growth factor receptor 2 (HER2). In this study, we analyzed the main intermolecular interactions between a drug used in the cancer treatment (5-fluorouracil) and HER2. Molecular modeling methods were also employed to assess the molecular structure, spectroscopic properties (FTIR and UV-Vis), NBO, QTAIM and HOMO-LUMO energies of 5-FU. From the docking simulations it was possible to analyze the interactions that occur between some residues in the binding site of HER2 and 5-FU. To validate the choice of basis set that was used in the NBO and QTAIM analyses, theoretical calculations were performed to obtain FT-IR and UV/Vis spectra, and the theoretical results are consistent with the experimental data, showing that the basis set chosen is suitable. For the maximum λ from the theoretical calculation (254.89 nm) of UV/Vis, the electronic transition from HOMO to LUMO occurs at 4.89 eV. From NBO analyses, we observed interactions between Asp863 and 5-FU, i.e. the orbitals with high transfer of electrons are LP O15 (donor NBO) and BD* (π) N1-H10 (acceptor NBO), being that the value of this interaction is 7.72 kcal/mol. Results from QTAIM indicate one main intermolecular H bond, which is necessary to stabilize the complex formed between the ligands and the biological target. Therefore, this study allowed a careful evaluation on the main structural, spectroscopic and electronic properties involved in the interaction between 5-FU and HER2, an important biological complex related to the cancer treatment.

  15. In silico analysis of the three-dimensional structures of the homodimer of uridine phosphorylase from Yersinia Pseudotuberculosis in the ligand-free state and in a complex with 5-fluorouracil

    Science.gov (United States)

    Lashkov, A. A.; Sotnichenko, S. E.; Mikhailov, A. M.

    2013-03-01

    Pseudotuberculosis is an acute infectious disease characterized by a lesion of the gastrointestinal tract. A positive therapeutic effect can be achieved by selectively suppressing the activity of uridine phosphorylase from the causative agent of the disease Yersinia pseudotuberculosis. The synergistic effect of a combination of the chemotherapeutic agent 5-fluorouracil and antimicrobial drugs, which block the synthesis of pyrimidine bases, on the cells of pathogenic protozoa and bacteria is described in the literature. The three-dimensional structures of uridine phosphorylase from Yersinia pseudotuberculosis ( YptUPh) both in the ligand-free state and in complexes with pharmacological agents are unknown, which hinders the search for and design of selective inhibitors of YptUPh. The three-dimensional structure of the ligand-free homodimer of YptUPh was determined by homology-based molecular modeling. The three-dimensional structure of the subunit of the YptUPh molecule belongs to α/β proteins, and its topology is a three-layer α/β/α sandwich. The subunit monomer of the YptUPh molecule consists of 38% helices and 24% β strands. A model of the homodimer structure of YptUPh in a complex with 5-FU was obtained by the molecular docking. The position of 5-FU in the active site of the molecule is very consistent with the known data on the X-ray diffraction structures of other bacterial uridine phosphorylases (the complex of uridine phosphorylase from Salmonella typhimurium ( StUPh) with 5-FU, ID PDB: 4E1V and the complex of uridine phosphorylase from Escherichia coli ( EcUPh) with 5-FU and ribose 1-phosphate, ID PDB: 1RXC).

  16. Needle Revision With 5-fluorouracil for the Treatment of Ahmed Glaucoma Valve Filtering Blebs: 5-Fluoruracil Needling Revision can be a Useful and Safe Tool in the Management of Failing Ahmed Glaucoma Valve Filtering Blebs.

    Science.gov (United States)

    Quaranta, Luciano; Floriani, Irene; Hollander, Lital; Poli, Davide; Katsanos, Andreas; Konstas, Anastasios G P

    2016-04-01

    To determine the outcome of needling with adjunctive 5-fluorouracil (5-FU) in patients with a failing Ahmed glaucoma valve (AGV) implant, and to identify predictors of long-term intraocular pressure (IOP) control. A prospective observational study was performed on consecutive patients with medically uncontrolled primary open-angle glaucoma (POAG) with AGV encapsulation or fibrosis and inadequate IOP control. Bleb needling with 5-FU injection (0.1 mL of 50 mg/mL) was performed at the slit-lamp. Patients were examined 1 week following the needling, and then at months 1, 3, and 6. Subsequent follow-up visits were scheduled at 6-month intervals for at least 2 years. Needling with 5-FU was repeated no more than twice during the first 3 months of the follow-up. Procedure outcome was determined on the basis of the recorded IOP levels. Thirty-six patients with an encapsulated or fibrotic AGV underwent 67procedures (mean 1.86 ± 0.83). Complete success, defined as IOP ≤ 18 mm Hg without medications, was obtained in 25% at 24 months of observation. The cumulative proportion of cases achieving either qualified (ie, IOP ≤ 18 mm Hg with medications) or complete success at 24 months of observation was 72.2%. In a univariate Cox proportional hazards model, age was the only variable that independently influenced the risk of failing 5-FU needling revision. Fourteen eyes (38.8%) had a documented complication. Needling over the plate of an AGV supplemented with 5-FU is an effective and safe choice in a significant proportion of POAG patients with elevated IOP due to encapsulation or fibrosis.

  17. [Enhancement effect of interferon gamma on the sensitivity of RT4 bladder cancer cells to 5'-deoxy-5-fluorouridine,and 5-fluorouracil through up-regulation of PD-ECGF/TP].

    Science.gov (United States)

    Li, Gang; Yan, Chun-Yin; Wen, Duan-Gai; Ding, Qiang; Zhang, Yuan-Fang

    2004-08-01

    Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is an essential enzyme in converting 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-fluorouracil (5-FU) to their active metabolites in vivo, and can be up-regulated by some cytokines such as interleukin-1, and interferon gamma (INFgamma). This study was to observe the regulative effect of INFgamma on expression of PD-ECGF/TP, and its relation with the anti-cancer effect of 5'-DFUR, and 5-FU on RT4 bladder cancer cells. PD-ECGF/TP mRNA, and protein expression were determined by reverse transcriptase polymerase chain reaction (RT-PCR), and Western blot analysis, respectively. Cytotoxicity of 5'-DFUR, and 5-FU against RT4 cells was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymetho-xyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Expression levels of PD-ECGF/TP mRNA and protein were elevated in RT4 cells after cultured with INFgamma. INFgamma reduced IC50s of 5'-DFUR [from (9.7+/-0.2) mmol/L to (3.7+/-0.9) mmol/L], and 5-FU [from (130.0+/-21.2) mmol/L to (49.3+/-18.4) mmol/L] in RT4 cells. INFgamma enhances cytotoxicity of 5'-DFUR, and 5-FU against RT4 cells through induction of PD-ECGF/TP. INFgamma/5'-DFUR or INFgamma/5-FU combination treatment may lead to better chemotherapeutic results in human bladder cancer.

  18. Combination of 5-fluorouracil and irinotecan on modulation of thymidylate synthase and topoisomerase I expression and cell cycle regulation in human colon cancer LoVo cells: clinical relevance.

    Science.gov (United States)

    Xu, Jian-Ming; Azzariti, Amalia; Tommasi, Stefania; Lacalamita, Rosanna; Colucci, Giuseppe; Johnston, Patrick G; Church, Stewart W; Paradiso, Angelo

    2002-11-01

    This study was designed to explore the possible interaction of 5-fluorouracil (5-FU) and 7-ethyl-10-hydroxycamptothecin (SN-38) in vitro. Human colon cancer LoVo cells were treated in both a dose- and time-dependent manner using clinically relevant concentrations of and exposure to 5-FU and/or SN-38. The expression of thymidylate synthase (TS), topoisomerase I, and cell cycle kinetics were evaluated by Western blot analysis and flow cytometry, respectively. Cytotoxicity was evaluated by MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide) assay. The cytotoxic effects of combination treatment were determined by median effect analysis. Topoisomerase I expression was downregulated following 12 hours of exposure to treatment, and topoisomerase I expression recovered 8 hours after SN-38 was removed. The TS expression was decreased following 24 hours of 5-FU and it remained at reduced levels for > 24 hours after removal of 5-FU. SN-38 induced an arrest at S/G2/M phase, reaching its maximum effect at 12 hours. This cell cycle arrest was reversed 24 hours after SN-38 was removed. 5-FU induced an arrest at the S phase, and maximum arrest occurred at 12 hours and lasted for > 48 hours. After 12 hours of sequential SN-38, LoVo cells were arrested in S phase, thereby potentiating the effect of 5-FU. Cytotoxicity studies confirmed the synergistic interaction between 5-FU and irinotecan. These findings suggest that the proper sequencing of 5-FU/irinotecan depends on regulation of topoisomerase I, and cell cycle kinetics

  19. Trabeculectomy with intraoperative 5-fluorouracil in Enugu,

    African Journals Online (AJOL)

    With adjunctive use of 5-FU during trabeculectomy the antimetabolite has its own potential complications. However, compared with mitomycin-C, at clinical concentrations, 5-FU causes temporary inhibition of fibroblast proliferation with late recovery after single application" 5-FU has a much less severe effect than MMC.

  20. [5-Fluorouracil in trabeculectomy: preliminary report].

    Science.gov (United States)

    Jeng, S; Ku, W C; Fan, D

    1989-01-01

    Subconjunctival 5-FU injections were used as an adjunctive therapy in trabeculectomy for high risk glaucoma patients. We injected 5 mg once a day for five to seven days as a routine treatment. For the first 10 eyes, the injections were started immediately after the operation. However, for the remaining 9 eyes, the injections began 24 to 48 hours postoperative. If the appearance of the bleb was not prominent or enriched in vascularity, the duration of the injections should be extended to 10 to 14 days. At least 8 months of follow-up were available for 19 eyes, including aphakic glaucoma, 8 eyes; neovascular glaucoma, 2 eyes; previous failed filter, 6 eyes; total collapse of the anterior chamber with leucoma adherence, 1 eye; glaucoma due to mesodermal dysgenesis, 1 eye; and juvenile glaucoma, 1 eye (whose fellow eye had received twice failed filtering procedures). The results revealed a success rate of 79% (intraocular pressure below 22mmHg with or without topical medication). The success rate for aphakic glaucoma was 63% (5/8), for neovascular glaucoma 100% (2/2) and for the failed filters 83% (5/6). We also presume that 5-FU injections would be effective in the treatment of to abnormally marked fibrous proliferations caused by age factors. The complications related to the use of 5-FU include corneal epithelial defect 4/9 (21%), conjunctival leak 3/9 (16%), subconjunctival hematoma 1/19 (5%), and conjunctival sterile ulcer 1/19 (5%).

  1. Cerebral venous angiomas

    Energy Technology Data Exchange (ETDEWEB)

    Agnoli, A.L.; Hildebrandt, G.

    1985-01-01

    Clinical symptoms and radiological signs in 15 patients with cerebral venous malformations are presented and the diagnostic problems discussed. The circulation time in combination with cerebral malformations and angiomas of the scalp are described. CT findings in cases of venous malformations of the brain stem are evaluated. Spot-like enhancement, as well as sharply demarcated round shaped enhancement are characteristic for venous angiomas. Cavernous angiomas usually present as homogenous or inhomogenous round shaped enhanced areas. (Author).

  2. Persistent portal venous gas.

    Science.gov (United States)

    Huurman, Volkert A L; Visser, Leo G; Steens, Stefan C A; Terpstra, Onno T; Schaapherder, Alexander F M

    2006-05-01

    This case report describes a patient diagnosed with ongoing portal venous gas, initiated by a rather common Campylobacter enterocolitis and maintained by septic thrombophlebitis and possibly by chronic cholecystitis. Cholecystectomy attenuated the patient's septic condition. The etiology of portal venous gas determines both the patient's prognosis and the choice for either conservative or surgical treatment. This report describes persistence of portal venous gas for a long period and a possible role for chronic cholecystitis as a cause.

  3. Long Term Survival Results of Surgery Alone versus Surgery plus 5-Fluorouracil and Leucovorin for Stage II and Stage III Colon Cancer: Pooled Analysis of NSABP C-01 through C-05 Baseline from Which to Compare Modern Adjuvant Trials

    Science.gov (United States)

    Wilkinson, Neal W.; Yothers, Greg; Lopa, Samia; Costantino, Joseph P.; Petrelli, Nicholas J.; Wolmark, Norman

    2010-01-01

    Background The objective of this study is to conduct a pooled analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) colon trials involving surgery and surgery plus 5-fluorouracil and leucovorin (5-FU/LV) to compare survival and establish a baseline from which to evaluate future studies. Methods All patients enrolled in NSABP adjuvant trials C-01 through C-05 with stage II and III disease who were treated with surgery or with surgery plus 5-FU/LV were examined for overall survival (OS), disease free survival (DFS), and recurrence free interval (RFI). Time-to-event by treatment group was examined using adjusted Kaplan-Meier estimates and multivariable Cox regression analysis. Results There were 2,966 eligible patients: 693 (23%) surgery and 2,273 (77%) surgery plus 5-FU/LV; 1,255 (42%) stage II and 1,711 (58%) stage III. Age ≥ 60 years {hazard ratio (HR)=1.36, P<0.000], male gender (HR=1.20, P=0.0012), and more nodes positive or fewer nodes examined (P< 0.0001) were associated with worse survival. At 5 years, the adjusted OS was 0.62 [confidence interval (CI)= 0.60-0.63] in the surgery group and 0.76 (CI= 0.74- 0.78) in the surgery plus 5-FU/LV group. Treatment with 5-FU/LV was associated with improved outcome compared with surgery: OS (HR=0.62, P<0.0001), DFS (HR=0.66, P<0.0001) and RFI (HR=0.64, P<0.0001). Improved OS with adjuvant treatment was seen in both stage II (HR=0.58, 95% CI=0.48-0.71) and stage III disease (HR=0.65, 95% CI=0.55-0.75). Conclusions This analysis demonstrates that treatment of colon cancer patients with 5-FU/LV following surgery provides benefit over surgery alone and can provide anticipated survival outcomes from which to compare modern adjuvant trials. PMID:20082144

  4. Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO

    Directory of Open Access Journals (Sweden)

    Luber Birgit

    2011-12-01

    Full Text Available Abstract Background The activity of the epidermal growth factor receptor (EGFR-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of KRAS (3%. The aim of the correlative tumour tissue studies was to investigate the relationship between EGFR gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX. Methods Patients included in this correlative study (n = 39 were a subset of patients from the clinical phase II study. The association between EGFR gene copy number, activation of the EGFR pathway, abundance and mutation of E-cadherin which plays an important role in these disorders, BRAF mutation and clinical outcome of patients was studied. EGFR gene copy number was assessed by FISH. Expression of the phosphorylated forms of EGFR and its downstream effectors Akt and MAPK, in addition to E-cadherin was analysed by immunohistochemistry. The frequency of mutant V600E BRAF was evaluated by allele-specific PCR and the mutation profile of the E-cadherin gene CDH1 was examined by DHPLC followed by direct sequence analysis. Correlations with overall survival (OS, time to progression (TTP and overall response rate (ORR were assessed. Results Our study showed a significant association between increased EGFR gene copy number (≥ 4.0 and OS in gastric and OGJ cancer, indicating the possibility that patients may be selected for treatment on a genetic basis. Furthermore, a significant correlation was shown between activated EGFR and shorter TTP and ORR, but not between activated EGFR and OS. No V600E BRAF mutations were identified. On the other hand, an

  5. Long-Term Follow-Up of a Phase II Trial of High-Dose Radiation With Concurrent 5-Fluorouracil and Cisplatin in Patients With Anal Cancer (ECOG E4292)

    Energy Technology Data Exchange (ETDEWEB)

    Chakravarthy, A. Bapsi, E-mail: bapsi.chak@vanderbilt.edu [Vanderbilt University Medical Center, Nashville, TN (United States); Catalano, Paul J. [Dana-Farber Cancer Institute, Boston, MA (United States); Martenson, James A. [Mayo Clinic, Rochester, MN (United States); Mondschein, Joshua K. [Vanderbilt University Medical Center, Nashville, TN (United States); Wagner, Henry [Pennsylvania State Hershey Cancer Institute, Hershey, PA (United States); Mansour, Edward G. [Case Western Reserve University, Cleveland, OH (United States); Talamonti, Mark S. [University of Chicago Pritzker School of Medicine, Evanston, IL (United States); Benson, Al Bowen [Northwestern University, Chicago, IL (United States)

    2011-11-15

    Purpose: Although chemoradiation using 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care in the treatment of anal cancer, many patients are unable to tolerate MMC. This Phase II clinical trial was performed to determine whether cisplatin could replace MMC in the treatment of anal cancer. Methods and Materials: Thirty-three patients with localized anal cancer were enrolled. One patient registered but never received any assigned therapy and was excluded from all analyses. Between February 1, 1993, and July 21, 1993, 19 patients were accrued to Cohort 1. Radiation consisted of 45 Gy to the primary tumor and pelvic nodes, followed by a boost to the primary and involved nodes to 59.4 Gy. A planned 2-week treatment break was used after 36 Gy. Concurrent chemotherapy consisted of 5-FU 1,000 mg/m{sup 2}/day on Days 1 to 4 and cisplatin 75 mg/m{sup 2} on Day 1. A second course of 5-FU and cisplatin was given after 36 Gy, when the patient resumed radiation therapy. Between April 4, 1996, and September 23, 1996, an additional 13 patients (Cohort 2) were accrued to the study and received the same treatment except without the planned treatment break. Results: Complete response was seen in 78% (90% CI, 63-89) of patients and was higher in patients who did not get a planned treatment break (92% vs. 68%). The overall Grade 4 toxicity rate was 31%. One treatment-related death (Grade 5) occurred in a patient who developed sepsis. The 5-year overall survival was 69%. Conclusions: Radiation therapy, cisplatin, and 5-FU resulted in an overall objective response (complete response + partial response) of 97%. Although the 5-year progression-free survival was only 55%, the overall 5-year survival was 69%. Given the excellent salvage provided by surgery, this study affirms that cisplatin-based regimens may be an alternative for patients who cannot tolerate the severe hematologic toxicities associated with mitomycin-based chemoradiation regimens.

  6. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.

    Science.gov (United States)

    Pelzer, Uwe; Schwaner, Ingo; Stieler, Jens; Adler, Mathias; Seraphin, Jörg; Dörken, Bernd; Riess, Hanno; Oettle, Helmut

    2011-07-01

    Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy. In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy. After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively. Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy

  7. Let-7 miRNA-binding site polymorphism in the KRAS 3′UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/− cetuximab

    Directory of Open Access Journals (Sweden)

    Kjersem Janne B

    2012-11-01

    Full Text Available Abstract Background Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6 within the 3′untranslated region (3′UTR of KRAS (rs61764370 and clinical outcome in metastatic colorectal cancer (mCRC patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin +/− cetuximab. Methods The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314. Results LCS6 frequencies did not vary between CRC patients (23%, individuals with polyps (20%, and healthy controls (20% (P = 0.50. No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS and overall survival (OS were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months versus 7.8 months (95% CI: 7.4-8.3 months, P = 0.16 and 23.5 (95% CI: 21.6-25.4 months versus 19.5 months (95% CI: 17.8-21.2 months, P = 0.31, respectively. Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%, however the difference was not statistically significant (interaction P = 0.16. Conclusions The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the

  8. Rapid blood clearance and lack of long-term renal toxicity of {sup 177}Lu-DOTATATE enables shortening of renoprotective amino acid infusion

    Energy Technology Data Exchange (ETDEWEB)

    Kashyap, Raghava; Eu, Peter [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne (Australia); Jackson, Price [Peter MacCallum Cancer Centre, Department of Physical Sciences, Melbourne (Australia); Hofman, Michael S.; Hicks, Rodney J. [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne (Australia); The University of Melbourne, Departments of Medicine and Radiology, Melbourne (Australia); Beauregard, Jean-Mathieu [Universite Laval, Department of Radiology, Quebec City (Canada); Zannino, Diana [Peter MacCallum Cancer Centre, Department of Biostatistics and Clinical Trials, Melbourne (Australia)

    2013-12-15

    The aim of the study was to investigate the feasibility of shortening the recommended 4-h renoprotective amino acid infusion in patients receiving peptide receptor chemoradionuclide therapy (PRCRT) using radiosensitizing 5-fluorouracil. We evaluated the clearance of radiopeptide from the blood, long-term nephrotoxicity in patients undergoing PRCRT with the conventional 4-h amino acid infusion and renal uptake in patients receiving an abbreviated infusion. The whole-blood clearance of {sup 177}Lu-DOTA-octreotate (LuTate) was measured in 13 patients receiving PRCRT. A retrospective analysis of short-term and long-term changes in glomerular filtration rate (GFR) in 96 consecutive patients receiving a 4-h infusion was performed. Renal LuTate retention estimated using quantitative SPECT/CT in 22 cycles delivered with a 2.5-h amino acid infusion was compared with that in 72 cycles with the 4-h infusion. LuTate demonstrated biexponential blood clearance with an initial clearance half-time of 21 min. Approximately 88 % of blood activity was cleared within 2 h. With the 4-h protocol, there was no significant change in GFR (1.2 ml/min mean increase from baseline; 95 % CI -6.9 to 4.4 ml/min) and no grade 3 or 4 nephrotoxicity at the end of induction PRCRT. The long-term decline in GFR after a median follow up of 22 months was 2.2 ml/min per year. There was no significant difference in the renal LuTate retention measured in patients receiving a 2.5-h amino acid infusion compared to those who had a 4-h infusion. The greatest renal exposure to circulating radiopeptide occurs in the first 1 - 2 h after injection. This, combined with the safety of LuTate PRCRT, allows consideration of an abbreviated amino acid infusion, increasing patient convenience and reducing human resource allocation. (orig.)

  9. Lifestyle and venous thrombosis

    NARCIS (Netherlands)

    Pomp, Elisabeth Rebekka

    2008-01-01

    In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), a large population-based case-control study, we investigated lifestyle factors as risk factors for venous thrombosis. Overweight, smoking and alcohol consumption were addressed and pregnancy and

  10. Home Infusions for Haemophilia

    African Journals Online (AJOL)

    6 Jan 1973 ... with a resulting speedier recovery and reduced loss of school/work time. Hopefully joint deformity would be reduced as well. These advantages are ... venous system for 'main line' drug addiction..The medicolegal implications need careful consideration as does the question of onus of responsibility. Several ...

  11. Deep Venous Thrombosis with Pulmonary Embolism Related to IVIg Treatment: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Michael T. Flannery

    2015-01-01

    Full Text Available IVIg therapy has potentially been related to arterial and venous therapy. We performed an Ovid review focusing on IVIg and thrombotic events. While a few case reports were reviewed case series and case control studies were particularly reviewed in relation to thrombotic events. Outcomes demonstrate a correlation between underlying cardiovascular risk factors with predominately arterial events which typically occurred within 4–24 hours of infusion. While venous events occurred less commonly they were associated with traditional risk factors and occurred later, typically, 1–7 days following infusion of IVIg. Potential causation of thrombotic events was discussed.

  12. [Developmental venous anomaly (DVA)].

    Science.gov (United States)

    Zimmer, A; Hagen, T; Ahlhelm, F; Viera, J; Reith, W; Schulte-Altedorneburg, G

    2007-10-01

    As congenital anatomic variants of venous drainage, developmental venous anomalies (DVA) represent up to 60% of all cerebral vascular malformations. The prior term "venous angioma" is a misnomer implicating an abnormal vascular structure with an increased bleeding risk. They are often found incidentally and are hardly ever symptomatic. Their morphologic characteristics are dilated vessels in the white matter, which converge on a greater collector vein, forming the typical caput medusae. They drain into the superficial or deep venous system. The frequent association with other, potentially bleeding-prone vascular malformations is clinically relevant, in particular cavernous angioma, which might require therapeutic action. Therefore, coincident vascular lesions need to be actively sought by appropriate additional imaging techniques.

  13. Venous thrombosis: an overview

    Energy Technology Data Exchange (ETDEWEB)

    Peterson, C.W.

    1986-07-01

    Venous thromboembolic disease contributes to morbidity and mortality in certain groups of hospitalized patients, particularly those who have undergone surgery. Although principles of treatment have changed relatively little during the past 20 years, significant advances have been made in the diagnosis of deep vein thrombosis (DVT). Venography, once the only reliable diagnostic technique, has been largely replaced by noninvasive tests: impedance plethysmography, venous Doppler, /sup 125/I-radiofibrinogen-uptake test, and phleborheography. Virchow's triad of stasis, vessel injury, and hypercoagulability remains a valid explanation of the pathogenesis of thrombus formation, but laboratory and clinical data have refined our knowledge of how these factors interact to result in clinically significant disease. Knowledge of the natural history of venous thrombosis, plus heightened awareness of the long-term morbidity and expense associated with the postphlebitic syndrome, have led to increased interest in preventing DVT. Clinically and economically, venous thrombosis is best managed by prevention. 61 references.

  14. Venous ulcer review

    Science.gov (United States)

    Bevis, Paul; Earnshaw, Jonothan

    2011-01-01

    Clinical question: What is the best treatment for venous ulcers? Results: Compression aids ulcer healing. Pentoxifylline can aid ulcer healing. Artificial skin grafts are more effective than other skin grafts in helping ulcer healing. Correction of underlying venous incompetence reduces ulcer recurrence. Implementation: Potential pitfalls to avoid are: Failure to exclude underlying arterial disease before application of compression.Unusual-looking ulcers or those slow to heal should be biopsied to exclude malignant transformation. PMID:21673869

  15. Venous ulcer review

    OpenAIRE

    Bevis, Paul; Earnshaw, Jonothan

    2011-01-01

    Paul Bevis, Jonothan Earnshaw Department of Vascular Surgery, Gloucestershire Royal Hospital, Great Western Road, Gloucester, UKDate of preparation: 3 February 2011Conflict of interest: None declared.Clinical question: What is the best treatment for venous ulcers?Results: Compression aids ulcer healing. Pentoxifylline can aid ulcer healing. Artificial skin grafts are more effective than other skin grafts in helping ulcer healing. Correction of underlying venous incompetence reduces ulcer recu...

  16. Significant air embolism: A possibility even with collapsible intravenous fluid containers when used with rapid infuser system

    Directory of Open Access Journals (Sweden)

    Deepanjali Pant

    2010-01-01

    Full Text Available Significant venous air embolism may develop acutely during the perioperative period due to a number of causes such as during head and neck surgery, spinal surgery, improper central venous and haemodialysis catheter handling, etc. The current trend of using self collapsible intravenous (IV infusion bags instead of the conventional glass or plastic bottles has several advantages, one of thaem being protection against air embolism. We present a 56-year-old man undergoing kidney transplantation, who developed a near fatal venous air embolism during volume resuscitation with normal saline in collapsible IV bags used with rapid infuser system. To our knowledge, this problem with collapsible infusion bags has not been reported earlier.

  17. Relationship between contractions of the uterus and concentration of PGF2α in uterine venous blood after luteolysis in gilts.

    Science.gov (United States)

    Stefańczyk-Krzymowska, S; Wąsowska, B; Gilun, P; Muszak, J; Grzegorzewski, W

    2012-02-01

    The origin and physiological significance of high pulses of prostaglandin F2α (PGF2α) in uterine venous blood that occur 2-3 days after luteolysis are not well understood. We studied the relationship between contractions of the uterus evoked by exogenous oxytocin (OT) and PGF2α concentration in uterine venous blood on day 17 of the porcine oestrous cycle. The infusion of OT into the uterine artery produced an immediate increase in the uterine intraluminal pressure (UIP) (p uterine venous blood (p uterine artery slightly decreased PGF2α concentration in uterine venous blood, but it did not suppress uterine contraction or the rapid increase in PGF2α concentration in uterine venous blood just after OT infusion (p uterine venous blood occurring after OT infusion on day 17 of the porcine oestrous cycle are mainly caused by the excretion with venous blood from the remodelled uterus and that PGF2α synthesis may contribute to this. These results suggest that the high spikes in PGF2α concentration that occur 2-3 days after luteolysis in pigs, sheep, cows and mares all have a similar origin. © 2011 Blackwell Verlag GmbH.

  18. Hormonal contraception and venous thromboembolism

    DEFF Research Database (Denmark)

    Lidegaard, Øjvind; Milsom, Ian; Geirsson, Reynir Tomas

    2012-01-01

    New studies about the influence of hormonal contraception on the risk of venous thromboembolism (VTE) have been published.......New studies about the influence of hormonal contraception on the risk of venous thromboembolism (VTE) have been published....

  19. Hepatic arterial infusion pump chemotherapy for colorectal liver metastases: an old technology in a new era.

    Science.gov (United States)

    Ko, Y J; Karanicolas, P J

    2014-02-01

    Aggressive treatment of colorectal cancer (crc) liver metastases can yield long-term survival and cure. Unfortunately, most patients present with technically unresectable metastases; conventional therapy in such patients consists of systemic therapy. Despite advances in the effectiveness of systemic therapy in the first-line setting, the tumour response rate and median survival remain low in the second-line setting. The preferential blood supply from the hepatic artery to crc liver metastases allows for excellent regional delivery of chemotherapy. Here, we review efficacy and safety data for hepatic artery infusion (hai) pump chemotherapy in patients with metastatic crc from the 5-fluorouracil era and from the era of modern chemotherapy. In selected patients with liver-only or liver-dominant disease who have progressed on first-line chemotherapy, hai combined with systemic agents is a viable therapeutic option when performed at experienced centres. Furthermore, significantly improved survival has been demonstrated with adjuvant hai therapy after liver resection in the phase iii setting. The complication rates and local toxicities associated with hai pump therapy are infrequent at experienced centres and can be managed with careful follow-up and early intervention. The major obstacles to the wide adoption of hai therapy include technical expertise for pump insertion and maintenance, and for floxuridine dose modification. The creation of formal preceptor-focused education and training in hai therapy for interdisciplinary medical professionals might encourage the creation and expansion of this liver-directed approach.

  20. Models of the venous system

    DEFF Research Database (Denmark)

    Mehlsen, J

    2000-01-01

    of the venous system require at least three elements: a resistor, a capacitor and an inductor, with the latter being of more importance in the venous than in the arterial system. Non-linearities must be considered in pressure/flow relations in the small venules, during venous collapse, or low flow conditions...

  1. In-line filters in central venous catheters in a neonatal intensive care unit

    NARCIS (Netherlands)

    van den Hoogen, A; Krediet, TG; Uiterwaal, CSPM; Bolenius, JFGA; Gerards, LJ; Fleer, A

    Nosocomial sepsis remains an important cause of morbidity in neonatal intensive care units. Central venous catheters (CVCs) and parenteral nutrition (TPN) are major risk factors. In-line filters in the intravenous (IV) administration sets prevent the infusion of particles, which may reduce

  2. Venous oxygen saturation.

    Science.gov (United States)

    Hartog, Christiane; Bloos, Frank

    2014-12-01

    Early detection and rapid treatment of tissue hypoxia are important goals. Venous oxygen saturation is an indirect index of global oxygen supply-to-demand ratio. Central venous oxygen saturation (ScvO2) measurement has become a surrogate for mixed venous oxygen saturation (SvO2). ScvO2 is measured by a catheter placed in the superior vena cava. After results from a single-center study suggested that maintaining ScvO2 values >70% might improve survival rates in septic patients, international practice guidelines included this target in a bundle strategy to treat early sepsis. However, a recent multicenter study with >1500 patients found that the use of central hemodynamic and ScvO2 monitoring did not improve long-term survival when compared to the clinical assessment of the adequacy of circulation. It seems that if sepsis is recognized early, a rapid initiation of antibiotics and adequate fluid resuscitation are more important than measuring venous oxygen saturation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Correlation of central venous pressure with venous blood gas analysis parameters; a diagnostic study

    Directory of Open Access Journals (Sweden)

    Sima Rahim-Taleghani

    2017-03-01

    Full Text Available Objective: This study was conducted to assess the correlation between central venous pressure (CVP and venous blood gas (VBG analysis parameters, to facilitate management of severe sepsis and septic shock in emergency department. Material and methods: This diagnostic study was conducted from January 2014 until June 2015 in three major educational medical centers, Tehran, Iran. For patients selected with diagnosis of septic shock, peripheral blood sample was taken for testing the VBG parameters and the anion gap (AG was calculated. All the mentioned parameters were measured again after infusion of 500 cc of normal saline 0.9% in about 1 h. Results: Totally, 93 patients with septic shock were enrolled, 63 male and 30 female. The mean age was 72.53 ± 13.03 and the mean Shock Index (SI before fluid therapy was 0.79 ± 0.30. AG and pH showed significant negative correlations with CVP, While HCO3 showed a significant positive correlation with CVP. These relations can be affected by the treatment modalities used in shock management such as fluid therapy, mechanical ventilation and vasopressor treatment. Conclusion: It is likely that there is a significant statistical correlation between VBG parameters and AG with CVP, but further research is needed before implementation of the results of this study. Keywords: Shock, Septic, Central venous pressure, Blood gas analysis, Emergency department, Emergency medicine

  4. II Infused Mice

    Directory of Open Access Journals (Sweden)

    Justin L. Wilson

    2012-01-01

    Full Text Available The anti-inflammatory properties of PPAR-α plays an important role in attenuating hypertension. The current study determines the anti-hypertensive and anti-inflammatory role of PPAR-α agonist during a slow-pressor dose of Ang II (400 ng/kg/min. Ten to twelve week old male PPAR-α KO mice and their WT controls were implanted with telemetry devices and infused with Ang II for 12 days. On day 12 of Ang II infusion, MAP was elevated in PPAR-α KO mice compared to WT (161±4 mmHg versus 145±4 mmHg and fenofibrate (145 mg/kg/day reduced MAP in WT + Ang II mice (134±7 mmHg. Plasma IL-6 levels were higher in PPAR-α KO mice on day 12 of Ang II infusion (30±4 versus 8±2 pg/mL and fenofibrate reduced plasma IL-6 in Ang II-treated WT mice (10±3 pg/mL. Fenofibrate increased renal expression of CYP4A, restored renal CYP2J expression, reduced the elevation in renal ICAM-1, MCP-1 and COX-2 in WT + Ang II mice. Our results demonstrate that activation of PPAR-α attenuates Ang II-induced hypertension through up-regulation of CYP4A and CYP2J and an attenuation of inflammatory markers such as plasma IL-6, renal MCP-1, renal expression of ICAM-1 and COX-2.

  5. Venous ulcer: what is new?

    Science.gov (United States)

    Raffetto, Joseph D; Marston, William A

    2011-01-01

    The pathophysiology of venous dermal abnormality in chronic venous ulcers is reflective of a complex interplay that involves sustained venous hypertension, inflammation, changes in the microcirculation, cytokine and matrix metalloproteinase activation, and altered cellular function. Red blood cells and macromolecules extravasate into the interstitium and activate endothelial cells. Endothelial expression of specific adhesion molecules recruits leukocytes and causes diapedesis of these cells into the dermal microvasculature, promoting an inflammatory response with activation of cytokines and proteinases. Altered cell function enhances a state of vulnerability in the surrounding tissues, initiating specific changes associated with venous disease. Ultimately, the persistent inflammatory-proteinase activity leads to advanced chronic venous insufficiency and ulcer formation. The mainstay of therapy in venous ulcer abnormality is correction of the underlying venous hypertension through compression therapy and/or surgery. Understanding the science involved in the pathophysiology of venous ulcer formation has led to the development of adjunctive treatment directed at the dysregulated molecular pathways. Randomized clinical trials are critical for determining the most effective evidence-based treatments for venous ulcer, and this review discusses important trials that have had a significant impact on venous ulcer healing. In addition, the authors have included subsections referred to as "Translational Implications for Therapy" in the basic science sections of the review to help bridge the basic science knowledge with clinical applications that may help to modulate the molecular abnormalities in the pathophysiologic cascade leading to venous ulcers.

  6. Administration of chemotherapy by an arteriovenous fistula in a patient with metastatic rectal cancer after life-threatening, port thrombosis-associated cava superior syndrome. An option for patients without possibility of peripheral or central venous access.

    Science.gov (United States)

    Stein, Alexander; Hiemer, Sonja; Jordan, Karin; Arnold, Dirk; Schmoll, Hans-Joachim

    2012-01-01

    Patients with solid tumors have an increased risk of venous thromboembolism, potentially related to a venous port system. In case of catheter-related thrombosis despite full anticoagulation, further treatment administration is difficult. A 41-year-old female patient with a K-Ras wild-type adenocarcinoma of the rectum was diagnosed with systemic disease in June 2008 after several local recurrences treated with surgery and additive chemotherapy. To administer chemotherapy with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) and bevacizumab, a venous port system into the vena subclavia was implanted. In April 2009, the computed tomography (CT) scan revealed a portassociated thrombosis with cava superior syndrome, despite treatment with phenprocoumon and an international normalized ratio (INR) of 3.75 at the time of the event. The port system was explanted. According to the possible relationship to bevacizumab, treatment was discontinued, followed by rapid disease progression. Access to peripheral veins became virtually impossible. Therefore, a radiocephalic fistula was established. For 9 months, the patient has been receiving several therapeutic agents with 20 punctures of the fistula, revealing no locoregional events (e.g. arterial, venous or cutaneous). The application of current therapeutic agents by an arteriovenous fistula seems to be a feasible option for patients with restricted peripheral or central vein status and/or medical history of thrombotic events disabling the use of a port system. Copyright © 2012 S. Karger AG, Basel.

  7. Chamomile infusion cryotherapy to prevent oral mucositis induced by chemotherapy: a pilot study.

    Science.gov (United States)

    Dos Reis, Paula Elaine Diniz; Ciol, Marcia A; de Melo, Nilce Santos; Figueiredo, Paulo Tadeu de Souza; Leite, André Ferreira; Manzi, Natália de Melo

    2016-10-01

    The aim of this study is to compare cryotherapy made only with water and cryotherapy made with chamomile infusion for prevention and reduction of intensity of oral mucositis in patients with cancer receiving 5-fluorouracil and leucovorin. This is a randomized pilot study with two groups: cryotherapy made only with water (control group, n = 18) and cryotherapy made with chamomile infusion (chamomile group, n = 20). Both groups were instructed to swish the ice around in their oral cavity for at least 30 min during chemotherapy. Assessment of oral mucosa occurred on days 8, 15, and 22 after the first day of chemotherapy. Fifty percent of the patients in the control and 30 % in the chamomile group developed oral mucositis. Mouth pain score was higher in patients in the control group on all evaluations (p = 0.02 for day 8, p = 0.09 for day 15, and p = 0.14 for day 22). Patients in the chamomile group never developed mucositis with grade 2 or higher. Presence of ulceration was statistically significant on day 8 (16 % in the control vs. 0 % in the chamomile group, p = 0.10), but not in days 15 and 22, although 11 % still had ulcerations in the control group and none in the chamomile group. The occurrence of oral mucositis was lower in patients in the chamomile group than in the control group. When compared to the controls, the chamomile group presented less mouth pain and had no ulcerations. Cryotherapy was well tolerated by both groups, and no toxicity related to chamomile was identified.

  8. Dicloxacillin: a higher risk than cloxacillin for infusion phlebitis.

    Science.gov (United States)

    Lanbeck, Peter; Odenholt, Inga; Paulsen, Otto

    2003-01-01

    Ever since dicloxacillin and cloxacillin were introduced in the 1960s, it has been known that they are associated with a high incidence of infusion phlebitis. Some in vitro studies and clinical experience have indicated that dicloxacillin is the more vessel-irritating of the 2 drugs. In this prospective observational study on 39 patients with 111 peripheral venous catheters (PVCs), the incidence of infusion phlebitis was compared between these 2 drugs. The incidence of phlebitis was 38% with dicloxacillin and 21% with cloxacillin; which, compared by logistic regression with other risk factors as covariates, was significant [odds ratio 5.06, 95% confidence interval (95% CI) 1.45-17.60]. Since the duration of catheterization is also an important risk factor, Cox regression was performed, and the difference between the 2 drugs was still significant (proportional hazard rate 3.48, 95%, CI 1.64-7.38). The only other significant risk factor found in the study was the insertion site; the risk was higher in PVCs inserted in the forearm/antecubital fossa than in the hand/wrist. The infusion time and dilution of the infusate were not significant risk factors.

  9. Genetics in chronic venous disease.

    Science.gov (United States)

    Grant, Yasmin; Onida, Sarah; Davies, Alun

    2017-02-01

    Chronic venous disease is highly prevalent in the Western world, with varicose veins being the most common form of clinical manifestation. With recent developments in sequencing technology, clinicians and geneticists alike are embarking on a journey to identify and unravel the genetic candidates of chronic venous disease. There is now currently substantial evidence to suggest the presence of genetic influences in the aetiology and pathology of venous disease. Despite this, the precise nature and profile of the genes involved in chronic venous disease remain a poorly understood entity. Moreover, it is strikingly apparent that the majority of venous genetic studies conducted over the past decade do not adhere to fundamental research principles. The emergence of high-throughput genotyping platforms permits a more systematic search for inherited components of venous disease. Pursuing a genome-wide frontier has the potential to reveal novel critical metabolic pathways and explain the genetic susceptibility of chronic venous disease. An expedited knowledge of the genetic factors in the aetiology of venous disease may translate into better prevention or treatment, which would benefit patients suffering from its clinical sequelae. Researchers should be urged to foster collaborative links and design a genome-wide case-control association study as an international consortium to provide a statistically robust paradigm in the field of chronic venous disease genetics. This will carry promise for clinically relevant progress and represent a first step towards better understanding of the genetics of chronic venous disease aetiology.

  10. Central Venous Access in the Pediatric Population With Emphasis on Complications and Prevention Strategies.

    Science.gov (United States)

    Duesing, Lori A; Fawley, Jason A; Wagner, Amy J

    2016-08-01

    Central venous catheters are often necessary in the pediatric population. Access may be challenging, and each vessel presents its own unique set of risks and complications. Central venous catheterization is useful for hemodynamic monitoring, rapid fluid infusion, and administration of hyperosmolar medications, including vasopressors, antibiotics, chemotherapy, and parenteral nutrition. Recent advances have improved the catheters used as well as techniques for insertion. A serious complication of central access is infection, which is associated with morbidity, mortality, and significant financial costs. Reduction of catheter-related bloodstream infections is realized with use of ethanol locks, single lumens when appropriate, and prudent adherence to insertion and maintenance bundles. Ultrasound guidance used for central venous catheter placement improves accuracy of placement, reducing time and unsuccessful insertion and complication rates. Patients with central venous catheters are best served by multidisciplinary team involvement. © 2016 American Society for Parenteral and Enteral Nutrition.

  11. Infusion's greenfield subsidiary in Poland

    NARCIS (Netherlands)

    Williams, C.; van Eerde, W.; The, D.

    2012-01-01

    The president of Infusion Development Corporation was reviewing the progress of the new subsidiary the company had set up 15 months earlier in Krakow, Poland. The purpose of the subsidiary was to work with other Infusion offices around the world to provide innovative software development services to

  12. Understanding Guyton's venous return curves

    National Research Council Canada - National Science Library

    Beard, Daniel A; Feigl, Eric O

    2011-01-01

    ...) was experimentally increased the right atrial pressure decreased, Arthur Guyton and coworkers proposed an interpretation that right atrial pressure represents a back pressure restricting venous return...

  13. Vasopressin-induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection.

    Science.gov (United States)

    Bown, L Sand; Ricksten, S-E; Houltz, E; Einarsson, H; Söndergaard, S; Rizell, M; Lundin, S

    2016-05-01

    To minimize blood loss during hepatic surgery, various methods are used to reduce pressure and flow within the hepato-splanchnic circulation. In this study, the effect of low- to moderate doses of vasopressin, a potent splanchnic vasoconstrictor, on changes in portal and hepatic venous pressures and splanchnic and hepato-splanchnic blood flows were assessed in elective liver resection surgery. Twelve patients were studied. Cardiac output (CO), stroke volume (SV), mean arterial (MAP), central venous (CVP), portal venous (PVP) and hepatic venous pressures (HVP) were measured, intraoperatively, at baseline and during vasopressin infusion at two infusion rates (2.4 and 4.8 U/h). From arterial and venous blood gases, the portal (splanchnic) and hepato-splanchnic blood flow changes were calculated, using Fick's equation. CO, SV, MAP and CVP increased slightly, but significantly, while systemic vascular resistance and heart rate remained unchanged at the highest infusion rate of vasopressin. PVP was not affected by vasopressin, while HVP increased slightly. Vasopressin infusion at 2.4 and 4.8 U/h reduced portal blood flow (-26% and -37%, respectively) and to a lesser extent hepato-splanchnic blood flow (-9% and -14%, respectively). The arterial-portal vein lactate gradient was not significantly affected by vasopressin. Postoperative serum creatinine was not affected by vasopressin. Short-term low to moderate infusion rates of vasopressin induced a splanchnic vasoconstriction without metabolic signs of splanchnic hypoperfusion or subsequent renal impairment. Vasopressin caused a centralization of blood volume and increased cardiac output. Vasopressin does not lower portal or hepatic venous pressures in this clinical setting. © 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  14. Neonatal Infusion Therapy

    Directory of Open Access Journals (Sweden)

    Ye. A. Zhukov

    2008-01-01

    Full Text Available Objective: to study whether 20% albumin might be postoperatively used in the newborn. Subjects and methods. The study included 64 neonatal infants with various congenital surgical diseases: esophageal atresia (34.1%, congenital low and high ileus (43.9%, diaphragmatic hernia (12.1%, and gastroschisis (5.7%. On days 1 and 2 after birth, all the infants underwent correction of a defect. The rate of neonatal shock elimination was studied, by using the traditional scheme and transfusion of highly concentrated 20% albumin solution (20% plasbumin (Talecris Biotherapeutics. A study group comprised 12 neonates aged 0 to 3 days. For stabilization of blood pressure and emergence from shock, they received highly concentrated 20% albumin solution by the authors’ scheme (at an infusion rate of 20 ml/kg/hour until BP stabilized in the early postoperative period. A control group consisted of 52 neonatal infants who had the similar surgical interventions and received the complete standard complex of infusion-transfusion therapy: 10% glucose + physiological solution in a ratio of 1:1 at a rate of 20 ml/kg/hour, then 6% hydroxyethyl starch preparations in a dose of 3 ml/kg/hour. The control points in the study were as follows: mortality rate, the rate of normalization of BP and diuresis within the first 24 hours after surgery, the severity of generalized edema and the stabilization of total blood protein by day 10, and the duration of artificial ventilation (AV. All the neonates underwent monitoring of vital indices: ECG, systolic, diastolic, and mean BP, and tissue oxygen saturation (SaO2. Statistical processing involved estimation of the significance of changes, by using Student’s test. Results. Mortality rates were 9.8 and 22.3% in the group of neonates receiving 20% albumin against shock and in the control having the traditional treatment, respectively. A significant acceleration of BP normalization was noted in the study group (1.5±0.12 hours as

  15. Venous function after pharmacomechanical thrombolysis for ...

    African Journals Online (AJOL)

    Background: Chronic venous insufficiency is an important complication following iliofemoral deep venous thrombosis. Early thrombus removal may preserve venous function and prevent this complication. This study represents the largest reported South African series of pharmacomechanical thrombolysis for iliofemoral ...

  16. Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis

    Directory of Open Access Journals (Sweden)

    L. Rahal

    Full Text Available Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min in randomized groups. The following groups were studied: controls (fluid infusion, N = 4, E1 (enalaprilat infusion followed by fluid infusion, N = 5 and E2 (fluid infusion followed by enalaprilat infusion, N = 5. All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO, portal vein blood flow (PVBF, systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

  17. Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis

    Directory of Open Access Journals (Sweden)

    L. Rahal

    2006-09-01

    Full Text Available Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min in randomized groups. The following groups were studied: controls (fluid infusion, N = 4, E1 (enalaprilat infusion followed by fluid infusion, N = 5 and E2 (fluid infusion followed by enalaprilat infusion, N = 5. All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO, portal vein blood flow (PVBF, systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

  18. Pressurized Intravenous Fluid Administration in the Professional Football Player: A Unique Setting for Venous Air Embolism.

    Science.gov (United States)

    Fibel, Kenton H; Barnes, Ronnie P; Kinderknecht, James J

    2015-07-01

    Venous air embolism (VAE) is a potentially life-threatening event that is most commonly associated with certain surgical procedures, although this theoretical complication of pressurized rapid infusion of intravenous (IV) fluids has been described. This series of cases describes 4 athletes who presented with continuous coughing and other chest complaints after peripheral IV infusion of normal saline through manual pressurized infusion. Symptoms resolved within 20 minutes, and these incidences did not interfere with resuming athletic competition with no recurrence of symptoms or complications. These cases are most consistent with varying degrees of VAE and reveal the risk of VAE associated with pressurized peripheral IV fluid administration along with the unique clinical presentation of more modest forms of VAE in an awake patient. Becoming more knowledgeable about IV infusion technique and understanding potential pitfalls can be helpful in reducing future incidences of VAE.

  19. Central venous catheter - dressing change

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000156.htm Central venous catheter - dressing change To use the sharing features on this page, please enable JavaScript. You have a central venous catheter. This is a tube that goes into a ...

  20. Chronic Venous Disease under pressure

    NARCIS (Netherlands)

    S.W.I. Reeder (Suzan)

    2013-01-01

    textabstractIn chapter 1 we provide a general introduction of this thesis. Chronic venous disease (CVD) is a common medical condition that affects 2-64% of the worldwide population and leads to leg ulcers in 1% of the Western population. Venous leg ulceration (VLU) has an unfavorable prognosis with

  1. Venous Thromboembolism in Adolescents

    Directory of Open Access Journals (Sweden)

    Aneta Samková

    2012-01-01

    Full Text Available The incidence of venous thromboembolism (VTE during childhood is low with two peaks – neonatal and adolescent age. This retrospective study is focused on clinical characteristics of VTE during adolescence. The main goals are to assess the most frequent inherited and acquired risk factors and to evaluate the benefit of D-dimers in diagnostics of venous thromboemblism. The data of 18 adolescents were analysed – 16 girls (88.9%, 2 boys (11.1%. In 9 patients (50% thrombosis of the lower limb deep veins was diagnosed, six patients (33.3% suffered from symptomatic pulmonary embolism (PE and 3 patients (16.7% from thrombosis at unusual sites. One patient had an idiopathic VTE, the mean number of the inherited and acquired risk factors was 2.6. The most frequent inherited risk factor was Leiden mutation of factor V (27.8%. The most frequent acquired risk factor was oral contraception (OC in 12 out of 16 girls (75%. All of our patients on oral contraception had one or more additional risk factors. 10 out of 18 (55.6% patients with VTE had elevated activity of factor VIII. The sensitivity of D-dimers was low (50% in patients with distal lower limb thrombosis, but very high (100% in patients with PE.

  2. GIVIO-SITAC 01: A randomized trial of adjuvant 5-fluorouracil and folinic acid administered to patients with colon carcinoma--long term results and evaluation of the indicators of health-related quality of life. Gruppo Italiano Valutazione Interventi in Oncologia. Studio Italiano Terapia Adiuvante Colon.

    Science.gov (United States)

    Zaniboni, A; Labianca, R; Marsoni, S; Torri, V; Mosconi, P; Grilli, R; Apolone, G; Cifani, S; Tinazzi, A

    1998-06-01

    In 1989, the authors began a randomized trial to determine whether 5-fluorouracil and high dose folinic acid (HD-FUFA) would increase the event free and overall survival of patients with resectable Dukes B and C (AJCC/UICC Stage II and Stage III) colon carcinoma, and to assess the toxicity of the treatment and its impact on selected health-related quality-of-life indicators. Early results were published as a part of an international multicenter pooled analysis (IMPACT) in 1995. The purpose of this report is to update the survival data for patients enrolled in the trial and describe their reported perceptions of their own health and quality of life. The trial involved multiple treatment centers, with a centralized randomization between surgery alone and surgery with chemotherapy. The HD-FUFA regimen employed consisted of 5-fluorouracil (370 mg/m2) plus folinic acid (200 mg/m2) administered daily for 5 days every 4 weeks for 6 cycles. Patients' perceptions of their own health status were obtained by means of 3 self-administered questionnaires, which were completed by patients at the time of discharge from the treatment center and at 6 and 24 months after randomization. Overall, 888 patients with resected Dukes B2 and C colon carcinoma were enrolled in the trial. HD-FUFA significantly reduced mortality by 25% (95% confidence interval, 5-41%; P=0.02) and events by 31% (95% confidence interval, 14-45%; P < or = 0.001). Compliance with treatment was good; more than 80% of patients completed the planned therapy. Toxicity was mild, and oral mucositis was the main side effect. None of the health-related quality-of-life parameters investigated (emotional status, worry about the future, changes in social life, impact of the disease, follow-up, and global quality of life) seemed to be affected by the treatment to which patients were allocated. A positive trend in the evolution of patients' psychologic status was observed. Long term results of this SITAC study confirm that HD

  3. Correlation of central venous pressure with venous blood gas analysis parameters; a diagnostic study.

    Science.gov (United States)

    Rahim-Taleghani, Sima; Fatemi, Alireza; Alavi Moghaddam, Mostafa; Shojaee, Majid; Abushouk, Abdelrahman Ibrahim; Forouzanfar, Mohammad Mehdi; Baratloo, Alireza

    2017-03-01

    This study was conducted to assess the correlation between central venous pressure (CVP) and venous blood gas (VBG) analysis parameters, to facilitate management of severe sepsis and septic shock in emergency department. This diagnostic study was conducted from January 2014 until June 2015 in three major educational medical centers, Tehran, Iran. For patients selected with diagnosis of septic shock, peripheral blood sample was taken for testing the VBG parameters and the anion gap (AG) was calculated. All the mentioned parameters were measured again after infusion of 500 cc of normal saline 0.9% in about 1 h. Totally, 93 patients with septic shock were enrolled, 63 male and 30 female. The mean age was 72.53 ± 13.03 and the mean Shock Index (SI) before fluid therapy was 0.79 ± 0.30. AG and pH showed significant negative correlations with CVP, While HCO3 showed a significant positive correlation with CVP. These relations can be affected by the treatment modalities used in shock management such as fluid therapy, mechanical ventilation and vasopressor treatment. It is likely that there is a significant statistical correlation between VBG parameters and AG with CVP, but further research is needed before implementation of the results of this study.

  4. Hypoglycaemia secondary to labetalol infusion.

    Science.gov (United States)

    Immanni, Sudhir; Khan, Ehtesham Izhar; Staunton, Michael

    2011-05-01

    A 42-year-old multigravida with severe pre-eclampsia had an emergency caesarean section under spinal anaesthesia. Peri-operatively, her arterial pressure was controlled with oral methyldopa and an intravenous infusion of labetalol. Postoperatively, in the Intensive Care Unit, she had recurrent episodes of hypoglycaemia which required treatment with intravenous glucose. These episodes resolved when the labetalol infusion was stopped. Clinicians should be aware of the potential of labetalol to cause hypoglycaemia.

  5. Novel Pump Control Technology Accelerates Drug Delivery Onset in a Model of Pediatric Drug Infusion.

    Science.gov (United States)

    Parker, Michael J; Lovich, Mark A; Tsao, Amy C; Deng, Hao; Houle, Timothy; Peterfreund, Robert A

    2017-04-01

    Laboratory data suggest that newly initiated drug infusions reach steady-state delivery after a significant time lag. Depending on drug and carrier flow rates and the infusion system's common volume, lag times may exceed 20 or more minutes, especially in the neonatal/pediatric critical care environment. This study tested the hypothesis that a computer-executed algorithm controlling infusion pumps in a coordinated fashion predictably hastens the achievement of the intended steady-state drug delivery in a model of neonatal/pediatric drug infusion. We constructed an in vitro model of neonatal/pediatric drug infusions through a pediatric 4-Fr central venous catheter at total system flows of 2 mL/h or 12 mL/h, representing a clinically relevant infusion range. Methylene blue served as the model infused drug for quantitative analysis. A novel algorithm, based on Taylor Dispersion Theory of fluid flow through tubes and executed by a computer, generated flow patterns that controlled and coordinated drug and carrier delivery by syringe pumps. We measured the time to achieve the intended steady-state drug delivery by conventional initiation of the drug infusion ("turning on the drug pump") and by algorithm-controlled infusion initiation. At 2 mL/h total system flow, application of the algorithm reduced the time to achieve half of the intended drug delivery rate (T50) from 17 minutes [17, 18] to 3 minutes [3, 3] (median, interquartile range). At 12 mL/h total system flow, application of the algorithm reduced T50 from 6 minutes [6, 7] to 3 minutes [3, 3] The bootstrapped median difference is -14 (95% confidence interval [CI], -16 to -12, adjusted P=.00192) for 2 mL/h flow and -3 (95% CI, -4 to -3, adjusted P=.02061) for 12 mL/h flow. Compared with conventional initiation, the additional fluid required by the algorithm-directed infusion was 0.43 and 1.03 mL for the low- and high-infusion rates, respectively. The output of infusion pumps can be predictably controlled and

  6. Retrospective study on the application of reverse puncture of venous transfusion in clinical nursing

    Directory of Open Access Journals (Sweden)

    Xiao-lan HUANG

    2014-11-01

    Full Text Available As a conventional alternative of intravenous infusion, reverse puncture is a nursing method that can perform infusion relative to traditional consequent centripetal puncture technique.According to the literature review, the reverse puncture is not only to improve the distal venous utilization and to raise the success rate of the intravenous, but also reduce repeated puncture pain, to reduce medical expenses, to reduce nurse-patient disputes, this technology can timely solve puncture problems in emergency situation in clinical first line for nursing staff, as well as to regain people’s attention .It has clinical spread value.

  7. Cerebral venous thrombosis.

    Science.gov (United States)

    Ferro, José Manuel; Canhão, Patrícia; Aguiar de Sousa, Diana

    2016-12-01

    Cerebral venous thrombosis (CVT) has an incidence of 1.32/100,000/years in high-income countries, and higher in middle- and low-income countries. CVT is more frequent in infants and children young adults and females, especially during pregnancy/puerperium. CVT are now being diagnosed with increasing frequency because of the increased awareness and higher use of magnetic resonance imaging (MR) for investigating patients with acute and subacute headaches and new onset seizures. CVT rarely present as a stroke syndrome. Their most frequent presentations are isolated headache, intracranial hypertension syndrome, seizures, a lobar syndrome and encephalopathy. The confirmation of the diagnosis of CVT relies on the demonstration of thrombi in the cerebral veins and/or sinuses by MR/MR venography or veno CT. The more frequent risk factors/associated conditions for CVT are genetic prothrombotic conditions, antiphospholipid syndrome and other acquired prothrombotic diseases, including cancer, oral contraceptives, puerperium and pregnancy, infections and trauma. The prognosis of CVT is in general favorable, as acute death rate is below 5% and only 15% of the patients remain dependent or die. Treatment in the acute phase includes management of the associated condition, anticoagulation with either low molecular weight or unfractionated heparin, treatment of intracranial hypertension, prevention of recurrent seizures and headache relief. In patients in severe condition on admission or who deteriorate despite anticoagulation, local thrombolysis or thrombectomy is an option. Decompressive surgery is lifesaving in patients with large venous infarcts or hemorrhage with impending herniation. After the acute phase, patients should anticoagulated for a variable period of time, depending on their inherent thrombotic risk. CVT patients may experience recurrent seizures. Prophylaxis with anti-epileptic drugs is recommended after the first seizure, in those with hemispheric lesions. There

  8. Venous chest anatomy: clinical implications.

    Science.gov (United States)

    Chasen, M H; Charnsangavej, C

    1998-03-01

    This article provides a practical approach to the clinical implications and importance of understanding the collateral venous anatomy of the thorax. Routine radiography, conventional venography, computed tomography (CT), and magnetic resonance (MR) imaging studies provide correlative anatomic models for the demonstration of how interconnecting collateral vascular networks within the thorax maintain venous stability at all times. Five major systems comprise the collateral venous network of the thorax (Fig. 1). These include the paravertebral, azygos-hemiazygos, internal mammary, lateral thoracic, and anterior jugular venous systems (AJVS). The five systems are presented in the following sequence: (a) a brief introduction to the importance of catheter position and malposition in understanding access to the thoracic venous system, (b) the anatomy of the azygos-hemiazygos systems and their relationship with the paravertebral plexus, (c) the importance of the AJVS, (d) 'loop' concepts interconnecting the internal mammary and azygos-hemiazygos systems by means of the lateral thoracic and intercostal veins, and (e) the interconnecting venous networks on the thoracic side of the thoracoabdominal junction. Certain aspects of the venous anatomy of the thorax will not be discussed in this chapter and include (a) the intra-abdominal anastomoses between the superior and inferior vena cavae (IVC) via the internal mammary, lateral thoracic, and azygos-hemiazygos systems (beyond the scope of this article), (b) potential collateral vessels involving vertebral, parascapular, thyroidal, thymic, and other smaller veins that might anastomose with the major systems, and (c) anatomic variants and pitfalls that may mimic pathologic conditions (space limitations).

  9. Doppler ultrasound study and venous mapping in chronic venous insufficiency.

    Science.gov (United States)

    García Carriazo, M; Gómez de las Heras, C; Mármol Vázquez, P; Ramos Solís, M F

    2016-01-01

    Chronic venous insufficiency of the lower limbs is very prevalent. In recent decades, Doppler ultrasound has become the method of choice to study this condition, and it is considered essential when surgery is indicated. This article aims to establish a method for the examination, including venous mapping and preoperative marking. To this end, we review the venous anatomy of the lower limbs and the pathophysiology of chronic venous insufficiency and explain the basic hemodynamic concepts and the terminology required to elaborate a radiological report that will enable appropriate treatment planning and communication with other specialists. We briefly explain the CHIVA (the acronym for the French term "cure conservatrice et hémodynamique de l'insuffisance veineuse en ambulatoire"=conservative hemodynamic treatment for chronic venous insufficiency) strategy, a minimally invasive surgical strategy that aims to restore correct venous hemodynamics without resecting the saphenous vein. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

  10. Optimization of induction of mild therapeutic hypothermia with cold saline infusion: A laboratory experiment.

    Science.gov (United States)

    Fluher, Jure; Markota, Andrej; Stožer, Andraž; Sinkovič, Andreja

    2015-11-12

    Cold fluid infusions can be used to induce mild therapeutic hypothermia after cardiac arrest. Fluid temperature higher than 4°C can increase the volume of fluid needed, prolong the induction phase of hypothermia and thus contribute to complications. We performed a laboratory experiment with two objectives. The first objective was to analyze the effect of wrapping fluid bags in ice packs on the increase of fluid temperature with time in bags exposed to ambient conditions. The second objective was to quantify the effect of insulating venous tubing and adjusting flow rate on fluid temperature increase from bag to the level of an intravenous cannula during a simulated infusion. The temperature of fluid in bags wrapped in ice packs was significantly lower compared to controls at all time points during the 120 minutes observation. The temperature increase from the bag to the level of intravenous cannula was significantly lower for insulated tubing at all infusion rates (median temperature differences between bag and intravenous cannula were: 8.9, 4.8, 4.0, and 3.1°C, for non-insulated and 5.9, 3.05, 1.1, and 0.3°C, for insulated tubing, at infusion rates 10, 30, 60, and 100 mL/minute, respectively). The results from this study could potentially be used to decrease the volume of fluid infused when inducing mild hypothermia with an infusion of cold fluids.

  11. Optimization of induction of mild therapeutic hypothermia with cold saline infusion: A laboratory experiment

    Directory of Open Access Journals (Sweden)

    Jure Fluher

    2015-11-01

    Full Text Available Cold fluid infusions can be used to induce mild therapeutic hypothermia after cardiac arrest. Fluid temperature higher than 4°C can increase the volume of fluid needed, prolong the induction phase of hypothermia and thus contribute to complications. We performed a laboratory experiment with two objectives. The first objective was to analyze the effect of wrapping fluid bags in ice packs on the increase of fluid temperature with time in bags exposed to ambient conditions. The second objective was to quantify the effect of insulating venous tubing and adjusting flow rate on fluid temperature increase from bag to the level of an intravenous cannula during a simulated infusion. The temperature of fluid in bags wrapped in ice packs was significantly lower compared to controls at all time points during the 120 minutes observation. The temperature increase from the bag to the level of intravenous cannula was significantly lower for insulated tubing at all infusion rates (median temperature differences between bag and intravenous cannula were: 8.9, 4.8, 4.0, and 3.1°C, for non-insulated and 5.9, 3.05, 1.1, and 0.3°C, for insulated tubing, at infusion rates 10, 30, 60, and 100 mL/minute, respectively. The results from this study could potentially be used to decrease the volume of fluid infused when inducing mild hypothermia with an infusion of cold fluids.

  12. Central Venous Catheter (Central Line)

    Science.gov (United States)

    ... venous catheter (KATHeter), also known as a central line or CVC, is long, soft, thin, hollow tube ... into a large vein (blood vessel). A central line is much like an intravenous (IV) catheter that ...

  13. Clinical overview of venous thromboembolism

    African Journals Online (AJOL)

    circulation, causing either partial or complete obstruction of pulmonary blood flow (in 4–13% of ... Keywords:anticoagulants, deep vein thrombosis, DVT, embolus, NOAC, PE, pulmonary embolism, thromboprophylaxis, thrombus, venous thromboembolism ... Cigarette smoking, including passive smoking. Hypercoagulability ...

  14. Heritability of chronic venous disease

    OpenAIRE

    Fiebig, Andreas; Krusche, Petra; De Wolf, Andreas; Krawczak, Michael; Timm, Birgitt; Nikolaus, Susanna; Frings, Norbert; Schreiber, Stefan

    2010-01-01

    Varicose veins without skin changes have a prevalence of approximately 20% in Northern and Western Europe whereas advanced chronic venous insufficiency affects about 3% of the population. Genetic risk factors are thought to play an important role in the aetiology of both these chronic venous diseases (CVD). We evaluated the relative genetic and environmental impact upon CVD risk by estimating the heritability of the disease in 4,033 nuclear families, comprising 16,434 individuals from all ove...

  15. Human cadaver brain infusion model for neurosurgical training.

    Science.gov (United States)

    Olabe, Jon; Olabe, Javier; Sancho, Vidal

    2009-12-01

    Microneurosurgical technique and anatomical knowledge require extensive laboratory training before mastering these skills. There are diverse training models based on synthetic materials, anesthetized animals, cadaver animals, or human cadaver. Human cadaver models are especially beneficial because they are the closest to live surgery with the greatest disadvantage of lacking hemodynamic factors. We developed the "brain infusion model" to provide a simple but realistic training method minimizing animal use or needs for special facilities. Four human cadaveric brains donated for educational purposes were explanted at autopsy. Carotids and vertebral arteries were cannulated with plastic tubes and fixed with suture. Water was flushed through the tubings until the whole arterial vasculature was observed as clean. The cannulated specimens were fixed with formaldehyde. Tap water infusion at a flow rate of 10 L/h was infused through the arterial tubings controlled with a drip regulator filling the arterial tree and leaking into the interstitial and cisternal space. Multiple microneurosurgical procedures were performed by 4 trainees. Cisternal and vascular dissection was executed in a very realistic fashion. Bypass anastomosis was created as well as aneurysm simulation with venous pouches. Vessel and aneurysm clipping and rupture situations were emulated and solution techniques were trained. Standard microsurgical laboratories regularly have scarce opportunities for working with decapitated human cadaver heads but could have human brains readily available. The human brain infusion model presents a realistic microneurosurgical training method. It is inexpensive and easy to set up. Such simplicity provides the adequate environment for developing microsurgical techniques. Copyright 2009 Elsevier Inc. All rights reserved.

  16. Neonatal Venous Thromboembolism

    Directory of Open Access Journals (Sweden)

    Kristina M. Haley

    2017-06-01

    Full Text Available Neonates are the pediatric population at highest risk for development of venous thromboembolism (VTE, and the incidence of VTE in the neonatal population is increasing. This is especially true in the critically ill population. Several large studies indicate that the incidence of neonatal VTE is up almost threefold in the last two decades. Central lines, fluid fluctuations, sepsis, liver dysfunction, and inflammation contribute to the risk profile for VTE development in ill neonates. In addition, the neonatal hemostatic system is different from that of older children and adults. Platelet function, pro- and anticoagulant proteins concentrations, and fibrinolytic pathway protein concentrations are developmentally regulated and generate a hemostatic homeostasis that is unique to the neonatal time period. The clinical picture of a critically ill neonate combined with the physiologically distinct neonatal hemostatic system easily fulfills the criteria for Virchow’s triad with venous stasis, hypercoagulability, and endothelial injury and puts the neonatal patient at risk for VTE development. The presentation of a VTE in a neonate is similar to that of older children or adults and is dependent upon location of the VTE. Ultrasound is the most common diagnostic tool employed in identifying neonatal VTE, but relatively small vessels of the neonate as well as frequent low pulse pressure can make ultrasound less reliable. The diagnosis of a thrombophilic disorder in the neonatal population is unlikely to change management or outcome, and the role of thrombophilia testing in this population requires further study. Treatment of neonatal VTE is aimed at reducing VTE-associated morbidity and mortality. Recommendations for treating, though, cannot be extrapolated from guidelines for older children or adults. Neonates are at risk for bleeding complications, particularly younger neonates with more fragile intracranial vessels. Developmental alterations in the

  17. [Duplexsonography investigation in patients with venous ulcer].

    Science.gov (United States)

    Jeanneret-Gris, Christina

    2011-03-01

    Venous hypertension due to venous insufficiency causes venous ulcers. Duplexsonography is a widely accepted non invasive method to assess venous insufficiency with venous reflux measurements. Retrograde venous flow is defined as venous reflux. The testing of venous reflux is reliable if transvalvular pressure is sufficiently high and transvalvular flow velocity exceeds 30 cm/s. Reflux testing in the proximal leg veins (V. femoralis communis, V. femoralis, V. saphena magna) is done using a standardised Valsalva Manoeuvre (exspiration into a tube up to a pressure of 30 mmHg, pressure established within 0.5 seconds, pressure hold for 3 seconds). Distal leg vein testing (V. poplitea, V. tibialis posterior, V. saphena parva) is recommended with a two handed - compression distally to the tested veins. The most important parameter is venous reflux time, a cut off of > 2 seconds is recommended.

  18. Developmental venous anomaly (DVA); Developmental Venous Anomaly (DVA)

    Energy Technology Data Exchange (ETDEWEB)

    Zimmer, A.; Ahlhelm, F.; Viera, J.; Reith, W.; Schulte-Altedorneburg, G. [Universitaetsklinikum des Saarlandes, Klinik fuer Diagnostische und Interventionelle Neuroradiologie, Homburg/Saar (Germany); Hagen, T. [Radiologische Praxis, Augsburg (Germany)

    2007-10-15

    As congenital anatomic variants of venous drainage, developmental venous anomalies (DVA) represent up to 60% of all cerebral vascular malformations. The prior term ''venous angioma'' is a misnomer implicating an abnormal vascular structure with an increased bleeding risk. They are often found incidentally and are hardly ever symptomatic. Their morphologic characteristics are dilated vessels in the white matter, which converge on a greater collector vein, forming the typical caput medusae. They drain into the superficial or deep venous system. The frequent association with other, potentially bleeding-prone vascular malformations is clinically relevant, in particular cavernous angioma, which might require therapeutic action. Therefore, coincident vascular lesions need to be actively sought by appropriate additional imaging techniques. (orig.) [German] Als eine embryologische Variante der venoesen Drainage macht die so genannte ''developmental venous anomaly'' (DVA) etwa 60% aller zerebralen vaskulaeren Malformationen aus. Der vormalige Terminus ''venoeses Angiom'' sollte nicht mehr benutzt werden, da er abnormale Gefaessstrukturen mit einem erhoehten Blutungsrisiko impliziert. Die DVA werden oft inzidentell entdeckt und sind nur selten symptomatisch. Das typische Erscheinungsbild ist durch dilatierte, medusenhauptartig angeordnete venoese Marklagergefaesse gekennzeichnet, die in eine groessere Sammelvene drainieren. Der Abfluss erfolgt ueber das oberflaechliche oder tiefe Venensystem. Klinisch wichtig ist die haeufige Assoziation mit anderen zerebralen Gefaessmalformationen, insbesondere kavernoesen Angiomen, nach denen im Rahmen der Diagnostik explizit gesucht werden muss, da diese eine potenzielle Blutungsquelle darstellen und ein therapeutisches Vorgehen erfordern koennen. (orig.)

  19. Impact of noradrenaline infusion set on mean arterial pressure: a retrospective clinical study.

    Science.gov (United States)

    Genay, S; Décaudin, B; Ethgen, S; Barthélémy, C; Odou, P; Lebuffe, G

    2013-11-01

    Noradrenaline (NA) can be infused through various systems including single or double syringe pumps. The aim of this study was to define the best and most efficient infusion system in an emergency context. This was a retrospective clinical study based on the analysis of patients' hemodynamic data. Three infusion lines used presently in our postoperative ICU were compared through a retrospective clinical study: an NA syringe pump at 2mL/h and a saline carrier solution syringe pump at 8mL/h (infusion system 1- IS1) or 5mL/h (IS2), both connected to a very low dead-space volume set (V=0.046mL); IS3 with the same NA syringe at 2mL/h directly connected to the central venous catheter. Mean arterial pressure (MAP) was obtained from retrospective data analysis of ICU patients with postoperative septic shock criteria. Infusion systems were compared according to the time required to reach an MAP greater than 65mmHg after the onset of infusion. Data from 37 patients was analysed. The MAP objective was attained in 14:00 minutes (9:20 - 26:10, n=15) with IS1, in 19:10 minutes (12:20 - 27:20, n=13) with IS2 and in 34:10 minutes (23:10 - 62:30, n=9) with IS3 (P=0.00032). The use of a double syringe pump system associated with a very low dead-space volume infusion set appears to be the most appropriate system for NA infusion. Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

  20. Venous chest anatomy: clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    Chasen, M.H.; Charnsangavej, C. [Department of Diagnostic Imaging, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030 (United States)

    1998-03-01

    This article provides a practical approach to the clinical implications and importance of understanding the collateral venous anatomy of the thorax. Routine radiography, conventional venography, computed tomography (CT), and magnetic resonance (MR) imaging studies provide correlative anatomic models for the demonstration of how interconnecting collateral vascular networks within the thorax maintain venous stability at all times. Five major systems comprise the collateral venous network of the thorax ( Fig. 1 ). These include the paravertebral, azygos-hemiazygos, internal mammary, lateral thoracic, and anterior jugular venous systems (AJVS). The five systems are presented in the following sequence: (a) a brief introduction to the importance of catheter position and malposition in understanding access to the thoracic venous system, (b) the anatomy of the azygos-hemiazygos systems and their relationship with the paravertebral plexus, (c) the importance of the AJVS, (d) 'loop' concepts interconnecting the internal mammary and azygos-hemiazygos systems by means of the lateral thoracic and intercostal veins, and (e) the interconnecting venous networks on the thoracic side of the thoracoabdominal junction. Certain aspects of the venous anatomy of the thorax will not be discussed in this chapter and include (a) the intra-abdominal anastomoses between the superior and inferior vena cavae (IVC) via the internal mammary, lateral thoracic, and azygos-hemiazygos systems (beyond the scope of this article), (b) potential collateral vessels involving vertebral, parascapular, thyroidal, thymic, and other smaller veins that might anastomose with the major systems, and (c) anatomic variants and pitfalls that may mimic pathologic conditions (space limitations). (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  1. Contemporary diagnosis of venous malformation

    Directory of Open Access Journals (Sweden)

    Lee BB

    2013-11-01

    Full Text Available BB Lee,1 I Baumgartner21Department of Surgery, George Washington University, Washington, DC, USA; 2Swiss Cardiovascular Center, University Hospital Bern, Bern, SwitzerlandAbstract: Venous malformation is a congenital vascular malformation resulting from defective development during various stages of embryogenesis and selectively affecting the venous system. Depending on the embryologic stage when the developmental arrest occurred, the clinical presentation of venous malformation is extremely variable in location, extent, severity, natural progression, and hemodynamic impact. Extratruncular lesions occur in the earlier stages of embryonic life, and retain characteristics unique to mesenchymal cells (angioblasts, growing and proliferating when stimulated internally (eg, by menarche, pregnancy, and hormones or externally (eg, by trauma or surgery. These lesions also have a significant hemodynamic impact on the venous system involved, in addition to the risk of localized intravascular coagulopathy. However, truncal lesions, as defective developments along the late stage, no longer carry the risk of proliferation and recurrence due to lack of mesenchymal characteristics. Although, they often have serious hemodynamic consequences due to direct involvement of the main vein trunk. Therefore, a thorough clinical history and careful physical examination should be followed by an appropriate combination of noninvasive and less invasive tests (eg, Doppler ultrasonography, magnetic resonance imaging, computed tomography to confirm the clinical impression as well as to define the extent and severity of the venous malformation. Invasive tests, eg, phlebography or angiography, are seldom needed for the diagnosis per se. Additional evaluation for coagulation abnormalities, eg, D-dimer and fibrinogen levels, is generally recommended, especially for the treatment of surgery and endovascular candidates with extensive lesions to assess the localized intravascular