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Sample records for 5-fluorouracil combination chemotherapy

  1. Phase I Dose-Escalation Study of Docetaxel, Cisplatin, and 5-Fluorouracil Combination Chemotherapy in Patients With Advanced Esophageal Carcinoma

    PubMed Central

    Satomura, Hitoshi; Nakajima, Masanobu; Sasaki, Kinro; Yamaguchi, Satoru; Domeki, Yasushi; Takahashi, Masakazu; Muroi, Hiroto; Kubo, Tsukasa; Kikuchi, Maiko; Otomo, Haruka; Ihara, Keisuke; Kato, Hiroyuki

    2015-01-01

    A dose-escalation study of docetaxel (DOC), cisplatin (CDDP), and 5-fluorouracil (5-FU; DCF combination regimen) was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLT) in advanced esophageal carcinoma. Eighteen patients with esophageal carcinoma were enrolled and received DCF combination therapy at different dose levels. DLTs included febrile neutropenia and oral mucositis. DLT occurred in 2 out of 6 patients at level 2 and 3. The study proceeded to level 4, according to the protocol. The level 4 dose was defined as the MTD and the level 3 dose was defined as the RD. The RD for DCF combination chemotherapy for advanced esophageal carcinoma in the present study was 70 mg/m2 DOC plus 70 mg/m2 CDDP on day 1 plus 700 mg/m2 5-FU on days 1–5 at 4-week intervals. This regimen was tolerable and highly active. A phase II study has been started. PMID:26414837

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

    PubMed

    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. PMID:23485475

  3. Docetaxel in combination with 5-fluorouracil in patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy: a phase I, dose-finding study.

    PubMed

    Lortholary, A; Maillard, P; Delva, R; Boisdron-Celle, M; Perard, D; Vernillet, L; Besenval, M; Gamelin, E

    2000-09-01

    This phase I study evaluated the maximum tolerated dose, dose-limiting toxicity and recommended dose of docetaxel in combination with 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy. 32 patients received docetaxel at 60, 75, 85 or 100 mg/m(2) by 1-h intravenous (i.v.) infusion, followed, after a 1-h interval, by 5-FU at 250, 350, 500 or 750 mg/m(2)/day by continuous infusion over 5 days every 3 weeks. Dose-limiting stomatitis defined the maximum tolerated dose at a docetaxel dose of 100 mg/m(2) with 5-FU 750 mg/m(2)/day. None of 5 patients treated at the previous dose level (docetaxel 85 mg/m(2) with 5-FU 750 mg/m(2)/day) had a dose-limiting toxicity in the first cycle, and this was, therefore, considered the recommended dose. The combination was generally well tolerated. Grade 4 neutropenia was common (29 patients; 91%), but no patient experienced febrile neutropenia of duration >3 days requiring i.v. antibiotics. An objective response was achieved by 18 patients overall (56%), and in 4 out of 5 patients treated with the determined recommended dose. No pharmacokinetic interaction between docetaxel and 5-fluorouracil was apparent. The activity of docetaxel 85 mg/m(2) with 5-fluorouracil 750 mg/m(2)/day will be explored more extensively in phase II studies of patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy. PMID:10974625

  4. Combination adjuvant chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin after liver transplantation for hepatocellular carcinoma: a preliminary open-label study.

    PubMed

    Zhang, Qing; Chen, Hong; Li, Qin; Zang, Yunjin; Chen, Xinguo; Zou, Weilong; Wang, Letian; Shen, Zhong-Yang

    2011-12-01

    The purpose of this study was to evaluate the efficacy of postoperative adjuvant chemotherapy with FOLFOX regimen on the outcome after LT for HCC patients who did not meet the Milan criteria. Ninety-five consecutive HCC patients with liver cirrhosis undergoing LT were enrolled. Fifty-eight who did not meet the Milan criteria were randomized to open-label treatment with or without adjuvant chemotherapy after LT (n = 29/group). The FOLFOX chemotherapy protocol comprised 3-week cycles of oxaliplatin 100 mg/m(2) on day 1, leucovorin (calcium folinate, CF) 200 mg/m(2) on day 1 followed by 3-day, and 5-fluorouracil (5-FU) 2000 mg/m(2) as a 48-h continuous infusion, for up to six courses in the 1st year after transplantation. Median survival was extended by 4.57 months by combination chemotherapy. The 1- and 3-year survival rates were 89.7% and 79.3% with chemotherapy versus 69.0% and 62.1% without chemotherapy. The cumulative 1-year survival was significantly increased by chemotherapy (log-rank test, P = 0.043). The 6-month tumor-free survival rate was 24.1% higher with chemotherapy than without. The recurrence rate after LT was significantly different between the two groups at 6 months (P = 0.036), but not at 3 years (P = 0.102). The chemotherapy regimen was generally well tolerated. Post-LT adjuvant chemotherapy with oxaliplatin/5-FU/CF could not prevent tumor recurrence post-LT but may contribute to improve the survival of HCC patients who do not meet the Milan criteria. These results should be verified in a larger sample with a longer follow-up period. PMID:21809025

  5. Acute hyperammonemic encephalopathy after 5-fluorouracil based chemotherapy

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed Central

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

    2002-01-01

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

  8. Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats.

    PubMed

    Fan, Chiaming; Georgiou, Kristen R; McKinnon, Ross A; Keefe, Dorothy M K; Howe, Peter R C; Xian, Cory J

    2016-05-01

    The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation. PMID:26056019

  9. Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil

    PubMed Central

    Ueshima, Kazuomi; Kudo, Masatoshi; Tanaka, Masatoshi; Kumada, Takashi; Chung, Hobyung; Hagiwara, Satoru; Inoue, Tatsuo; Yada, Norihisa; Kitai, Satoshi

    2015-01-01

    We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m2, on days 1 and 8) and 5-FU (170-330 mg/m2, continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m2 of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m2 are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing. PMID:26734580

  10. Oxidative Stress-Related Genetic Polymorphisms Are Associated with the Prognosis of Metastatic Gastric Cancer Patients Treated with Epirubicin, Oxaliplatin and 5-Fluorouracil Combination Chemotherapy

    PubMed Central

    Zhao, Xiaoying; Qiu, Lixin; Liu, Xin; Liu, Rujiao; Guo, Weijian; He, Guang; Li, Jin; Zhu, Xiaodong

    2014-01-01

    Background Oxidative stress genes are related to cancer development and treatment response. In this study, we aimed to determine the predictive and prognostic roles of oxidative stress-related genetic polymorphisms in metastatic gastric cancer (MGC) patients treated with chemotherapy. Methods In this retrospective study, we genotyped nine oxidative stress-related single nucleotide polymorphisms (SNPs) in NQO1, SOD2, SOD3, PON1, GSTP1, GSTT1, and NOS3 (rs1800566, rs10517, rs4880, rs1799895, rs662, rs854560, rs1695, rs2266637, rs1799983, respectively) in 108 consecutive MGC patients treated with epirubicin, oxaliplatin, and 5-fluorouracil (EOF) regimen as the first-line chemotherapy and analyzed the association between the genotypes and the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results We found that, in addition to a lower pathological grade (p = 0.017), NQO1 rs1800566 CT/TT genotype was an independent predictive factor of poor PFS (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.23–3.16; p = 0.005). PON1 rs662 AA/AG genotype was significantly associated with poor OS (HR = 1.95, 95% CI = 1.07–3.54; p = 0.029). No associations were detected between the nine SNPs and DCR. Conclusions NQO1 rs1800566 is an independent predictive factor of PFS for MGC patients treated with EOF chemotherapy, and PON1 rs662 is a noteworthy prognostic factor of OS. Information on oxidative stress-related genetic variants may facilitate optimization of individualized chemotherapy in clinical practice. PMID:25545243

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

    PubMed

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

    2014-05-14

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

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

    PubMed Central

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

    2014-01-01

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

  13. 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

    SciTech Connect

    Prestwich, Robin J.; Oeksuez, Didem Colpan; Dyker, Karen; Coyle, Catherine; Sen, Mehmet

    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

  14. Combined Chemotherapy with Mitomycin C, Folinic Acid, and 5-Fluorouracil (MiFoFU) as Salvage Treatment for Patients with Liver Metastases from Breast Cancer — a Retrospective Analysis

    PubMed Central

    Eichbaum, Michael H.R.; Gast, Anne-Sybil; Bruckner, Thomas; Schneeweiss, Andreas; Sohn, Christof

    2008-01-01

    Summary Background The aim of this study was to analyze the activity and tolerability of a combined chemotherapy with mitomycin C, folinic acid, and 5-fluorouracil (MiFoFU) in patients with hepatic metastases from breast cancer, and in particular in patients with impaired liver function. Patients and Methods We retrospectively studied the charts of 44 patients who were treated with a MiFoFU combination therapy because of progressive metastatic breast cancer. Predominant site of metastases was the liver. Primary endpoints were response and time to progression (TTP); secondary endpoints were overall survival (OS) and tolerability. Results Median age prior to treatment was 59 years. A median of 6 treatment cycles were administered per patient. Clinical benefit rate amounted to 64%. A mean TTP of 9 months and a mean OS of 14 months were found. Main clinical signs of nonhematological toxicity were stomatitis, nausea, and diarrhea. Grade III/IV hematotoxicity was seen in only 9 patients. 16 patients showed clinical signs of liver dysfunction. A clinical benefit could be achieved in 8 of these patients. Conclusion MiFoFU combination chemotherapy is a well-tolerated treatment alternative in the palliative therapy of patients with liver metastases from breast cancer. Particularly in patients with hepatic dysfunction, this regimen seems to represent a helpful treatment option. PMID:21076607

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

    PubMed

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

    2009-12-01

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

  16. Chemotherapy related encephalopathy in a patient with Stage IV cervical carcinoma treated with cisplatin and 5-fluorouracil: a case report

    PubMed Central

    Fernando, Indrajit N; Hussain, Syed A; Yates, David A

    2009-01-01

    Introduction Chemotherapy related encephalopathy is commonly reported with certain forms of chemotherapy but few reports note an association with low dose 5-Fluorouracil. Case presentation A 57-year-old Caucasian lady received her first cycle of Cisplatin and 5-Fluorouracil for palliative treatment of cervical carcinoma, and presented several days later with signs of encephalopathy. Several causes were eliminated, and encephalopathy related to 5-Fluorouracil was thought to be the most likely cause. Magnetic Resonance Imaging of the head revealed changes related to the chemotherapy received. Symptoms resolved completely within three days of presentation. Conclusion Encephalopathy from low dose 5-Fluorouracil is not well documented in the literature. Fluid rehydration and supportive treatment is required. Signs and symptoms resolved completely with no residual effects on follow up. PMID:19830079

  17. Metronomic chemotherapy with 5-fluorouracil and cisplatin for inoperable malignant bowel obstruction because of peritoneal dissemination from gastric cancer

    PubMed Central

    Yang, S.; Li, S.; Yu, H.; Li, S.; Liu, W.; Liu, X.; Ma, H.

    2016-01-01

    Background Gastric cancer is the 2nd leading cause of cancer death worldwide. Malignant bowel obstruction (mbo) is a common complication in advanced gastric cancer because of peritoneal dissemination. A multicentre prospective study reported that patients with peritoneal dissemination of gastric origin survive for a median of 3.1 months. The aim of the present study was therefore to evaluate the efficacy and safety of metronomic combination chemotherapy with 5-fluorouracil and cisplatin in inoperable mbo from peritoneal dissemination in gastric cancer. Methods Gastric cancer patients diagnosed with inoperable mbo because of peritoneal dissemination were treated with infusional 5-fluorouracil 300 mg/m2 daily on days 1–5 and 8–12, and cisplatin 5 mg/m2 daily on days 1–4 and 8–11 every 3 weeks. The primary endpoint was symptom control (remission of obstruction); the secondary endpoint was symptom control time and survival; the tertiary endpoint was adverse effects. Results Between January 2013 and December 2014, 26 patients received the study treatment. Before treatment, 18 patients (69.2%) were nil per os, and 8 (30.8%) could consume liquids. After a mean of 3.3 cycles of the study treatment, just 4 patients (15.4%) was still nil per os. Of the remaining 22 patients, 3 (11.5%) could consume liquids, 7 (26.9%) could consume soft solids, and 12 (46.2%) ate a full diet. The improved ability to eat was statistically significant (p < 0.0001). Median duration of remission from mbo was 105 days. Median survival was 182 days. The 3-month survival rate was 69.2%, and the 6-month survival rate was 53.8%. Treatment was well tolerated, with grade iii toxicities consisting of thrombocytopenia in 1 patient (3.84%) and mucositis in 2 patients (7.7%). No abnormalities in serum creatinine were observed. Conclusions Metronomic combination chemotherapy with 5-fluorouracil and cisplatin is well tolerated and shows activity in inoperable mbo because of peritoneal dissemination in

  18. Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: The French SFRO-FFCD 97-04 Phase II trial

    SciTech Connect

    Mornex, Francoise . E-mail: francoise.mornex@chu-lyon.fr; Girard, Nicolas; Scoazec, Jean-Yves; Bossard, Nadine; Ychou, Marc; Smith, Denis; Seitz, Jean-Francois; Valette, Pierre-Jean; Roy, Pascal; Rouanet, Philippe; Ducreux, Michel; Partensky, Christian

    2006-08-01

    Purpose More than 80% of patients who undergo a potentially curative resection for pancreatic cancer develop local or distant recurrence. Neoadjuvant chemoradiotherapy might offer potential benefits regarding local and systemic control and survival. This multi-institutional Phase II trial explored the feasibility of preoperative chemoradiation in this situation. Methods and Materials Treatment consisted of concurrent radiotherapy (50 Gy within 5 weeks), and chemotherapy with 5-fluorouracil (300 mg/m{sup 2}/day, 5 days/week, 5 consecutive weeks) and cisplatin (20 mg/m{sup 2}/day, Days 1-5 and 29-33), followed by surgical resection of the pancreatic tumor in patients without progression. Results A total of 41 patients were enrolled. Of these, 38 (93%) received {>=}47 Gy; 30 patients (73%) received {>=}75% of the prescribed doses of chemotherapy. Surgical resection was performed in 26 patients (63%). Because of local or metastatic progression, 5 patients (12%) did not undergo surgery and 10 underwent surgery without resection of the pancreatic tumor. Operative mortality was 2.8%. Among 40 evaluable patients, 27 were successfully treated (67.5%; 95% CI, 50.9-81.4%). Conclusions Pancreatic cancer is chemo-radiosensitive. The proposed pre-operative scheme is feasible, does not prevent successful surgery, and must be tested on a Phase III setting. Yet, the large proportion of tumor progression during and after chemoradiation justifies the use of more efficient drugs such as Gemcitabine, and optimized radiotherapy including new techniques such as intensity-modulated radiation therapy.

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

    PubMed

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

    1993-06-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2004-12-01

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

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

    PubMed

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

    2012-06-01

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

  3. Concurrent Cyclophosphamide, Methotrexate, and 5-Fluorouracil Chemotherapy and Radiotherapy for Early Breast Carcinoma

    SciTech Connect

    Livi, Lorenzo Saieva, Calogero; Borghesi, Simona; Paoletti, Lisa; Meattini, Icro; Rampini, Andrea; Petrucci, Alessia; Scoccianti, Silvia; Paiar, Fabiola; Cataliotti, Luigi; Leonulli, Barbara Grilli; Bianchi, Simonetta; Biti, Gian Paolo

    2008-07-01

    Purpose: The optimal sequencing of adjuvant chemotherapy (CT) and radiation therapy (RT) in patients with early-stage breast cancer remains unclear. Patients and Methods: We retrospectively compared 485 patients treated with conservative breast surgery and postoperative whole-breast RT and six courses of CMF (cyclophosphamide 600 mg/m{sup 2}, methotrexate 40 mg/m{sup 2}, and 5-fluorouracil 600 mg/m{sup 2}) with 300 patients who received postoperative CMF only and with 509 patients treated with postoperative whole-breast RT only. The mean radiation dose delivered was 50 Gy (range, 46-52 Gy) with standard fractionation. The boost dose was 6-16 Gy according to resection margins and at the discretion of the radiation oncologist. Acute and late RT toxicity were scored using respectively the Radiation Therapy Oncology Group and the Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scale. Results: A slightly higher Grade 2 acute skin toxicity was recorded in the concurrent group (21.2% vs. 11.2% of the RT only group, p < 0.0001). RT was interrupted more frequently in the CMF/RT group respective to the RT group (8.5% vs. 4.1%; p = 0.006). There was no difference in late toxicity between the two groups. All patients in the concurrent group successfully received the planned dose of RT and CT. Local recurrence rate was 7.6% in CT/RT group and 9.8% in RT group; this difference was not statistically significant at univariate analysis (log-rank test p = 0.98). However, at multivariate analysis adjusted also for pathological tumor, pathological nodes, and age, the CT/RT group showed a statistically lower rate of local recurrence (p = 0.04). Conclusions: Whole-breast RT and concurrent CMF are a safe adjuvant treatment in terms of toxicity.

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

    PubMed Central

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

    1983-01-01

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

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

    PubMed

    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. PMID:2234455

  6. Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1)

    PubMed Central

    2012-01-01

    Background Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer. Methods Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0) and 30 mg/m2 (DL −1), plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm. Results Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50%) showed complete pathologic regression. Conclusions A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week. Trial registration number NCT01108042 (ClinicalTrials.gov Identifier) PMID:23083061

  7. Phase II trial of biweekly docetaxel, cisplatin, and 5-fluorouracil chemotherapy for advanced esophageal squamous cell carcinoma.

    PubMed

    Tanaka, Yoshihiro; Yoshida, Kazuhiro; Yamada, Atsuko; Tanahashi, Toshiyuki; Okumura, Naoki; Matsuhashi, Nobuhisa; Yamaguchi, Kazuya; Miyazaki, Tatsuhiko

    2016-06-01

    The prognosis of esophageal cancer patients is still unsatisfactory. Although a docetaxel, cisplatin, and 5-Fu (DCF) regimen has been reported, it is often difficult to accomplish because of severe toxicity. Therefore, we developed a new biweekly DCF (Bi-DCF) regimen and previously reported the recommended dose in a phase I dose-escalation study. We then performed a phase II study of Bi-DCF for advanced esophageal squamous cell carcinoma (SCC). Patients with clinical stage II/III were eligible. Patients received 2 courses of chemotherapy: docetaxel 35 mg/m(2) with cisplatin 40 mg/m(2) on days 1 and 15 and 400 mg/m(2) 5-fluorouracil on days 1-5 and 15-19 every 4 weeks. After completion of the chemotherapy, patients received esophagectomy. The primary endpoint was the completion rate of protocol treatment. Thirty-two patients were enrolled. The completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery) was 100 %. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (31.3 %). No treatment-related death was observed, and the incidence of operative morbidity was tolerable. The overall response rate after the chemotherapy was 90.3 %. This Bi-DCF regimen was well tolerated and highly active. This trial was registered with the University Hospital Medical Information Network (No. UMIN 000014625). PMID:26896963

  8. Neutropenia predicts better prognosis in patients with metastatic gastric cancer on a combined epirubicin, oxaliplatin and 5-fluorouracil regimen

    PubMed Central

    Zhao, Xiaoying; Peng, Wei; Sun, Si; Cao, Jun; Ji, Dongmei; Wang, Chenchen; Guo, Weijian; Li, Jin; Yin, Jiliang; Zhu, Xiaodong

    2015-01-01

    Chemotherapy-induced neutropenia (CIN) reportedly indicated better prognosis for some cancers. We retrospectively analyzed 150 evaluable metastatic gastric cancer (MGC) patients who had received first-line EOF5 (combination regimen of epirubicin, oxaliplatin and 5-day continuous infusion of 5-fluorouracil) treatment. We divided patients into three groups according to the worst grade of CIN: absent group (grade 0), moderate group (grade 1–2) and severe group (grade 3–4). Multivariate analyses of overall survival (OS) proved moderate and severe CIN were important prognostic factors whether regarding CIN as a time-varying covariate (TVC) or not. Compared with absent CIN, hazard ratio (HR) for moderate and severe CIN were 0.31 (95% confidential interval (CI): 0.17–0.55; P < 0.001) and 0.36 (95% CI: 0.20–0.64; P = 0.001) respectively with TVC; and were 0.31 (95% CI: 0.17–0.56; P < 0.001) and 0.34 (95% CI: 0.19–0.61; P < 0.001) respectively without TVC. In progression-free survival (PFS) analyses, moderate and severe CIN showed similar results. In the landmark group (n = 122 patients) analyses with TVC, moderate and severe CIN remained prognostic factors for PFS, while only moderate CIN was prognostic factor for OS. CIN predicted longer OS and PFS in MGC patients treated with first-line EOF5 chemotherapy. PMID:26528696

  9. Combined radiation therapy, mitomycin C, and 5-fluorouracil for locally recurrent rectal carcinoma: results of a pilot study.

    PubMed

    Wong, C S; Cummings, B J; Keane, T J; Dobrowsky, W; O'Sullivan, B; Catton, C N

    1991-10-01

    Twenty-two patients underwent combined radiation therapy (XRT), mitomycin C (MMC), and 5-fluorouracil (5FU) for rectal carcinoma, locally recurrent following either abdominoperineal or anterior resections. All patients presented with symptomatic unresectable pelvic cancer. The protocol XRT doses were 45-50 Gy/20/4-6 weeks. Chemotherapy consisted of MMC 10 mg/m2 on day 1, and 5FU 15 mg/kg/day on days 1, 2, and 3 of XRT, both given by intravenous bolus injection. Only 2 of 22 patients remained NED at 5 years following treatment. All but four patients eventually experienced progression of pelvic disease. Ten of 22 patients were unable to complete the treatment protocol because of excessive acute hematological and gastrointestinal toxicity. Five patients developed neutropenic sepsis, one of whom died. Combined XRT, MMC, and 5FU as used in this study had no apparent advantage over XRT alone in terms of pelvic disease or survival, and produced significant toxicity. PMID:1938526

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

    PubMed Central

    Duke, Roseline; Ikpeme, Anthonia

    2015-01-01

    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. PMID:26819790

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

    PubMed

    Duke, Roseline; Ikpeme, Anthonia

    2015-01-01

    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. PMID:26819790

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

    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. PMID:20863677

  15. Inoperable nonmetastatic squamous cell carcinoma of the esophagus managed by concomitant chemotherapy (5-fluorouracil and cisplatin) and radiation therapy

    SciTech Connect

    Seitz, J.F.; Giovannini, M.; Padaut-Cesana, J.; Fuentes, P.; Giudicelli, R.; Gauthier, A.P.; Carcassonne, Y. )

    1990-07-15

    Thirty-five patients with nonmetastatic squamous cell carcinoma of the esophagus were treated with chemotherapy (5-fluorouracil, cisplatin) and concomitant split-course radiation therapy. All of the patients presented with dysphagia. Treatment consisted of two courses of chemotherapy with 5-FU (1 g/m2/day in continuous infusion for 5 days (days 1 to 5 and days 29 to 33) ) and cisplatin (70 mg/m2 intravenous bolus at days 2 and 30). Radiation therapy was concomitant in two courses delivering 20 Gy in 5 days (days 1 to 5 and days 29 to 33). On the first day of treatment, endoscopic peroral dilation or Nd-YAG laser therapy was usually carried out. At the end of the treatment, all of the patients were capable of oral nutrition. Histoendoscopic confirmation was made 8 weeks after the beginning of the therapy. Twenty-five of the 35 patients had a complete response with negative biopsy findings. There was only one serious complication (fatal myelosuppression) in the only patient who received more than two courses of chemotherapy. Sixteen patients died and 19 were still alive at 3 to 42 months after the beginning of treatment. Overall median survival for the 35 patients is 17 months. Actuarial survival was 55 +/- 18% at 1 year and 41 +/- 21% at 2 years. The median survival of the Stage I and II patients is 28 months. These results confirm that concomitant chemoradiotherapy is capable of producing a very high histoendoscopic complete response rate and improved 1-year and 2-year survival. The use of concentrated split-course radiotherapy enabled the authors to reduce the total length of the treatment to two periods of 5 days, with results that are similar to previous studies using classic radiotherapy for a 5-week to 7-week period.

  16. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy.

    PubMed

    Paré, L; Marcuello, E; Altés, A; del Río, E; Sedano, L; Salazar, J; Cortés, A; Barnadas, A; Baiget, M

    2008-10-01

    To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments. PMID:18797464

  17. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy

    PubMed Central

    Paré, L; Marcuello, E; Altés, A; Río, E del; Sedano, L; Salazar, J; Cortés, A; Barnadas, A; Baiget, M

    2008-01-01

    To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments. PMID:18797464

  18. Relationship between antitumor effect and metabolites of 5-fluorouracil in combination treatment with 5-fluorouracil and guanosine in ascites Sarcoma 180 tumor system

    SciTech Connect

    Iigo, M.; Kuretani, K.; Hoshi, A.

    1983-12-01

    The antitumor activity of (6-14C)5-fluorouracil ((6-14C)FUra) against ascites Sarcoma 180 was significantly enhanced by coadministration of guanosine, and slightly by adenosine, but not by cytidine or uridine. In advanced ascites Sarcoma 180, guanosine also enhanced the action of FUra, but adenosine, uridine, and cytidine did not. The potentiation of antitumor activity by guanosine was reversed by addition of cytidine. The antitumor activity of FUra was significantly potentiated when guanosine was administered either 0 to 15 min before or 5 min after FUra. Changes in metabolites of FUra after potentiation by guanosine were investigated. The potentiation of antitumor activity of FUra by guanosine was considered to be due to an increase in incorporation of FUra into FUra-nucleotides and RNA in the tumor cells.

  19. Recurrence 11 years after complete response to gemcitabine, 5-Fluorouracil, and Cisplatin chemotherapy followed by radiotherapy in a patient with advanced pancreatic cancer: a case report.

    PubMed

    Uchihara, Tomoyuki; Yamashita, Yo-Ichi; Hualin, Wang; Takeishi, Kazuki; Itoh, Shinji; Harimoto, Norihumi; Yoshizumi, Tomoharu; Aishima, Shinichi; Shirabe, Ken; Baba, Hideo; Maehara, Yoshihiko

    2015-05-01

    A 63-year-old man diagnosed with locally advanced pancreatic ductal adenocarcinoma (PDAC; stage IIa) was treated with chemotherapy (gemcitabine, 5-fluorouracil and cisplatin) followed by radiotherapy. He had complete response by imaging and relapse-free survival for 11 years. However, he subsequently presented with local tumor recurrence and underwent pancreaticoduodenectomy followed by chemotherapy; a partial response was achieved. As in liver metastasis of colonic cancer, complete response by imaging in PDAC may not mean pathological complete response. We would propose the importance of adjuvant surgery for a patient with PDAC with complete response by imaging after chemoradiotherapy. PMID:25964569

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

    PubMed

    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

  1. A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer

    PubMed Central

    Wan, Dante D.; Schellenberg, Devin; Lim, Howard J.

    2016-01-01

    Background There are no randomized phase III trials comparing 5-fluorouracil/mitomycin (FM) versus capecitabine/mitomycin (CM) in combination with radiotherapy (RT) for locally advanced anal cancer. We aim to evaluate the outcomes of patients treated with FM and CM at our institution. Methods Patients with stage I–III anal cancer who initiated curative-intent RT (50–54 Gy) with either CM or FM between 1998 and 2013 at the BC Cancer Agency were reviewed. Cox proportional models were used to analyze the impact of regimen on disease-free survival (DFS) and anal cancer-specific survival (ACSS). Results A total of 300 patients were included. Baseline characteristics were well-distributed between the groups. A total of 194 patients (64.6%) received FM and 106 (35.3%) CM. The 2-year DFS was 79.7% for CM [95% confidence intervals (95% CI), 71.1–88.3%] and 78.8% for FM (95% CI, 73–84.6%); 2-year ACSS was 88.7% for CM (95% CI, 81.8–95.5%) and 87.5% for FM (95% CI, 82.8–92.2%). On multivariate analysis, only HIV status, clinical T size (≤5 vs. >5 cm), and N status (negative vs. positive) remained as significant prognostic factors for both DFS and ACSS. Chemotherapy regimen (CM vs. FM) had no impact on either DFS [P=0.995; hazard ratios (HR) =0.99; 95% CI, 0.57–1.74] or ACSS (P=0.847; HR =0.93; 95% CI, 0.46–1.86). Conclusions In our population-based study, CM and FM concomitant with RT achieved similar DFS and ACSS. Substitution of capecitabine for infusional 5-FU may therefore be a reasonable option for patients and physicians who prefer to avoid the inconvenience and potential complications of a central infusional device. PMID:27563458

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

    PubMed

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

    1984-07-01

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

  3. Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC-FFCD 9710.

    PubMed

    Dahan, Laetitia; Bonnetain, Frank; Rougier, Philippe; Raoul, Jean-Luc; Gamelin, Eric; Etienne, Pierre-Luc; Cadiot, Guillaume; Mitry, Emmanuel; Smith, Denis; Cvitkovic, Frédérique; Coudert, Bruno; Ricard, Floriane; Bedenne, Laurent; Seitz, Jean-François

    2009-12-01

    The aim of this randomized multicenter phase III trial was to compare chemotherapy and interferon (IFN) in patients with metastatic carcinoid tumors. Patients with documented progressive, unresectable, metastatic carcinoid tumors were randomized between 5-fluorouracil plus streptozotocin (day 1-5) and recombinant IFN-alpha-2a (3 MU x 3 per week). Primary endpoint was progression-free survival (PFS). From February 1998 to June 2004, 64 patients were included. The two arms were well matched for median age, sex ratio, PS 0-1, previous chemotherapy, surgery, or radiotherapy. The median PFS for chemotherapy was 5.5 months versus 14.1 for IFN (hazard ratio=0.75 (0.41-1.36)). Overall survival (OS), tolerance, and effects on carcinoid symptoms were not significantly different. Despite a trend in favor of IFN, there was no difference in PFS and OS in advanced metastatic carcinoid tumors and therapeutic effect of both treatments was mild. PMID:19726540

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

    PubMed Central

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

    2015-01-01

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

  5. Novel Resveratrol and 5-Fluorouracil Coencapsulated in PEGylated Nanoliposomes Improve Chemotherapeutic Efficacy of Combination against Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Sethuraman, Swaminathan

    2014-01-01

    Increasing consumption of tobacco and alcohol has led to a steady increase in the incidence of head and neck cancers in Asia. The drawbacks associated with the existing chemotherapeutic and surgical interventions have necessitated the development of a safer alternative for therapy of head and neck cancers. In this study we have explored the synergistic therapeutic potential of a phytochemical and chemotherapeutic agent using PEGylated liposomes as a delivery vehicle. Resveratrol and 5-fluorouracil were successfully coencapsulated in a single PEGylated nanoliposome. The thermal analysis and the nuclear magnetic resonance results revealed that resveratrol localized near the glycerol backbone of the liposomal membrane while 5-fluorouracil localized closer to the phosphate moiety, which influenced the release kinetics of both drugs. The nanoformulation was tested in vitro on a head and neck cancer cell line NT8e and was found to exhibit a GI50 similar to that of free 5-fluorouracil. Further, gene expression studies showed that the combination of resveratrol and 5-fluorouracil exhibited different effects on different genes that may influence the net antagonistic effect. The coencapsulation of resveratrol and 5-fluorouracil in a liposomal nanocarrier improved the cytotoxicity in comparison with the free drug combination when tested in vitro. PMID:25114900

  6. The combination of 5-fluorouracil plus p53 pathway restoration is associated with depletion of p53-deficient or mutant p53-expressing putative colon cancer stem cells.

    PubMed

    Huang, Catherine; Zhang, Xiang M; Tavaluc, Raluca T; Hart, Lori S; Dicker, David T; Wang, Wenge; El-Deiry, Wafik S

    2009-11-01

    The cancer stem cell hypothesis suggests that rare populations of tumor-initiating cells may be resistant to therapy, lead to tumor relapse and contribute to poor prognosis for cancer patients. We previously demonstrated the feasibility of p53 pathway restoration in p53-deficient tumor cell populations using small molecules including ellipticine or its derivatives. We now establish a single cell p53-regulated green fluorescent protein (EGFP)-reporter system in human DLD1 colon tumor cells expressing mutant p53 protein. We use these p53-EGFP reporter DLD1 cells to investigate the status of p53 transcriptional activity in putative colon cancer stem cell populations following exposure to p53 pathway-restoring drugs and/or classical chemotherapy. We demonstrate induction of p53-specific EGFP reporter fluorescence following overexpression of p53 family member p73 by an Adenovirus vector. We further show that p53-reporter activity is induced in DLD1 putative cancer stem cell side-populations analyzed by their Hoechst dye efflux properties following treatment with the p53 pathway restoring drug ellipticine. Combination of ellipticine with the cytotoxic agent 5-fluorouracil resulted in increased cytotoxicity as compared to either agent alone and this was associated with depletion of putative cancer stem cell populations as compared with 5-FU alone treatment. Our results support the feasibility of therapeutic targeting of mutant p53 in putative cancer stem cells as well as the potential to enhance cytotoxic chemotherapy. PMID:19923910

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

    PubMed

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

    2014-11-01

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

  8. Phase I and II studies of the combination of recombinant human interferon-gamma and 5-fluorouracil in patients with advanced colorectal carcinoma.

    PubMed

    Ajani, J A; Rios, A A; Ende, K; Abbruzzese, J L; Edwards, C; Faintuch, J S; Saks, S; Gutterman, J U; Levin, B

    1989-04-01

    Based on the in vitro and in vivo data suggesting synergistic cytolysis by the combination of 5-fluorouracil and interferon-gamma against a variety of malignant cell lines including a human colon carcinoma cell line (HT-29), we initiated studies in patients with advanced colon or rectal carcinoma. Forty-six patients received 5-fluorouracil as an intravenous injection on days 1-5 and recombinant human interferon-gamma as an intramuscular injection on days 1-14, followed by a rest period of 14 days; courses were repeated every 28 days. In the phase I study, cohorts of two patients received a stepwise dose level increase to achieve the maximum tolerated dose (MTD), at which a total of six patients were studied. The dose levels constituting the MTD were as follows: 5-fluorouracil (500 g/m2/day) and recombinant gamma-interferon (0.5 mg/m2/day). Four patients achieved a partial response in the phase I study. In the phase II study, 30 patients received therapy at the MTD. Among 29 evaluable patients in the phase II study, two patients achieved a partial response. Common toxicities included malaise, fever, anorexia, nausea and vomiting, and diarrhea. Transient severe myelosuppression was common but did not result in significant morbidity. Our data suggest that the combination of 5-fluorouracil and recombinant gamma-interferon did not have the same antitumor effect in patients as it had in the preclinical experiments. PMID:2499663

  9. Effect of GSTP1 and ABCC4 gene polymorphisms on response and toxicity of cyclophosphamide-epirubicin-5-fluorouracil-based chemotherapy in Bangladeshi breast cancer patients.

    PubMed

    Islam, Md Siddiqul; Islam, Mohammad Safiqul; Parvin, Salma; Ahmed, Maizbah Uddin; Bin Sayeed, Muhammad Shahdaat; Uddin, Mir Muhammad Nasir; Hussain, Syed Md Akram; Hasnat, Abul

    2015-07-01

    The most important cytotoxic drug namely, cyclophosphamide used in breast cancer along with epirubicin and 5-fluorouracil, is transported by ABCC transporters and detoxified by glutathione S-transferases (GSTs). The activities of these enzymes and transporters may vary in different population due to the presence of genetic polymorphisms. This study was aimed to evaluate the effects of GSTP1rs1695 and ABCC4rs9561778 polymorphisms on the response and toxicities produced by chemotherapy used in the treatment of Bangladeshi breast cancer patients. A total of 200 and 56 patients with invasive breast cancers were recruited from different public and private hospitals of Bangladesh of which 117 patients received neoadjuvant chemotherapy to examine the response as well as the toxicity, and another 139 patients received adjuvant chemotherapy to evaluate only the toxicity. Genetic polymorphisms of the mentioned genes were detected by using Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR RFLP). Patients carrying AG and AG plus GG genotype of GSTP1rs1695 were more likely to have a good response, whereas no association of ABCC4rs9561778 was found with the chemotherapy response. Patients carrying GT and GT plus TT genotypes of ABCC4rs9561778 were found to be associated with anemia, neutropenia, leukopenia, and gastrointestinal toxicities when compared with GG genotype whereas no association was found with thrombocytopenia. GSTP1rs1695 was not associated with any type of toxicities investigated. Our result indicates that GSTP1rs1695 polymorphism was strongly associated with the response of chemotherapy, whereas ABCC4rs9561778 polymorphism was significantly related with chemotherapy-induced toxicities. PMID:25677905

  10. An individualized prognostic signature for gastric cancer patients treated with 5-Fluorouracil-based chemotherapy and distinct multi-omics characteristics of prognostic groups

    PubMed Central

    Li, Xiangyu; Cai, Hao; Zheng, Weicheng; Tong, Mengsha; Li, Hongdong; Ao, Lu; Li, Jing; Hong, Guini; Li, Mengyao; Guan, Qingzhou; Yang, Sheng; Yang, Da; Lin, Xu; Guo, Zheng

    2016-01-01

    5-Fluorouracil (5-FU)-based chemotherapy is currently the first-line treatment for gastric cancer. In this study, using gene expression profiles for a panel of cell lines with drug sensitivity data and two cohorts of patients, we extracted a signature consisting of two gene pairs (KCNE2 and API5, KCNE2 and PRPF3) whose within-sample relative expression orderings (REOs) could robustly predict prognoses of gastric cancer patients treated with 5-FU-based chemotherapy. This REOs-based signature was insensitive to experimental batch effects and could be directly applied to samples measured by different laboratories. Taking this unique advantage of the REOs-based signature, we classified gastric cancer samples of The Cancer Genome Atlas (TCGA) into two prognostic groups with distinct transcriptional characteristics, circumventing the usage of confounded TCGA survival data. We further showed that the two prognostic groups displayed distinct copy number, gene mutation and DNA methylation landscapes using the TCGA multi-omics data. The results provided hints for understanding molecular mechanisms determining prognoses of gastric cancer patients treated with 5-FU-based chemotherapy. PMID:26840027

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

    PubMed

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

    2004-02-01

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

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

    PubMed

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

    2013-09-01

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

  13. Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses.

    PubMed

    Harrop, Richard; Drury, Noel; Shingler, William; Chikoti, Priscilla; Redchenko, Irina; Carroll, Miles W; Kingsman, Susan M; Naylor, Stuart; Griffiths, Richard; Steven, Neil; Hawkins, Robert E

    2008-07-01

    Modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax) has been evaluated in an open label phase II study in metastatic colorectal cancer patients. The primary objective was to assess the safety and immunogenicity of TroVax injected before, during and after treatment with 5-fluorouracil, leukovorin and irinotecan. TroVax was administered to 19 patients with metastatic colorectal cancer. Twelve patients had blood samples taken following each of the six injections and were considered to be evaluable for assessment of immunological responses. Both antibody and cellular responses specific for the tumor antigen 5T4 and the viral vector MVA were monitored throughout the study. Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity. Of the 12 patients who were evaluable for assessment of immune responses, ten mounted 5T4-specific antibody responses with titers ranging from 10 to > 5,000. IFNgamma ELISPOT responses specific for 5T4 were detected in 11 patients with frequencies exceeding one in 1,000 PBMCs in five patients. Eight patients presented with elevated circulating CEA concentrations, six of whom showed decreases in excess of 50% during chemotherapy and four had CEA levels which remained stable for > 1 month following completion of chemotherapy. Of the 19 intention to treat (ITT) patients, one had a CR, six had PRs and five had SD. Potent 5T4-specific cellular and/or humoral immune responses were induced in all 12 evaluable patients and were detectable in most patients during the period in which chemotherapy was administered. These data demonstrate that TroVax can be layered on top of chemotherapy regimens without any evidence of enhanced toxicity or reduced immunological or therapeutic efficacy. PMID:18060404

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

    PubMed

    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. PMID:26722420

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

    PubMed Central

    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. PMID:26722420

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

    PubMed Central

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

    1996-01-01

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

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

    PubMed

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

    2016-07-01

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

  18. Randomized study of sinusoidal chronomodulated versus flat intermittent induction chemotherapy with cisplatin and 5-fluorouracil followed by traditional radiotherapy for locoregionally advanced nasopharyngeal carcinoma

    PubMed Central

    Lin, Huan-Xin; Hua, Yi-Jun; Chen, Qiu-Yan; Luo, Dong-Hua; Sun, Rui; Qiu, Fang; Mo, Hao-Yuan; Mai, Hai-Qiang; Guo, Xiang; Xian, Li-Jian; Hong, Ming-Huang; Guo, Ling

    2013-01-01

    Neoadjuvant chemotherapy plus radiotherapy is the most common treatment regimen for advanced nasopharyngeal carcinoma (NPC). Whether chronomodulated infusion of chemotherapy can reduce its toxicity is unclear. This study aimed to evaluate the toxic and therapeutic effects of sinusoidal chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) and 5-fluorouracil (5-FU) followed by radiotherapy in patients with locoregionally advanced NPC. Patients with biopsy-diagnosed untreated stages III and IV NPC (according to the 2002 UICC staging system) were randomized to undergo 2 cycles of sinusoidal chronomodulated infusion (Arm A) or flat intermittent constant rate infusion (Arm B) of DDP and 5-FU followed by radical radiotherapy. Using a “MELODIE” multi-channel programmed pump, the patients were given 12-hour continuous infusions of DDP (20 mg/m2) and 5-FU (750 mg/m2) for 5 days, repeated every 3 weeks for 2 cycles. DDP was administered from 10:00 am to 10:00 pm, and 5-FU was administered from 10:00 pm to 10:00 am each day. Chronomodulated infusion was performed in Arm A, with the peak deliveries of 5-FU at 4:00 am and DDP at 4:00 pm. The patients in Arm B underwent a constant rate of infusion. Radiotherapy was initiated in the fifth week, and both arms were treated with the same radiotherapy techniques and dose fractions. Between June 2004 and June 2006, 125 patients were registered, and 124 were eligible for analysis of response and toxicity. The major toxicity observed during neoadjuvant chemotherapy was neutropenia. The incidence of acute toxicity was similar in both arms. During radiotherapy, the incidence of stomatitis was significantly lower in Arm A than in Arm B (38.1% vs. 59.0%, P = 0.020). No significant differences were observed for other toxicities. The 1-, 3-, and 5-year overall survival rates were 88.9%, 82.4%, and 74.8% for Arm A and 91.8%, 90.2%, and 82.1% for Arm B. The 1-, 3-, and 5-year progression-free survival rates were 91

  19. A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes

    PubMed Central

    Agier, Nicolas; Delacroix, Hervé; Marisa, Laetitia; Brasnu, Daniel; Aggerbeck, Lawrence P.; Badoual, Cécile; Barouki, Robert; Aggerbeck, Martine

    2012-01-01

    Background It is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other therapeutic options. Further, it is of interest to know to what extent a gene signature, which identifies patients with tumors that will not respond to a particular induction chemotherapy, is applicable when additional chemotherapeutic agents are added to the regimen. Methodology/Principal Findings To identify genes that predict tumor resistance to induction with cisplatin/5-fluorouracil (PF) or PF and a taxane, we analyzed patient tumor biopsies with whole genome microarrays and quantitative reverse transcriptase-PCR (TLDA) cards. A leave one out cross-validation procedure allowed evaluation of the prediction tool. A ten-gene microarray signature correctly classified 12/13 responders and 7/10 non-responders to PF (92% specificity, 82.6% accuracy). TLDA analysis (using the same classifier) of the patients correctly classified 12/12 responders and 8/10 non-responders (100% specificity, 90.9% accuracy). Further, TLDA analysis correctly predicted the response of 5 new patients and, overall, 12/12 responders and 13/15 non-responders (100% specificity, 92.6% accuracy). The protein products of the genes constituting the signature physically associate with 27 other proteins, involved in regulating gene expression, constituting an interaction network. In contrast, TLDA-based prediction (with the same gene signature) of responses to induction with PF and either of two taxanes was poor (0% specificity, 25% accuracy and 33.3% specificity, 25% accuracy). Conclusions/Significance Successful transfer of the microarray-based gene signature to an independent, PCR-based technology suggests that TLDA-based signatures could be a useful hospital-based technology for determining therapeutic

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

    SciTech Connect

    Short, Michala; Halkett, Georgia; Borg, Martin; Zissiadis, Yvonne; Kneebone, Andrew; Spry, Nigel

    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.

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

    PubMed Central

    Martino-Echarri, Estefania

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  3. Radiotherapy and Concomitant Intra-Arterial Docetaxel Combined With Systemic 5-Fluorouracil and Cisplatin for Oropharyngeal Cancer: A Preliminary Report-Improvement of Locoregional Control of Oropharyngeal Cancer

    SciTech Connect

    Oikawa, Hirobumi Nakamura, Ryuji; Nakasato, Tatsuhiko; Nishimura, Kohji; Sato, Hiroaki; Ehara, Shigeru

    2009-10-01

    Purpose: To confirm the advantage of chemoradiotherapy using intra-arterial docetaxel with intravenous cisplatin and 5-fluorouracil. Patients and Methods: A total of 26 oropharyngeal cancer patients (1, 2, 2, and 21 patients had Stage I, II, III, and IVa-IVc, respectively) were treated with two sessions of this chemoradiotherapy regimen. External beam radiotherapy was delivered using large portals that included the primary site and the regional lymph nodes initially (range, 40-41.4 Gy) and the metastatic lymph nodes later (60 or 72 Gy). All tumor-supplying branches of the carotid arteries were cannulated, and 40 mg/m{sup 2} docetaxel was individually infused on Day 1. The other systemic chemotherapy agents included 60 mg/m{sup 2} cisplatin on Day 2 and 500 mg/m{sup 2} 5-fluorouracil on Days 2-6. Results: The primary response of the tumor was complete in 21 (81%), partial in 4 (15%), and progressive in 1 patient. Grade 4 mucositis, leukopenia, and dermatitis was observed in 3, 2, and 1 patients, respectively. During a median follow-up of 10 months, the disease recurred at the primary site and at a distant organ in 2 (8%) and 3 (12%) patients, respectively. Three patients died because of cancer progression. Two patients (8%) with a partial response were compromised by lethal bleeding from the tumor bed or chemotherapeutic toxicity. The 3-year locoregional control rate and the 3-year overall survival rate was 73% and 77%, respectively. Conclusion: This method resulted in an excellent primary tumor response rate (96%) and moderate acute toxicity. Additional follow-up is required to ascertain the usefulness of this modality.

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

    PubMed Central

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

    2010-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay

    2016-03-01

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

  6. 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

    PubMed Central

    Dekeister, Kathleen; Viguier, Jean Louis; Martin, Xavier; Nguyen, Anh Minh; Boyle, Helen; Flechon, Aude

    2016-01-01

    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. PMID:27194981

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

    SciTech Connect

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

    2005-07-01

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

  8. Successful capecitabine rechallenge following 5-fluorouracil-induced Takotsubo syndrome

    PubMed Central

    Abdelrahman, Mohamed; McCarthy, Michael T.; Yusof, Haliana; Osman, Nemer

    2016-01-01

    Cardiac toxicity is a widely reported complication of fluoropyrimidine chemotherapies (5-fluorouracil and capecitabine); however, Takotsubo syndrome (TS) is less widely reported. There is little data available describing the viability of fluoropyrimidine rechallenge after fluoropyrimidine-induced TS. We report the case of Ms X, a 41-year-old woman with metastatic oesophageal cancer, who developed acute onset left ventricular dysfunction, with a measured left ventricular ejection fraction of 15% on cycle 1 day 3 of FOLFOX chemotherapy, after disconnection of the fluorouracil infusion pump. Her symptoms resolved over 2 days, and an echocardiogram returned to normal within 2 weeks. 5-Fluorouracil was discontinued, and replaced with capecitabine, without recurrence of symptoms. The remainder of her treatment was uneventful. This is the second case to describe successful capecitabine retreatment following 5-fluorouracil-induced TS. PMID:26989494

  9. Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer.

    PubMed

    Hofheinz, R-D; Willer, A; Weisser, A; Gnad, U; Saussele, S; Kreil, S; Hartmann, J T; Hehlmann, R; Hochhaus, A

    2004-05-17

    Mitomycin C (MMC) in combination with infusional 5-fluorouracil (FU) plus folinic acid (FA) is an effective treatment for metastatic gastrointestinal cancer. Anthracyclines are commonly used in the treatment of upper gastrointestinal cancer. The aim of this study was to determine the maximum tolerated dose of liposomal, pegylated doxorubicin (Caelyx) in combination with infusional 5-FU/sodium FA and MMC. Escalating doses of Caelyx (15-25-30-35 mg m(-2) corresponding to dose levels I-IV) were applied on days 1 and 29, given to fixed doses of 24-h 5-FU (2000 mg m(-2)) and sodium FA (500 mg m(-2), mixed with 5-FU in one pump) weekly for 6 weeks, and MMC 7 mg m(-2) on days 8 and 36. At least three patients were treated at each dose level. A total of 25 patients are evaluable. No dose-limiting toxicity (DLT) was observed on level I (n=3). On level II, DLT occurred in three out of five patients (mucositis and leucopenia). Owing to the early DLTs at this dose, we added a 20 mg m(-2) Caelyx dose level (Ia). In total, 17 patients were treated at this dose level. Among these, only two patients experienced DLT in cycle one and 37 complete cycles have been administered in association with a low toxicity profile. The median dose intensity was 100% for each drug during the first course and no treatment delay exceeding 7 days was required. The recommended dose of 4-weekly Caelyx in combination with weekly 24-h 5-FU/sodium FA and 4-weekly MMC is 20 mg m(-2). Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer. PMID:15138468

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

    PubMed Central

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

    2015-01-01

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

  11. Efficacy of cisplatin, 5-fluorouracil, and paclitaxel regimen for carcinoma of the esophagus.

    PubMed

    Belani, C P; Luketich, J D; Landreaneau, R J; Kim, R; Ramanathan, R K; Day, R; Ferson, P F; Keenan, R J; Posner, M; Seeger, J; Lembersky, B

    1997-12-01

    Eighteen patients with esophageal carcinoma (16 adenocarcinoma, two squamous cell carcinoma) were treated with two cycles of induction chemotherapy consisting of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 (3-hour infusion), cisplatin 20 mg/m2/d x 4 days, and 5-fluorouracil 1 g/m2/d (continuous infusion x 4 days) separated by a 28-day interval before surgical resection. After resection, patients received two more cycles of the same regimen. A thorough staging evaluation was performed before patients were enrolled in the study. The salient chemotherapy toxicities included grade 3 nausea (two patients), grade 3 vomiting (two patients), grades 3 and 4 diarrhea (one patient each), and grades 3 and 4 neutropenia (two and 10 patients, respectively). No deaths occurred due to toxicity. Surgical resection was attempted in all 18 patients (100%) after two cycles of induction chemotherapy. Esophageal resection was successfully completed in 17 patients. Liver metastases were noted at laparotomy in the one patient who subsequently did not undergo esophageal resection. Surgical complications were minor, and no postoperative deaths occurred. Fifteen patients received two additional cycles of the paclitaxel/5-fluorouracil/cisplatin regimen postoperatively, two received only one cycle, and one refused further therapy. Of 15 patients alive, 14 show no evidence of disease. The 1-year actuarial survival rate of this group of patients is 82%. In conclusion, the paclitaxel/5-fluorouracil/cisplatin combination is well tolerated and is an active regimen in esophageal carcinoma. PMID:9427275

  12. Clinical studies of combined photodynamic therapy using 5-fluorouracil and methyl-aminolevulinate in patients at high risk for squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Lohser, Sara; Tellez, Alejandra; Wene, Lauren; Ishak, Rim; Anand, Sanjay

    2013-03-01

    Photodynamic therapy (PDT) using aminolevulinic acid or its methyl ester, methyl-aminolevulinate (MAL), is an increasingly recognized approach for treating squamous neoplasia of the skin. Advantages of MAL-PDT include its ability to cover broad diseased areas (field treatment), and to do multiple sessions with little-to-no risk of scarring or mutagenesis. MAL-PDT is especially valuable in certain populations at high risk for skin cancer, including Caucasian patients with extensive solar damage, and organ transplant recipients (OTR) who take immunosuppressive drugs to prevent graft rejection. The latter group has a 65-200 fold increased risk of developing squamous cell carcinoma (SCC), a major cause of mortality. Therapeutic options for those patients, other than frequent surgeries, are very limited. Topical 5-Fluorouracil (5-FU), frequently prescribed in normal patients for pre-SCC of the skin, is only minimally effective in the OTR group. MAL-PDT, however, has ~40% efficacy for pre-SCC in OTR patients. Based upon our preclinical studies in mouse tumor models, which showed that preconditioning with 5-FU can drive higher accumulation of target protoporphyins (PpIX), we proposed a rational combination regimen of 5-FU and MAL-PDT in humans. A clinical trial was designed to test the hypothesis that a combination of 5-FU followed by MAL-PDT will elevate PpIX levels and achieve better clinical outcomes in high-risk OTR patients. Primary endpoints include PpIX levels and biochemical markers (p53) measured noninvasively and in skin biopsies. Lesion clearance and recurrence (via photographs and clinical exam) are secondary endpoints. Ongoing results of this clinical trial are presented.

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

    PubMed Central

    2009-01-01

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

  14. A randomized Phase II clinical study of combining panitumumab and bevacizumab, plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) compared with FOLFIRI alone as second-line treatment for patients with metastatic colorectal cancer and KRAS mutation

    PubMed Central

    Liu, Yuguo; Luan, Lijuan; Wang, Xingli

    2015-01-01

    Background This study investigated the efficacy and safety of a new treatment strategy of combining panitumumab and bevacizumab, plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) versus FOLFIRI alone as second-line chemotherapy for metastatic colorectal cancer (mCRC) patients with known V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) mutation status. Methods Patients with mCRC who had known KRAS tumor status and unsuccessful previous oxaliplatin-based chemotherapy were included in the study. They were randomly assigned to two groups to receive panitumumab and bevacizumab plus FOLFIRI, or FOLFIRI alone. In panitumumab and bevacizumab plus FOLFIRI group, patients were given 4 mg/kg panitumumab and bevacizumab plus FOLFIRI every 2 weeks. Results In all, 65 patients were assigned to panitumumab and bevacizumab plus FOLFIRI group, and 77 to FOLFIRI alone group. For WT KRAS patients, the median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI], 2.4–7.5 months) for panitumumab and bevacizumab plus FOLFIRI and 3.8 months (95% CI, 3.0–6.7 months) for FOLFIRI alone; median overall survival (OS) was 15.2 months (95% CI, 8.9–19.7 months) for panitumumab and bevacizumab plus FOLFIRI and 11.0 months (95% CI, 8.2–15.4 months) for FOLFIRI alone. For MU KRAS patients, median PFS was 5.1 months (95% CI, 2.7–10.2 months) for panitumumab and bevacizumab plus FOLFIRI and 4.1 months (95% CI, 2.5–8.4 months) for FOLFIRI alone; median OS was 12.8 months (95% CI, 7.8–15.8 months) for panitumumab and bevacizumab plus FOLFIRI and 10.5 months (95% CI, 6.1–15.3 months) for FOLFIRI alone. Grade 3 and 4 adverse events were associated with panitumumab and bevacizumab plus FOLFIRI but tolerable among patients. Conclusion Patients with mCRC can be safely and efficiently treated with second-line chemotherapy of combining panitumumab and bevacizumab plus FOLFIRI, despite their KRAS mutation status. PMID:25999741

  15. Symptomatic 5-fluorouracil-induced sinus bradycardia.

    PubMed

    Lee, A D; McKay, M J

    2011-07-01

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

  16. Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer

    PubMed Central

    Zhang, Minmin; Wei, Wei; Liu, Jianlun; Yang, Huawei; Jiang, Yi; Tang, Wei; Li, Qiuyun; Liao, Xiaoming

    2016-01-01

    The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC) vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC), followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT) vs taxotere (T), in axillary lymph node (LN)-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1) who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1) to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4–6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027) and objective remission rate (87% vs 73%, P=0.048) compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001) and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034) but less phlebitis (3% vs 14%, P=0.035). XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively. PMID:27354816

  17. Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer.

    PubMed

    Zhang, Minmin; Wei, Wei; Liu, Jianlun; Yang, Huawei; Jiang, Yi; Tang, Wei; Li, Qiuyun; Liao, Xiaoming

    2016-01-01

    The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC) vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC), followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT) vs taxotere (T), in axillary lymph node (LN)-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1) who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1) to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4-6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027) and objective remission rate (87% vs 73%, P=0.048) compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001) and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034) but less phlebitis (3% vs 14%, P=0.035). XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively. PMID:27354816

  18. A Retrospective, Multicenter Study of the Tolerance of Induction Chemotherapy With Docetaxel, Cisplatin, and 5-Fluorouracil Followed by Radiotherapy With Concomitant Cetuximab in 46 Cases of Squamous Cell Carcinoma of the Head and Neck

    SciTech Connect

    Buiret, Guillaume; Combe, Claire; Favrel, Veronique; Pommier, Pascal; Martin, Laurent; Ecochard, Rene; Fayette, Jerome; Tartas, Sophie; Ramade, Antoine; Ceruse, Philippe

    2010-06-01

    Purpose: To investigate, in a multicenter study, the tolerance of induction chemotherapy (ICT) and external radiotherapy (ERT) with concomitant cetuximab in the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods: Clinical data from 46 patients with Stage III or IV nonmetastatic SCCHN who received docetaxel, cisplatin, and 5-fluorouracil as ICT, followed by ERT with concomitant cetuximab, were retrospectively analyzed. Clinical safety (weight, allergy, mucositis, and dermatitis) and paraclinical safety (levels of hemoglobin, polynuclear neutrophils, and creatinine clearance) were studied. The primary objective was the proportion of patients who completed the protocol. Results: The percentage of patients completing ICT was 73.9%, ERT 93.5%, and cetuximab 69.6%. Induction chemotherapy was better tolerated than that previously reported. The rates of temporary suspensions of radiation (39.1%, mean duration of 13 days) and hospitalization (26.1%) during ERT with concomitant cetuximab were high. Weight loss during treatment (21.4% of patients lost >10% of their body weight), radiodermatitis, and radiomucositis were the main causes of temporary suspension of treatment, although Grade 4 dermatitis was not experienced. There were no allergic reactions to cetuximab. Conclusion: The completed protocol rate for SCCHN patients receiving ICT and ERT with concomitant cetuximab is high and the toxicity acceptable. Future improvements to protocol will be possible through early action and systematic implementation of nutritional support coupled with antibiotic treatment upon the first signs of radiodermatitis. These data could be useful for prospective studies on the safety and efficacy of this protocol.

  19. A Case of 5-Fluorouracil Induced Encephalopathy

    PubMed Central

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

    2010-01-01

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

  20. Evaluation of topical external medicine for 5-fluorouracil-induced oral mucositis in hamsters.

    PubMed

    Mitsuhashi, Hiromi; Suemaru, Katsuya; Li, Bingjin; Cui, Ranji; Araki, Hiroaki

    2006-12-01

    Oral ulcerative mucositis is a common and painful toxicity associated with chemotherapy for cancer. Current treatment for chemotherapy-induced oral mucositis is largely palliative, and no adequate treatment with conclusive evidence exists. The purpose of this study was to evaluate the potential effectiveness of the topical external medicines used in clinical settings, and the authors investigated the effects of 1% azulene ointment, 0.12% dexamethasone ointment, and polaprezinc-sodium alginate suspension on an animal model for oral mucositis induced by chemotherapy. Oral mucositis was induced in hamsters through a combination treatment of 5-fluorouracil and mild abrasion of the cheek pouch. Each drug was administered topically to the oral mucosa of hamsters, and the process of healing of damaged oral mucositis was examined by measuring the size of the mucositis. Azulene ointment did not reduce the size of the mucositis compared with the vaseline-treated control group. Polaprezinc-sodium alginate suspension significantly improved the recovery from 5-fluorouracil-induced damage. In contrast, local treatment with dexamethasone exacerbated the mucositis markedly. These results suggested the healing effect of polaprezinc-sodium alginate suspension and the risk of steroids to severe oral mucositis induced by chemotherapy. PMID:17046745

  1. Concomitant 5-fluorouracil infusion and high-dose radiation for stage III non-small cell lung cancer

    SciTech Connect

    Lokich, J.; Chaffey, J.; Neptune, W. )

    1989-09-01

    Thirty patients with Stage III non-small cell lung cancer were entered on a trial to evaluate the feasibility of combined radiation and concomitant 5-fluorouracil infusion. Patients had received prior debulking surgery (nine), induction chemotherapy (16), or no therapy (five). Radiation employed standard fractionation (180-200 rad/day) administered to a median cumulative dose of 5500 rad (range, 4500-6200 rad). 5-Fluorouracil was infused 24 hours per day throughout the period of radiation at a dose of 300 mg/m2/day for a median of 42 days (range, 28-56 days). Radiation complications included pneumonitis three of 30 (10%) and esophagitis (27%). Chemotherapy complications included stomatitis, two of 27 (7%), and hand-foot syndrome, three of 30 (10%). Treatment interruptions were necessary in six of 30 (20%) and four of 30 required parenteral nutrition. At a median follow-up of 12 months 26/30 (87%) maintained local control and eight had distant metastases (three of whom presented with Stage IV disease). 5-Fluorouracil delivered continuously throughout standard fractionation radiation to high cumulative doses is feasible and practical. Comparative clinical trials of the various combined radiation and chemotherapy schedules employed are in order. One additional clinical observation was the identification of six of 30 (20%) with brain metastases at presentation or after 12 months, all of whom had adenocarcinoma histologic subtype.

  2. 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

    SciTech Connect

    Ch'ang, Hui-Ju; Lin, Yu-Lin; Wang, Hsiu-Po; Chiu, Yen-Feng; Chang, Ming-Chu; Hsu, Chih-Hung; Tien, Yu-Wen; Chen, Jen-Shi; Hsieh, Ruey-Kuen; Lin, Pin-Wen; Shan, Yan-Shen; Cheng, Ann-Lii; Chang, Jang-Yang; Whang-Peng, Jacqueline; Hwang, Tsann-Long; 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

  3. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells.

    PubMed

    Soo, Jaslyn Sian-Siu; Ng, Char-Hong; Tan, Si Hoey; Malik, Rozita Abdul; Teh, Yew-Ching; Tan, Boon-Shing; Ho, Gwo-Fuang; See, Mee-Hoong; Taib, Nur Aishah Mohd; Yip, Cheng-Har; Chung, Felicia Fei-Lei; Hii, Ling-Wei; Teo, Soo-Hwang; Leong, Chee-Onn

    2015-10-01

    Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers. PMID:26276035

  4. Intermediate dose 5-fluorouracil-induced encephalopathy.

    PubMed

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

    2006-01-01

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

  5. Effect of 5-Fluorouracil on Thymidine Phosphorylase Activity in Model Experiment.

    PubMed

    Stashkevich, M A; Khomutov, E V; Dumanskii, Yu V; Matvienko, A G; Zinkovich, I I

    2016-03-01

    Variations in thymidine phosphorylase activity in rat liver were studied in 1, 3, 6, 12, and 24 h after intraperitoneal bolus injection of 5-fluorouracil. Enzyme activity was measured by HPLC. A 2-fold decrease in enzyme activity was observed 3 h after 5-fluorouracil administration and persisted for 12 h. This additional effect of the cytostatic should be taken into account in choosing chemotherapy protocol. PMID:27021101

  6. Gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, granulocyte-macrophage colony-stimulating factor, and interleukin-2 (GOLFIG) versus FOLFOX chemotherapy in metastatic colorectal cancer patients: the GOLFIG-2 multicentric open-label randomized phase III trial.

    PubMed

    Correale, Pierpaolo; Botta, Cirino; Rotundo, Maria S; Guglielmo, Annamaria; Conca, Raffaele; Licchetta, Antonella; Pastina, Pierpaolo; Bestoso, Elena; Ciliberto, Domenico; Cusi, Maria G; Fioravanti, Antonella; Guidelli, Giacomo M; Bianco, Maria T; Misso, Gabriella; Martino, Elodia; Caraglia, Michele; Tassone, Pierfrancesco; Mini, Enrico; Mantovani, Giovanni; Ridolfi, Ruggero; Pirtoli, Luigi; Tagliaferri, Pierosandro

    2014-01-01

    The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m(2), day 1); oxaliplatin (85 mg/m(2), day 2); levofolinate (100 mg/m(2), days 1-2), 5-fluorouracil (5-FU) (400 mg/m(2) in bolus followed by 24 h infusion at 800 mg/m(2),days 1-2), sc. GM-CSF (100 μg, days 3-7); sc. aldesleukin (0·5 MIU bi-daily, days 8-14 and 17-30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95% confidence interval (CI), 6·9-11.5) vs. median 5.70 (95% CI, 3.38-8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35-0.77), P=0·002] and response rate [66.1% (95% CI, 0.41-0.73) vs. 37·0% (95% CI, 0.28-0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09-25.18) vs. 14.57 mo (95% CI, 9.07-20.07); HR: 0·79 (95% CI, 0.52-1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4(+) T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3(+)CD4(+)CD25(+)FoxP3(+)) T cells. Taken together, these findings provide proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC. PMID:24316553

  7. A Phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer

    SciTech Connect

    Navarro, Matilde . E-mail: mnavarrogarcia@ico.scs.es; Dotor, Emma; Rivera, Fernando; Sanchez-Rovira, Pedro; Vega-Villegas, Maria Eugenia; Cervantes, Andres; Garcia, Jose Luis; Gallen, Manel; Aranda, Enrique

    2006-09-01

    Purpose: The aim of this study was to evaluate the efficacy and tolerance of preoperative chemoradiotherapy (CRT) with irinotecan (CPT-11) and 5-fluorouracil (5-FU) in patients with resectable rectal cancer. Methods and Materials: Patients with resectable T3-T4 rectal cancer and Eastern Cooperative Oncology Group performance status <2 were included. CPT-11 (50 mg/m{sup 2} weekly) and 5-FU (225 mg/m{sup 2}/day continuous infusion, 5 days/week) were concurrently administered with radiation therapy (RT) (45 Gy, 1.8 Gy/day, 5 days/week), during 5 weeks. Results: A total of 74 patients were enrolled: mean age, 59 years (20-74 years; SD, 11.7). Planned treatment was delivered to most patients (median relative dose intensity for both drugs was 100%). Grade 3/4 lymphocytopenia occurred in 35 patients (47%), neutropenia in 5 (7%), and anemia in 2 (3%). Main Grade 3 nonhematologic toxicities were diarrhea (14%), asthenia (9%), rectal mucositis (8%), and abdominal pain (8%). Of the 73 resected specimens, 13.7% (95% confidence interval [CI], 6.8-23.7) had a pathologic complete response and 49.3% (95% CI, 37.4-61.3) were downstaged. Additionally, 66.7% (95% CI, 51.1-80.0) of patients with ultrasound staged N1/N2 disease had no pathologic evidence of nodal involvement after CRT. Conclusions: This preoperative CRT schedule has been shown to be effective and feasible in a large population of patients with resectable rectal cancer.

  8. 5-Fluorouracil-induced Tako-Tsubo-like syndrome.

    PubMed

    Basselin, Cécile; Fontanges, Thierry; Descotes, Jacques; Chevalier, Philippe; Bui-Xuan, Bernard; Feinard, Gwennaelle; Timour, Quadiri

    2011-02-01

    Tako-Tsubo cardiomyopathy (also known as apical ballooning syndrome) is a relatively new clinical entity characterized by reversible left ventricular dysfunction. Its clinical presentation and electrocardiographic findings are similar to acute myocardial infarction but without significant coronary artery disease. Cardiotoxicity is a major complication of various anticancer drugs; however, only a few cases of Tako-Tsubo cardiomyopathy associated with anticancer drugs, including 5-fluorouracil, have been reported. We describe a 48-year-old man who developed acute coronary syndrome, thought to be similar to Tako-Tsubo syndrome, after receiving a chemotherapy regimen consisting of 5-fluorouracil, oxaliplatin, and calcium folinate (FOLFOX protocol) for colic adenocarcinoma. Approximately 24 hours after receiving his first cycle of chemotherapy, the patient, who did not have a history of cardiovascular disease, developed chest pain, with abnormal electrocardiographic results and a mildly increased troponin T level. Coronary angiography did not show any significant coronary lesions. Echocardiography revealed marked left ventricular dysfunction (left ventricular ejection fraction [LVEF] 15%) with severe hypokinesia in all apical and median segments. The patient was stabilized with the introduction of an intraaortic balloon pump and pressor therapy. One month later, myocardial magnetic resonance imaging confirmed total recovery of left ventricular systolic function. Thus, the second chemotherapy cycle was administered at half the dose-intensity, along with ramipril and diltiazem. The chemotherapy regimen was well tolerated. Two weeks later, at the end of the third chemotherapy cycle, administered using the full-dose regimen, the patient experienced cardiac arrest, necessitating cardiopulmonary resuscitation. After transfer to the cardiology intensive care unit, acute heart failure recurred (LVEF 35%). Normal recovery of left ventricular function occurred a few days later

  9. Infusional 5-Fluorouracil and ZD1839 (Gefitinib-Iressa) in Combination With Preoperative Radiotherapy in Patients With Locally Advanced Rectal Cancer: A Phase I and II Trial (1839IL/0092)

    SciTech Connect

    Valentini, Vincenzo; De Paoli, Antonino; Gambacorta, Maria Antonietta Mantini, Giovanna; Ratto, Carlo; Vecchio, Fabio Maria; Barbaro, Brunella; Innocente, Roberto; Rossi, Carlo; Boz, Giovanni; Barba, Maria Cristina; Frattegiani, Alessandro; Lupattelli, Marco; Doglietto, Giovan Battista

    2008-11-01

    Purpose: To report the final data of a Phase I and II study (1839IL/0092) on the combination of an anti-epidermal growth factor receptor drug (gefitinib), infusional 5-fluorouracil, and preoperative radiotherapy in locally advanced, resectable rectal cancer. Methods and Materials: Patients received 45 Gy in the posterior pelvis plus a boost of 5.4 Gy on the tumor and corresponding mesorectum. Infusional 5-fluorouracil (5-FU) and gefitinib (250 and 500 mg/day) were delivered during all radiotherapy course. An IORT boost of 10 Gy was allowed. The main endpoints of the study were to establish dose-limiting toxicity (DLT) and to evaluate the rate of pathologic response according to the tumor regression grade (TRG) Mandard score. Results: A total of 41 patients were enrolled. The DLT was not reached in the 6 patients enrolled in the dose-escalation part of the study. Of the 33 patients in the Phase II, TRG 1 was recorded in 10 patients (30.3%) and TRG 2 in 7 patients (21.2 %); overall 17 of 33 patients (51.5%) had a favorable endpoint. Overall, Grade 3+ toxicity was recorded in 16 patients (41%); these included Grade 3+ gastrointestinal toxicity in 8 patients (20.5%), Grade 3+ skin toxicity in 6 (15.3%), and Grade 3+ genitourinary toxicity in 4 (10.2%). A dose reduction of gefitinib was necessary in 24 patients (61.5%). Conclusions: Gefitinib can be associated with 5-FU-based preoperative chemoradiation at the dose of 500 mg without any life-threatening toxicity and with a high pCR (30.3%). The relevant rate of Grade 3 gastrointestinal toxicity suggests that 250 mg would be more tolerable dose in a neaoadjuvant approach with radiotherapy and infusional 5-FU.

  10. A Case Report of Long-Term Survival following Hepatic Arterial Infusion of L-Folinic Acid Modulated 5-Fluorouracil Combined with Intravenous Irinotecan and Cetuximab Followed by Hepatectomy in a Patient with Initially Unresectable Colorectal Liver Metastases

    PubMed Central

    Van Bael, Kobe; Jansen, Yanina; Seremet, Teofila; Engels, Benedikt; Delvaux, Georges

    2015-01-01

    A 43-year-old women admitted to our hospital for weight loss, anorexia, and abdominal pain was diagnosed with sigmoid neoplasm and multiple bilobar liver metastases. This patient received six cycles of systemic FOLFOX prior to a laparoscopically assisted anterior resection of the rectosigmoid for a poorly differentiated invasive adenocarcinoma T2N2M1, K-RAS negative (wild type). Hepatic arterial infusion (HAI) of L-folinic acid modulated 5-fluorouracil (LV/5-FU) with intravenous (iv) irinotecan (FOLFIRI) and cetuximab as adjuvant therapy resulted in a complete metabolic response (CR) with CEA normalization. A right hepatectomy extended to segment IV was performed resulting in (FDG-)PET negative remission for 7 months. Solitary intrahepatic recurrence was effectively managed by local radiofrequent ablation following 6c FOLFIRI plus cetuximab iv. Multiple lung lesions and recurrence of pulmonary and local lymph node metastases were successfully treated with fractionated stereotactic radiotherapy (50 Gy) and iv LV/5-FU/oxaliplatin (FOLFOX) plus cetuximab finally switched to panitumumab with CR as a result. At present the patient is in persistent complete remission of her stage IV colorectal cancer, more than 5 years after initial diagnosis of the advanced disease. Multidisciplinary treatment with HAI of chemotherapy (LV/5-FU + CPT-11) plus EGFR-inhibitor can achieve CR of complex unresectable LM and can even result in hepatectomy with possible long-term survival. PMID:26064730

  11. Targeting the microRNA-21/AP1 axis by 5-fluorouracil and pirarubicin in human hepatocellular carcinoma

    PubMed Central

    He, Xiaodong; Li, Jingjing; Guo, Weidong; Liu, Wei; Yu, Jia; Song, Wei; Dong, Lei; Wang, Fang; Yu, Shuangni; Zheng, Yi; Chen, Songsen; Kong, Yan; Liu, Changzheng

    2015-01-01

    MicroRNAs function as oncomiRs and tumor suppressors in diverse cancers. However, the utility of specific microRNAs in predicting the clinical benefit of chemotherapy has not been well-established. Here, we investigated the correlation between microRNA-21 expression and hepatic arterial infusion chemotherapy with 5-fluorouracil and pirarubicin (HAIC) for hepatocellular carcinoma (HCC). We found that HCC patients with low microRNA-21 levels in tumors tended to have a longer time to recurrence and disease-free survival. We demonstrated that microRNA-21 suppression in combination with 5-fluorouracil and pirarubicin treatment inhibited tumor growth in subcutaneous xenograft mice models. Mechanistically, the AP-1 and microRNA-21-mediated axis was verified to be a therapeutic target of cytotoxic drugs and deregulation of this axis led to an enhanced cell growth in HCC. Taken together, our findings demonstrate that microRNA-21 is a chemotherapy responsive microRNA and can serve as a prognostic biomarker for HCC patients undergoing HAIC. Targeting microRNA-21 enhances the effect of chemotherapeutic drugs, thereby suggesting that microRNA-21 suppression in combination with HAIC may be a novel approach for HCC treatment. PMID:25544773

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

    PubMed

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

    2008-06-01

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

  13. Development and utilization of a combined LC-UV and LC-MS/MS method for the simultaneous analysis of tegafur and 5-fluorouracil in human plasma to support a phase I clinical study of oral UFT®/leucovorin.

    PubMed

    Peer, Cody J; McManus, Terence J; Hurwitz, Herbert I; Petros, William P

    2012-06-01

    Tegafur is a 5-fluorouracil (5-FU) prodrug widely used outside the United States to treat colorectal cancer as well as cancers of the head and neck. The resulting plasma concentrations of tegafur are much higher than those of 5-FU; thus, analytical methods are needed that are sensitive enough to detect low plasma concentrations of 5-FU and robust enough to simultaneously analyze tegafur. Previous LC-MS/MS methods have either failed to demonstrate the ability to simultaneously measure low 5-FU and high tegafur plasma levels, or failed to be applicable in clinical studies. Our goal was to develop a method capable of measuring low concentrations of 5-FU (8-200 ng/ml) and high concentrations of tegafur (800-20,000 ng/ml) in human plasma and to subsequently evaluate the utility of the method in patient samples collected during a phase I clinical study where oral doses of either 200mg or 300 mg UF®/LV (uracil and tegafur in a 4:1 molar ratio plus leucovorin) were administered. A combined LC-MS/MS and LC-UV method was developed utilizing negative ion atmospheric pressure ionization (API). The method provides an accuracy and precision of <10% and <6%, respectively, for both analytes. Material recoveries from the liquid-liquid extraction technique were 97-110% and 86-91% for tegafur and 5-FU, respectively. Utilization of this method to determine tegafur and 5-FU plasma concentrations followed by noncompartmental pharmacokinetic analyses successfully estimated pharmacokinetic parameters (C(MAX), t(MAX) and AUC(0-10h)) in the clinical study patients. Overall, this method is ideal for the simultaneous bioanalysis of low levels of 5-FU and relatively higher levels of its prodrug, tegafur, in human plasma for clinical pharmacokinetic analysis. PMID:22565063

  14. RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Carcinoma of the Anal Canal

    SciTech Connect

    Kachnic, Lisa A.; Winter, Kathryn; Myerson, Robert J.; Goodyear, Michael D.; Willins, John; Esthappan, Jacqueline; Haddock, Michael G.; Rotman, Marvin; Parikh, Parag J.; Safran, Howard; Willett, Christopher G.

    2013-05-01

    Purpose: A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in reducing grade 2+ combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811. Methods and Materials: T2-4N0-3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT, prescribed per stage: T2N0, 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3, 45 Gy elective nodal, 50.4 Gy ≤3 cm or 54 Gy >3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions. The primary endpoint is described above. Planned secondary endpoints assessed all AEs and the investigator’s ability to perform DP-IMRT. Results: Of 63 accrued patients, 52 were evaluable. Tumor stage included 54% II, 25% IIIA, and 21% IIIB. In primary endpoint analysis, 77% experienced grade 2+ gastrointestinal/genitourinary acute AEs (9811 77%). There was, however, a significant reduction in acute grade 2+ hematologic, 73% (9811 85%, P=.032), grade 3+ gastrointestinal, 21% (9811 36%, P=.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<.0001) with DP-IMRT. On initial pretreatment review, 81% required DP-IMRT replanning, and final review revealed only 3 cases with normal tissue major deviations. Conclusions: Although the primary endpoint was not met, DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2008-05-01

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

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

    PubMed

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

    2016-05-01

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

  18. Treatment dilemmas of cetuximab combined with chemotherapy for metastatic colorectal cancer

    PubMed Central

    Wen, Feng; Li, Qiu

    2016-01-01

    Although monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) have largely enriched the available therapeutic choices for colorectal cancer (CRC), the understanding and management of their associated clinical toxicities are limited. In addition, the combined strategies of administering EGFR mAbs and traditional cytotoxic agents, such as 5-fluorouracil, oxaliplatin and irinotecan, have resulted in a more complicated management of CRC treatment-related side effects compared with EGFR mAb monotherapy. We believe that a thorough recognition of the toxicities of EGFR mAb drugs is essential for physicians to increase the therapeutic index in the treatment of CRC. This review aims to summarize the existing information regarding the treatment dilemmas of cetuximab combined with chemotherapy in the management of metastatic CRC. PMID:27340349

  19. Treatment dilemmas of cetuximab combined with chemotherapy for metastatic colorectal cancer.

    PubMed

    Wen, Feng; Li, Qiu

    2016-06-21

    Although monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) have largely enriched the available therapeutic choices for colorectal cancer (CRC), the understanding and management of their associated clinical toxicities are limited. In addition, the combined strategies of administering EGFR mAbs and traditional cytotoxic agents, such as 5-fluorouracil, oxaliplatin and irinotecan, have resulted in a more complicated management of CRC treatment-related side effects compared with EGFR mAb monotherapy. We believe that a thorough recognition of the toxicities of EGFR mAb drugs is essential for physicians to increase the therapeutic index in the treatment of CRC. This review aims to summarize the existing information regarding the treatment dilemmas of cetuximab combined with chemotherapy in the management of metastatic CRC. PMID:27340349

  20. 5-fluorouracil-induced leukoencephalopathy in patients with breast cancer.

    PubMed

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

    2001-06-01

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

  1. Understanding Resistance to Combination Chemotherapy

    PubMed Central

    Pritchard, Justin R.; Lauffenburger, Douglas A.; Hemann, Michael T.

    2014-01-01

    Summary The current clinical application of combination chemotherapy is guided by a historically successful set of practices that were developed by basic and clinical researchers 50-60 years ago. Thus, in order to understand how emerging approaches to drug development might aid the creation of new therapeutic combinations, it is critical to understand the defining principles underlying classic combination therapy and the original experimental rationales behind them. One such principle is that the use of combination therapies with independent mechanisms of action can minimize the evolution of drug resistance. Another is that in order to kill sufficient cancer cells to cure a patient, multiple drugs must be delivered at their maximum tolerated dose – a condition that allows for enhanced cancer cell killing with manageable toxicity. In light of these models, we aim to explore recent genomic evidence underlying the mechanisms of resistance to the combination regimens constructed on these principles. Interestingly, we find that emerging genomic evidence contradicts some of the rationales of early practitioners in developing commonly used drug regimens. However, we also find that the addition of recent targeted therapies has yet to change the current principles underlying the construction of anti-cancer combinatorial regimens, nor have they made substantial inroads into the treatment of most cancers. We suggest that emerging systems/network biology approaches have an immense opportunity to impact the rational development of successful drug regimens. Specifically, by examining drug combinations in multivariate ways, next generation combination therapies can be constructed with a clear understanding of how mechanisms of resistance to multi-drug regimens differ from single agent resistance. PMID:23164555

  2. French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC)

    SciTech Connect

    Bensadoun, Rene-Jean . E-mail: rene-jean.bensadoun@nice.fnclcc.fr; Benezery, Karen; Dassonville, Olivier; Magne, Nicolas; Poissonnet, Gilles; Ramaioli, Alain; Lemanski, Claire; Bourdin, Sylvain; Tortochaux, Jacques; Peyrade, Frederic; Marcy, Pierre-Yves; Chamorey, Emmanuel Phar; Vallicioni, Jacques; Seng Hang; Alzieu, Claude; Gery, Bernard; Chauvel, Pierre; Schneider, Maurice; Santini, Jose; Demard, Francois; Calais, Gilles

    2006-03-15

    Background: Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis. Following a previous phase II study, this phase III multicenter trial was conducted between November 1997 and March 2002. Methods: Nontreated, strictly unresectable cases were eligible. Twice-daily radiation: two fractions of 1.2 Gy/day, 5 days per week, with no split (D1{sup {yields}}D46). Total tumor doses: 80.4 Gy/46 day (oropharynx), 75.6 Gy/44 day (hypopharynx). Chemotherapy (arm B): Cisplatin 100 mg/m{sup 2} (D1, D22, D43); 5FU, continuous infusion (D1{sup {yields}}D5), 750 mg/m{sup 2}/day cycle 1; 430 mg/m{sup 2}/day cycles 2 and 3. Results: A total of 163 evaluable patients. Grade 3-4 acute mucositis 82.6% arm B/69.5% arm A (NS); Grade 3-4 neutropenia 33.3% arm B/2.4% arm A (p < 0.05). Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months (p < 0.01). At 24 months, overall survival (OS), disease-free survival (DFS), and specific survival (SS) were significantly better in arm B. OS: 37.8% arm B vs. 20.1% arm A (p = 0.038); DFS: 48.2% vs. 25.2% (p = 0.002); SS: 44.5% vs. 30.2% (p 0.021). No significant difference between the two arms in the amount of side effects at 1 and 2 years. Conclusion: For these unresectable cases, chemoradiation provides better outcome than radiation alone, even with an 'aggressive' dose-intensity radiotherapy schedule.

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

    PubMed

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

    2016-08-01

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

  4. [5-fluorouracil, high dose folinic acid and mitomycin C in the treatment of advanced digestive cancers].

    PubMed

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

    1994-02-01

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

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

    PubMed

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

    1995-08-01

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

  6. Irinotecan and capecitabine combination chemotherapy in a patient with triple-negative breast cancer relapsed after adjuvant chemotherapy with anthracycline and taxane.

    PubMed

    Lee, Anna; Go, Se-Il; Lee, Won Sup; Lee, Un Seok; Kim, Moon Jin; Kang, Myoung Hee; Lee, Gyeong-Won; Kim, Hoon-Gu; Kang, Jung Hun; Jeon, Kyung-Nyeo; Cho, Jae Min; Lee, Jeong-Hee

    2015-01-01

    The most effective regimen for taxane- and anthracycline-refractory triple-negative breast cancer (TNBC) has not yet been established. Capecitabine was approved by the US Food and Drug Administration for the treatment of advanced breast cancer and has shown efficacy in advanced breast cancer refractory to anthracyclines and taxanes. Irinotecan has synergism with 5-fluorouracil and shows efficacy in advanced breast cancer. Here we report on a patient with TNBC who relapsed with widespread bone and lung metastases shortly after adjuvant anthracycline followed by taxane chemotherapy. She achieved a metabolic complete response with irinotecan and capecitabine combination therapy and had 10 months' progression-free survival and 22 months' overall survival. She relapsed with and died of brain metastasis without any definite signs of progression of the lung and bone lesions she had had before the irinotecan and capecitabine combination therapy. To validate this favorable result, larger clinical trials are warranted in patients with metastatic or relapsed TNBC. PMID:25702650

  7. Outcomes of Chemoradiotherapy With 5-Fluorouracil and Mitomycin C for Anal Cancer in Immunocompetent Versus Immunodeficient Patients

    SciTech Connect

    Seo, Yuji; Kinsella, Michael T.; Reynolds, Harry L.; Chipman, Gregory; Remick, Scot C.; Kinsella, Timothy J.

    2009-09-01

    Purpose: Information is limited as to how we should treat invasive anal squamous cell carcinoma (SCC) in patients with chronic immunosuppression, since the majority of clinical studies to date have excluded such patients. The objective of this study is to compare treatment outcomes in immunocompetent (IC) versus immunodeficient (ID) patients with invasive anal SCC treated similarly with combined modality therapy. Methods and Materials: Between January 1999 and March 2007, a total of 36 consecutive IC and ID patients received concurrent chemoradiotherapy using three-dimensional conformal radiotherapy with infusional 5-fluorouracil and mitomycin C. The IC and ID groups consisted of 19 and 17 patients, respectively, with 14 human immunodeficiency virus-positive (HIV+) and 3 post-solid organ transplant ID patients. There were no significant differences in tumor size, T stage, N stage, chemotherapy doses, or radiation doses between the two groups. Results: With a median follow-up of 3.1 years, no differences were found in overall survival, disease-specific survival, and colostomy-free survival. Three-year overall survival was 83.6% (95% CI = 68.2-100) and 91.7% (95% CI = 77.3-100) in the IC and ID groups, respectively. In addition, there were no differences in acute and late toxicity profiles between the two groups. In the human immunodeficiency virus-positive patients, Cox modeling showed no difference in overall survival by pretreatment CD4 counts (hazard ratio = 0.994, 95% CI = 0.98-1.01). No correlation was found between CD4 counts and the degree of acute toxicities. Conclusion: Our data suggest that standard combined modality therapy with three-dimensional conformal radiotherapy and 5-fluorouracil plus mitomycin C is as safe and effective for ID patients as for IC patients.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-05-01

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

  10. Novel Combination Chemotherapy for Localized Ewing Sarcoma

    Cancer.gov

    In this clinical trial, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide to a standard chemotherapy regimen improves overall survival in patients with extracranial Ewing

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

    SciTech Connect

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

    2009-07-15

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

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

    PubMed Central

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

    1996-01-01

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

  13. Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer

    SciTech Connect

    Schneider, Bryan J.; McGinn, Cornelius J.; Chang, Alfred E.; Colletti, Lisa M.; Normolle, Daniel P.; Hejna, Gwen F. P.A.; Zalupski, Mark M. . E-mail: Zalupski@umich.edu

    2005-12-01

    Purpose: The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. Methods and Materials: Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m{sup 2} and cisplatin 35 mg/m{sup 2} were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m{sup 2} daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. Results: Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. Conclusion: Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.

  14. The competition of drugs to serum albumin in combination chemotherapy: NMR study

    NASA Astrophysics Data System (ADS)

    Sułkowska, A.; Bojko, B.; Równicka, J.; Rezner, P.; Sułkowski, W. W.

    2005-06-01

    Combination chemotherapy with cyclophosphamide (CM), metotrexate and 5-fluorouracil (FU) is used in treatment of patients with breast carcinoma. Although clinical toxicity of CM combinated with FU is greater than that of CM, the levels were clinically acceptable. The mechanism of competition of CM and FU to bovine serum albumin (BSA) was examined with the use of 1H and 13C NMR spectroscopy. The chemical shifts and the linewidth of individual proton and carbon resonances of each drug were measured as a function of the drug/BSA molar ratio in order to analyse the drug-protein interaction and the molecular motion of the drug. The effect of the second drug used in the combination chemotherapy on the analysed NMR parameters is discussed. It was found that FU and CM bind to BSA at molar ratio drug/BSA 160 and 330, respectively. The formation of lev-BSA complex was not confirmed. Whereas it was proved that in the presence of both lev and CM the number of FU molecules bound with BSA increases. It was also observed that FU induces the rising of the affinity between lev and BSA.

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

    PubMed

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

    1998-01-01

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

  16. Concurrent Chemoradiation With Carboplatin-5-Fluorouracil Versus Cisplatin in Locally Advanced Oropharyngeal Cancers: Is More Always Better?

    SciTech Connect

    Barkati, Maroie; Fortin, Bernard; Soulieres, Denis; Clavel, Sebastien; Despres, Phillipe; Charpentier, Danielle; Tabet, Jean-Claude; Guertin, Louis; Olivier, Marie-Jo; Coulombe, Genevieve; Donath, David; Nguyen-Tan, Phuc Felix

    2010-02-01

    Purpose: The optimal chemotherapy regimen remains undefined in the treatment of locally advanced oropharyngeal cancer by concomitant chemoradiation. This article compares two platinum-based chemotherapy regimens. Methods and Materials: In this retrospective study, we reviewed all consecutive patients treated for Stage III or IVA-B oropharyngeal cancer using either a combination of carboplatin and 5-fluorouracil (5FU) every 3 weeks or high-dose cisplatin every 3 weeks concomitant with definitive radiation therapy. Results: A total of 200 patients were treated with carboplatin-5FU and 53 patients with cisplatin. Median potential follow-up was 43 months. The 3-year overall survival rates for carboplatin-5FU and cisplatin respectively were 79.1% and 74.9% (p = 0.628), the 3-year disease-free survival rates were 76.0% and 71.3% (p = 0.799), and the 3-year locoregional control rates were 88.4% and 94.2% (p = 0.244). Conclusions: We could not demonstrate differences between these two regimens, which both proved efficacious. Polychemotherapy and monochemotherapy therefore seem comparable in this retrospective analysis.

  17. Combined chemotherapy plus endostar with sequential stereotactic radiotherapy as salvage treatment for recurrent esophageal cancer with severe dyspnea: A case report and review of the literature

    PubMed Central

    XU, MINGFANG; HUANG, HUAN; XIONG, YANLI; PENG, BO; ZHOU, ZEJUN; WANG, DONG; YANG, XUEQIN

    2014-01-01

    For the majority of inoperable esophageal cancer cases, chemoradiotherapy is the most suitable treatment option. Cetuximab may provide certain benefits, however, this can be an expensive therapy. Additionally, stereotactic body radiation therapy (SBRT) is typically contraindicated for esophageal cancer due to the potential for esophageal perforation and stenosis. The use of combined chemotherapy plus endostar with sequential SBRT for the treatment of esophageal squamous cancer has not been reported. In the current study, the case of a 71-year-old female with esophageal squamous cancer diagnosed 2 years prior is presented. Surgery and four cycles of cisplatin plus 5-fluorouracil chemotherapy had been administered. The patient showed recurrence at the paratracheal lymph node, exhibited severe dyspnea (grade III) and required a semi-liquid diet. Four cycles of the docetaxel, 5-fluorouracil and nedaplatin regimen plus endostar (3 mg; days 1–14; intravenously) with sequential SBRT (3300 cGy in 10 fractions) was administered. Following treatment, the symptoms of the patient completely disappeared, and objective efficacy evaluation indicated complete remission. At the time of writing, the patient is living without discomfort and the progression-free survival is >8 months. In conclusion, the present case indicates that combined treatment of chemotherapy and endostar with sequential stereotactic radiotherapy is a safe and effective option for the management of esophageal cancer. PMID:24959263

  18. Development and assessment of novel all-in-one parenteral formulations with integrated anticoagulant properties for the concomitant delivery of 5-fluorouracil and calcium folinate.

    PubMed

    Locke, Julie M; Stutchbury, Tamantha K; Vine, Kara L; Gamble, Allan B; Clingan, Philip R; Bremner, John B; Ranson, Marie

    2009-10-01

    5-Fluorouracil in combination with its biomodulator folinic acid maintains a pivotal position in current anticancer treatment regimens. However, limitations in clinical management persist with the administration of these drugs. These limitations are associated with the use of a high pH to maintain 5-fluorouracil in solution, resulting in high rates of phlebitis and catheter blockages. Herein, we describe and compare initial studies on novel all-in-one formulations of 5-fluorouracil and folinic acid incorporating either sulfated or hydroxypropyl beta-cyclodextrins at physiological pH that potentially address these issues. All formulations markedly improved the stability of supersaturated solutions of 5-fluorouracil in the presence of folinic acid. In-vitro evaluation of the PC-3, HCT-116, MDA-MB-231, PC-14, and COLO-201 human carcinoma cell lines showed that all formulations exhibited equivalent or better cytotoxicity compared with cells exposed to 5-fluorouracil and folinic acid. Thus, these cyclodextrins do not compromise the cytotoxicity of 5-fluorouracil. Preliminary in-vivo dose tolerance profiles of the formulations were also equivalent to 5-fluorouracil and folinic acid administered separately. Furthermore, given the association between thrombosis and cancer, the potentially beneficial anticoagulant activity of the sulfated cyclodextrin-based formulations was also confirmed in vitro. Extended activated partial thromboplastin times and prothrombin times were observed for the sulfated cyclodextrins in human plasma both as individual compounds and as components of the formulations. In conclusion, these novel all-in-one formulations maintain the in-vitro potency while overcoming the accepted incompatibility of 5-fluorouracil and folinic acid, and represent improved injectable forms of 5-fluorouracil that may reduce phlebitis, catheter blockages, and thromboembolic events. PMID:19606016

  19. Continuous infusion of 5-fluorouracil with alpha 2b interferon for advanced colorectal carcinoma.

    PubMed Central

    Ferguson, J. E.; Hulse, P.; Lorigan, P.; Jayson, G.; Scarffe, J. H.

    1995-01-01

    Thirty patients with symptomatic colorectal carcinoma were commenced on treatment with 5-fluorouracil (2.5 g week-1) administered by continuous intravenous infusion and alpha 2b interferon (3 x 10(6) U s.c. three times a week). Six out of 30 patients (20%) achieved a partial response. Three patients (10%) had stable disease and 21 patients (70%) progressed on treatment. Twenty patients (67%) completed ten or more weeks of treatment. In nine patients, treatment was withdrawn after 2-9 weeks because of disease progression or death. One patient's treatment was interrupted by emergency surgery. The median survival for all patients was 210 days (7 months). The principal side-effects were oral mucositis (12/30 patients), nausea (8/30 patients) and transient diarrhoea (4/30 patients), and initial constitutional symptoms due to alpha 2b interferon. The combination of low-dose continuous infusional 5-fluorouracil and low-dose alpha 2b interferon is well tolerated but has no obvious advantage over alternative infusional regimens using 5-fluorouracil as a single agent. PMID:7599051

  20. Concurrent Liposomal Cisplatin (Lipoplatin), 5-Fluorouracil and Radiotherapy for the Treatment of Locally Advanced Gastric Cancer: A Phase I/II Study

    SciTech Connect

    Koukourakis, Michael I.

    2010-09-01

    Purpose: Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin-based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin{sup TM}). Methods and Materials: Lipoplatin was given at a dose of 120mg/m{sup 2}/week, 5-fluorouracil at 400mg/m{sup 2}/week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively. Results: Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles. Conclusions: Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer.

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

    PubMed

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

    2016-04-18

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

  2. Effects of thymidine phosphorylase on tumor aggressiveness and 5-fluorouracil sensitivity in cholangiocarcinoma

    PubMed Central

    Thanasai, Jongkonnee; Limpaiboon, Temduang; Jearanaikoon, Patcharee; Sripa, Banchob; Pairojkul, Chawalit; Tantimavanich, Srisurang; Miwa, Masanao

    2010-01-01

    AIM: To evaluate the role of thymidine phosphorylase (TP) in cholangiocarcinoma using small interfering RNA (siRNA). METHODS: A human cholangiocarcinoma-derived cell line KKU-M139, which has a naturally high level of endogenous TP, had TP expression transiently knocked down using siRNA. Cell growth, migration, in vitro angiogenesis, apoptosis, and cytotoxicity were assayed in TP knockdown and wild-type cell lines. RESULTS: TP mRNA and protein expression were decreased by 87.1% ± 0.49% and 72.5% ± 3.2%, respectively, compared with control cells. Inhibition of TP significantly decreased migration of KKU-M139, and suppressed migration and tube formation of human umbilical vein endothelial cells. siRNA also reduced the ability of TP to resist hypoxia-induced apoptosis, while suppression of TP reduced the sensitivity of KKU-M139 to 5-fluorouracil. CONCLUSION: Inhibition of TP may be beneficial in decreasing angiogenesis-dependent growth and migration of cholangiocarcinoma but may diminish the response to 5-fluorouracil chemotherapy. PMID:20355241

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2014-04-01

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

  6. 5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection.

    PubMed

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

    2015-01-01

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

  7. A combined modality therapeutic approach to metastatic anal squamous cell carcinoma with systemic chemotherapy and local therapy to sites of disease: case report and review of literature

    PubMed Central

    Warren, Graham W.; Okun, Sherry; Peterson, Lindsay L.

    2016-01-01

    Cases of metastatic anal carcinoma managed with a combination of systemic chemotherapy and local therapies to both solitary sites of metastases and the primary site have been reported in the literature. We present a case of a 55-year-old male with metastatic anal squamous cell carcinoma to the liver treated with induction chemotherapy with cisplatin (CDDP) and 5-fluorouracil (5FU) followed by liver resection and radiation to the anal primary with concurrent 5FU and mitomycin. This approach resulted in control of disease without evidence of recurrence, and no increased toxicities now 19 months from initial diagnosis to time of reporting. This novel approach resulted in a good treatment response as documented by imaging and symptom improvement and a long disease free interval. PMID:27284490

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

    PubMed

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

    2015-01-01

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

  9. Shape resonance spectra of uracil, 5-fluorouracil, and 5-chlorouracil

    SciTech Connect

    Kossoski, F.; Varella, M. T. do N.; Bettega, M. H. F.

    2014-01-14

    We report on the shape resonance spectra of uracil, 5-fluorouracil, and 5-chlorouracil, as obtained from fixed-nuclei elastic scattering calculations performed with the Schwinger multichannel method with pseudopotentials. Our results are in good agreement with the available electron transmission spectroscopy data, and support the existence of three π* resonances in uracil and 5-fluorouracil. As expected, the anion states are more stable in the substituted molecules than in uracil. Since the stabilization is stronger in 5-chlorouracil, the lowest π* resonance in this system becomes a bound anion state. The present results also support the existence of a low-lying σ{sub CCl{sup *}} shape resonance in 5-chlorouracil. Exploratory calculations performed at selected C–Cl bond lengths suggest that the σ{sub CCl{sup *}} resonance could couple to the two lowest π* states, giving rise to a very rich dissociation dynamics. These facts would be compatible with the complex branching of the dissociative electron attachment cross sections, even though we cannot discuss any details of the vibration dynamics based only on the present fixed-nuclei results.

  10. Pharmacokinetics and tissue distribution of intraperitoneal 5-fluorouracil with a novel carrier solution in rats

    PubMed Central

    Wei, Zhi-Gang; Li, Guo-Xin; Huang, Xiang-Cheng; Zhen, Li; Yu, Jiang; Deng, Hai-Jun; Qing, Shan-Hua; Zhang, Ce

    2008-01-01

    AIM: To compare the pharmacokinetics and tissue distribution of 5-fluorouracil administered intraperitoneally with two isotonic carrier solutions: HAES-steri (neotype 6% hydroxyethyl starch), a novel carrier solution with middle molecular weight and physiologic saline (0.9% sodium chloride solution), a traditional carrier solution for intraperitoneal chemotherapy, in rats. METHODS: A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Each group was further randomized according to the intraperitoneal dwell period (1, 3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and quantitated. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography. RESULTS: The mean volumes remaining in the peritoneal cavity were significantly higher with HAES-steri than those with physiologic saline at 1, 6, 12, 18, and 24 h (P = 0.047, 0.009, 0.005, 0.005 and 0.005 respectively, the percentages of remaining peritoneal fluid volume were 89.9 ± 5.6 vs 83.4 ± 4.9, 79.9 ± 2.8 vs 56.2 ± 15.7, 46.8 ± 5.5 vs 24.7 ± 9.7, 23.0 ± 2.8 vs 0.0 ± 0.0 and 4.2 ± 1.7 vs 0.0 ± 0.0 respectively). Mean concentrations in peritoneal fluid were significantly higher with HAES-steri than those with physiologic saline at 3, 12 and 18 h (P = 0.009, 0.009 and 0.005 respectively, the concentrations were 139.2768 ± 28.2317 mg/L vs mg/L, 11.5427 ± 3.0976 mg/L vs 0.0000 ± 0.0000 mg/L and 4.7724 ± 1.0936 mg/L vs 0.0000 ± 0.0000 mg/L respectively). Mean plasma 5-fluorouracil concentrations in portal vein were significantly higher with HAES-steri at 3, 12, 18 and 24 h (P = 0.009, 0.034, 0.005 and 0.019 respectively, the concentrations were 3.3572 ± 0.8128 mg/L vs 0.8794 ± 0.2394 mg/L, 0.6203 ± 0.9935 mg/L vs 0.0112 ± 0.0250 mg/L, 0.3725 ± 0.3871 mg/L vs 0.0000 ± 0.0000 mg/L, and 0.2469 ± 0.1457 mg/L vs 0.0000 ± 0

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-12-01

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

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

    PubMed Central

    Wyatt, Michael D.; Wilson, David M.

    2008-01-01

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

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

    PubMed

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

    2014-11-14

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

  15. Treatment of verruca plana with 5% 5-fluorouracil ointment.

    PubMed

    Lee, S; Kim, J G; Chun, S I

    1980-01-01

    11 patients with verruca plana were treated with 5% 5-Fluorouracil ointment as a twice daily topical application with open dressing. The patients were chosen among those who failed to be cured with avrious topical agents such as salicylic acid, vitamin A acid and dinitrochlorobenzene (DNCB), or even with carbon dioxide cryotherapy, oral administration of methotrexate and intramuscular injection of sodium cacodylate. In 9 patients, all the treated warts completely disappeared within 3--5 weeks. 2 of these patients had recurrence after 3 weeks and 2 months, respectively. In 2 patients, some lesions disppeared while others failed to be healed. The major clinical adverse reactions were hyperpigmentation (8 cases), erythema (5 cases) and erosion (5 cases). PMID:7389971

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2012-07-01

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

  18. Emu Oil Combined with Lyprinol™ Reduces Small Intestinal Damage in a Rat Model of Chemotherapy-Induced Mucositis.

    PubMed

    Mashtoub, Suzanne; Lampton, Lorrinne S; Eden, Georgina L; Cheah, Ker Y; Lymn, Kerry A; Bajic, Juliana E; Howarth, Gordon S

    2016-10-01

    Chemotherapy-induced mucositis is characterized by inflammation and ulcerating lesions lining the alimentary tract. Emu Oil and Lyprinol™ have independently demonstrated their therapeutic potential in intestinal inflammatory disorders, including mucositis. We investigated Emu Oil and Lyprinol™ in combination for their further potential to alleviate chemotherapy-induced mucositis in rats. Rats were gavaged with (1 ml) water, Olive Oil, Emu Oil + Olive Oil, Lyprinol™ + Olive Oil or Emu Oil + Lyprinol™ from Days 0 to 7, injected with saline (control) or 5-Fluorouracil (5-FU) on Day 5 and euthanized on Day 8. Myeloperoxidase (MPO) activity (indicative of acute inflammation), histological severity scores, and intestinal architecture were quantified. Myeloperoxidase activity was significantly increased in the jejunum and ileum following 5-FU, compared to saline controls. Both Olive Oil and Emu Oil + Lyprinol™ significantly reduced jejunal MPO levels (1.8-fold and 1.7-fold, respectively), whereas only Emu Oil + Lyprinol™ significantly decreased ileal MPO levels, relative to 5-FU controls. All oil treatments decreased histological severity scores in the jejunum and ileum, and normalized crypt depth in the mid small intestine, relative to 5-FU controls. Emu Oil combined with Lyprinol™ partially reduced acute small intestinal inflammation. Isolating bioactive constituents of these naturally sourced oils could provide a more targeted strategy to protect against intestinal mucositis. PMID:27618153

  19. North Central Cancer Treatment Group Phase II study of 5-fluorouracil and high-dose levamisole for gastric and gastroesophageal cancer using survival as the primary endpoint of efficacy.

    PubMed

    Burch, P A; Keppen, M D; Schroeder, G; Rubin, J; Krook, J E; Dalton, R J; Gerstner, J B; Jancewicz, M T; Ebbert, L P

    1999-10-01

    At present there is no established standard chemotherapy for advanced gastric cancer. Combination regimens have yielded response rates at times exceeding 50% but with no improvement in survival compared to single agents. This study examined the role of 5-fluorouracil and high-dose levamisole in a phase II setting using survival as the main endpoint. Patients with advanced carcinomas of the stomach or gastroesophageal junction were treated with 5-fluorouracil, 450 mg/m2 IV days 1 to 5, and levamisole, 100 mg/m2 orally three times daily on days 1 to 3, and 50 mg/m2 tid days 4 to 5 every 5 weeks. To allow more rapid accrual and to study a population that more accurately reflects the makeup of patients treated in clinical practice, patients with both measurable and nonmeasurable disease were entered in this study. Two of fifteen (13%) patients with measurable disease experienced a partial response to treatment. The adjusted 1-year survival rate for the 44 patients entered was 29.6%, which is similar to the historical 1-year survival of 30% observed in a group of nearly 400 patients treated in prior North Central Cancer Treatment Group studies. This regimen offers no improvement in therapeutic activity for advanced gastric cancer. This study design, however, allows rapid screening of phase II regimens in patients who would usually be candidates for phase III trials. PMID:10521068

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2015-07-01

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

  2. Paradoxical effect of capecitabine in 5-fluorouracil-induced cardiotoxicity: A case vignette and literature review.

    PubMed

    Saneeymehri, Seyyedeh S; Markey, Kelly R; Mahipal, Amit

    2016-06-01

    5-fluorouracil is a chemotherapeutic agent that plays an important role in the treatment of various cancers including head and neck and gastrointestinal malignancies. Therapy with 5-fluorouracil is rarely associated with cardiotoxic effects including angina, heart failure, myocardial infarction and cardiac arrest, resulting in discontinuation at the expense of sub-optimal treatment of the targeted malignancy. In this article, we review the literature reported on 5-fluorouracil-associated cardiotoxicity and present a case of a patient who experienced chest pain on 5-fluorouracil. The cardiac symptoms subsided after initiation of capecitabine, the oral formulation of 5-fluorouracil. To our knowledge, this is only the second reported case where 5-fluorouracil was successfully replaced by capecitabine without recurrence of cardiac symptoms. Capecitabine may be a viable option for patients who develop 5-fluorouracil-induced chest pain. However, large clinical trials are warranted to confirm these findings. Currently, there is insufficient evidence to recommend an optimal approach for safe and effective alternative treatment for patients who experience 5-fluorouracil-induced cardiac adverse events. PMID:25852107

  3. Radiation dose escalation by simultaneous modulated accelerated radiotherapy combined with chemotherapy for esophageal cancer: a phase II study

    PubMed Central

    Zhai, Tiantian; Chang, Daniel; Chen, Zhijian; Huang, Ruihong; Zhang, Wuzhe; Lin, Kun; Guo, Longjia; Zhou, Mingzhen; Li, Dongsheng; Li, Derui; Chen, Chuangzhen

    2016-01-01

    The outcomes for patients with esophageal cancer (EC) underwent standard-dose radical radiotherapy were still disappointing. This phase II study investigated the feasibility, safety and efficacy of radiation dose escalation using simultaneous modulated accelerated radiotherapy (SMART) combined with chemotherapy in 60 EC patients. Radiotherapy consisted of 66Gy at 2.2 Gy/fraction to the gross tumor and 54Gy at 1.8 Gy/fraction to subclinical diseases simultaneously. Chemotherapy including cisplatin and 5fluorouracil were administered to all patients during and after radiotherapy. The data showed that the majority of patients (98.3%) completed the whole course of radiotherapy and concurrent chemotherapy. The most common ≥ grade 3 acute toxicities were neutropenia (16.7%), followed by esophagitis (6.7%) and thrombopenia (5.0%). With a median follow-up of 24 months (5-38) for all patients and 30 months (18-38) for those still alive, 11 patients (18.3%) developed ≥ Grade 3 late toxicities and 2 (3.3%) of them died subsequently due to esophageal hemorrhage. The 1- and 2-year local-regional control, distant metastasis-free survival, disease-free survival and overall survival rates were 87.6% and 78.6%, 86.0% and 80.5%, 75.6% and 64.4%, 86.7% and 72.7%, respectively. SMART combined with concurrent chemotherapy is feasible in EC patients with tolerable acute toxicities. They showed a trend of significant improvements in local-regional control and overall survival. Further follow-up is needed to evaluate the late toxicities. PMID:26992206

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

    PubMed

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

    2010-07-01

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

  5. Leucovorin, 5-fluorouracil, and gemcitabine: a phase I study.

    PubMed

    Poplin, E; Roberts, J; Tombs, M; Grant, S; Rubin, E

    1999-01-01

    Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU). The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0-2, and signed informed consent. Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m2, 5FU 255 mg/m2 and gemcitabine 600 mg/m2. 5FU and gemcitabine were escalated in tandem to 340 mg/m2 and 800 mg/m2 and thereafter to 425 mg/m2 and 1000 mg/m2, respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1-32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses. The maximum tolerated dose is leucovorin 20 mg/m2, 5FU 340 mg/m2, and gemcitabine 800 mg/m2. The impact of drug sequence remains undetermined. PMID:10555123

  6. Photocatalytic treatment of wastewater from 5-fluorouracil manufacturing

    SciTech Connect

    Anheden, M.; Goswami, D.Y.; Svedberg, G.

    1996-02-01

    This paper presents some of the experimental results from a study conducted to demonstrate the potential use of photocatalytic oxidation for decolorization and chemical oxygen demand (COD) reduction of wastewater from 5-fluorouracil manufacturing. A series of batch experiments, were carried out using diluted solutions of the wastewater with 0.1% w/v TiO{sub 2}. Low pressure mercury lamps were used to simulate the UV part of sunlight. The experiments showed that a complete decolorization and a substantial reduction of COD was achieved within 20 hours with a 20% solution. During the reaction period, the ph was noted to decrease considerably, indicating formation of acids. Adding hydrogen peroxide to the solution was found to significantly increase the reaction rates. Adding 2,400 ppm of H{sub 2}O{sub 2} gave an 80% decrease in color in one hour and a 70--80% decrease in COD in 20 hours. The influence of UV-light intensity was also examined. This experiment showed that with a UV-intensity of 15 W/m2, i.e., a cloudy day, the decolorization rate was still considerable, while the COD reduction rate was very low.

  7. 5-Fluorouracil-resistant strain of Methanobacterium thermoautortrophicum

    SciTech Connect

    Nagle, D.P. Jr.; Teal, R.; Eisenbraun, A.

    1987-09-01

    Growth of Methanobacterium thermoautotrophicum Marburg is inhibited by the pyrimidine, 5-fluorouracil (FU). It was shown previously that methanogenesis is not inhibited to the same extent as growth. A spontaneously occurring FU-resistant strain (RTAE-1) was isolated from a culture of strain Marburg. The growth of both strains was inhibited by 5-fluorodeoxyuridine but not 5-fluorocytosine, and the wild type was more susceptible to inhibition by 5-azauracil and 6-azauracil than was strain RTAE-1. The cellular targets for the pyrimidine analogs are not known. When the accumulation of /sup 14/C-labeled uracil or FU by the two strains was compared, the wilt type took up 15-fold more radiolabel per cell than did the FU-resistant strain. In the wild type, radiolabel from uracil was incorporated into the soluble pool, RNA, and DNA. The metabolism of uracil appeared to involve a uracil phosphoribosyltransferase activity. Strain Marburg extracts contained this enzyme, whereas FU-resistant strain RTAE-1 extracts had less than 1/10 as much activity. Although it is possible that a change in permeability to the compounds plays a role in the stable resistance of strain RTAE-1, the fact that it lacks the ability to metabolize pyrimidines to nucleotides is sufficient to account for its phenotype.

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

    PubMed

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

    2014-03-01

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

  9. 5-Fluorouracil modulation of radiosensitivity in cultured human carcinoma cells.

    PubMed

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

    1991-02-01

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

  10. 5-Fluorouracil loaded Eudragit fibers prepared by electrospinning.

    PubMed

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

    2015-11-30

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

  11. Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C.

    PubMed

    Cummings, B J; Keane, T J; O'Sullivan, B; Wong, C S; Catton, C N

    1991-10-01

    One hundred ninety-two patients with primary epidermoid cancer of the anal canal were treated by a series of prospectively designed, sequential non-randomized protocols of radiation alone (RT), radiation with concurrent 5-Fluorouracil and Mitomycin C (FUMIR), or radiation with concurrent 5-Fluorouracil only (FUR). The 5-year cause-specific survival rates were 69% overall, 68% RT, 76% FUMIR, 64% FUR. The primary tumor was controlled by radiation with or without chemotherapy in 68% (130/191) overall, 56% (32/57) by RT, 86% (59/69) by FUMIR, 60% (39/65) by FUR. The results with FUMIR were significantly better than with either RT alone or FUR, and except in tumors up to 2 cm in size, this superiority was found in all T stages. Regional lymph node metastases were controlled in 33 of 38 (87%) overall. The finding of clinically detectable regional lymph node metastases at presentation did not affect survival significantly in any treatment group. Anorectal function was preserved in 88% of the patients in whom the primary tumor was controlled, and in 64% overall. The delivery of 5FU and MMC concurrently with uninterrupted radical irradiation, 50 Gy in 20 fractions in 4 weeks, produced severe acute and late normal tissue morbidity. Split course treatment, and reduction of the daily fractional dose to 2 Gy, diminished the severity of normal tissue damage. Omission of Mitomycin C reduced acute hematological toxicity, but was associated with a decreased primary tumor control rate. The most effective treatment protocols as measured by survival rates, primary anal tumor control rates, and the likelihood of conservation of anorectal function included the administration of both Mitomycin C and 5-Fluorouracil concurrently with radiation therapy. PMID:1938508

  12. Inflammatory breast cancer: results of antracycline-based neoadjuvant chemotherapy.

    PubMed

    Ozmen, Vahit; Cabioglu, Neslihan; Igci, Abdullah; Dagoglu, Temel; Aydiner, Adnan; Kecer, Mustafa; Bozfakioglu, Yavuz; Dinçer, Maktav; Bilir, Ayhan; Topuz, Erkan

    2003-01-01

    Twenty-three patients with inflammatory breast cancer treated with a combined modality approach including anthracycline-based induction chemotherapy-surgery-chemotherapy-radiotherapy were reviewed. Twelve patients (52.2%) received FAC (5-fluorouracil, adriamycin, cyclophosphamide) and 11 patients (47.8%) were treated with FEC (5-fluorouracil, epirubicin, cyclophosphamide) induction chemotherapy for three cycles every 3 weeks. Surgery was followed by the initial chemotherapy or second-line chemotherapy for an additional six cycles to complete nine cycles and radiotherapy, respectively. The median overall survival (OS) time was 27 months and the median disease-free survival (DFS) was 13 months. Furthermore, patients treated with FAC induction chemotherapy have been found to have longer median OS and DFS periods compared to patients with FEC induction chemotherapy in both univariate and multivariate analysis. In conclusion, the superiority of doxorubicin-containing chemotherapy over epirubicin-containing chemotherapy should be established in larger randomized studies and more effective chemotherapeutic agents such as taxans are required for better survival rates in inflammatory breast cancer patients. PMID:12603379

  13. 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.

    PubMed

    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. PMID:9167745

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

    PubMed

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

    2016-08-01

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

  15. Comparative study of actinic keratosis treatment with 3% diclofenac sodium and 5% 5-fluorouracil*

    PubMed Central

    Segatto, Majoriê Mergen; Dornelles, Sérgio Ivan Torres; Silveira, Vera Bauer; Frantz, Gabriela de Oliveira

    2013-01-01

    BACKGROUND Actinic keratosis is a frequent lesion which occurs in sunlight exposed areas. Diclofenac sodium and 5-Fluorouracil are effective, non-invasive and easy-to-apply topical treatment options. OBJECTIVES To assess and compare the effectiveness of 3% diclofenac sodium associated with 2.5% hyaluronic acid and of 5% 5-Fluorouracil for the treatment of actinic keratosis, as well as the patient's degree of satisfaction and tolerability. METHODS 28 patients with a clinical diagnosis of actinic keratosis were randomized to receive diclofenac sodium or 5-Fluorouracil and were clinically assessed before and after treatment as well as 8 weeks after the end of treatment. Modified versions of the Investigator and Patient Global Improvement Scores were used. RESULTS The average number of lesions in the diclofenac sodium group before and after treatment was 13.6 and 6.6 (p<0,001), respectively, while it was 17.4 and 3.15 (p<0.001) in the 5-Fluorouracil group. There was a significant reduction in the number of lesions in the 5-Fluorouracil group in relation to the diclofenac sodium group (p<0.001). To the non-blinded physician, there was a higher satisfactory therapeutic response in the 5-Fluorouracil group (p<0.001); to the blinded physician, there was a higher satisfactory response in this same group, although not statistically significant (p=0.09). There was a high degree of satisfaction in both groups (73% in the diclofenac sodium group and 77% in the 5-Fluorouracil group; p=0.827). Regarding adverse effects, the diclofenac sodium group presented a higher degree of satisfaction (93.3% vs 38.4%; p=0.008). Erythema, edema, crusts and itching were significantly higher in the 5-Fluorouracil group. CONCLUSION We concluded that 5-Fluorouracil was more effective; however, it showed lower tolerability than diclofenac sodium. PMID:24173178

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2011-04-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2014-12-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2008-01-01

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

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

    PubMed Central

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

    1998-01-01

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

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

    PubMed

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

    2010-01-01

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

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

    SciTech Connect

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

    2012-01-01

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

  5. Effect of intralesional 5 fluorouracil injection in primary pterygium

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2011-02-01

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

  7. Molecularly imprinted polymer for recognition of 5-fluorouracil by RNA-type nucleobase pairing.

    PubMed

    Huynh, Tan-Phat; Pieta, Piotr; D'Souza, Francis; Kutner, Wlodzimierz

    2013-09-01

    A 6-aminopurine (adenine) derivative of bis(2,2'-bithienyl)methane, vis., 4-[2-(6-amino-9H-purin-9-yl)ethoxy]phenyl-4-[bis(2,2'-bithienyl)methane] or Ade-BTM, was designed and synthesized for recognition of 5-fluorouracil (FU), an antitumor chemotherapy agent, by RNA-type (nucleobase pairing)-driven molecular imprinting. The prepolymerization complex stoichiometry involved one FU molecule and two molecules of the Ade-BTM functional monomer. Molecular structure of this complex was thermodynamically optimized via density functional theory at the B3LYP/3-21G* level. The stability constant of the FU-Ade-BTM complex of 1:2 stoichiometry was K = 2.17(±0.07) × 10(7) M(-2), as determined by titration with quenching of fluorescence of the bis(2,2'-bithienyl)methane moiety of Ade-BTM by the FU titrant, in benzonitrile, at 352 nm excitation. Next, (5-fluorouracil)-templated molecularly imprinted polymer (MIP-FU) films were deposited on indium-tin oxide (ITO) or Au film-coated glass slides, Pt disk electrodes, or 10-MHz quartz crystal resonators by potentiodynamic electropolymerization from solution of FU, Ade-BTM, and tris([2,2'-bithiophen]-5-yl)methane (TTM) cross-linking monomer at FU:Ade-BTM:TTM = 1:2:3 mol ratio. Then UV-visible and Fourier transform infrared (FT-IR) spectra of the MIP-FU films were recorded to confirm the FU template presence in the MIP-FU film and its subsequent release by extraction with methanol from this film. For determination of the stability constant of the complex of the MIP cavity and FU, piezoelectric microgravimetry (PM) under both batch- and flow-injection analysis conditions was used. For sensing application, three different transduction platforms [differential pulse voltammetry (DPV), capacitive impedimetry (CI), and PM] were integrated with the MIP-FU recognition unit. The limit of detection (LOD) was 56 nM, 75 nM, and 0.26 mM, for these chemosensors, respectively, indicating suitability of the former two for FU determination in blood

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

    PubMed

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

    2014-03-01

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

  9. Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy

    PubMed Central

    Ranganath, Praveen; Einhorn, Lawrence; Albany, Costantine

    2015-01-01

    Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curable neoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayed CINV. Mechanism and pattern of CINV with multiday chemotherapy may differ from those in single day chemotherapy and therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy. PMID:26425563

  10. Transcription factor-binding sites in the thymidylate synthase gene: predictors of outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin?

    PubMed

    Paré, L; Marcuello, E; Altés, A; del Rio, E; Sedano, L; Barnadas, A; Baiget, M

    2008-10-01

    The identification of clinical and genetic parameters to predict the outcome in advanced colorectal cancer is a key issue in the management of this disease. We ascertained whether the clinical determinants of survival defined in a large cohort of patients treated with 5-fluorouracil (5-FU) (European Organization for the Research and Treatment of Cancer, EORTC model) also apply to 109 colorectal cancer patients receiving a therapy including oxaliplatin/5-FU as their first-line treatment. Our results confirm the considerable discriminatory power of the clinical model proposed in patients treated with a combined chemotherapy regimen. With the aim of identifying additional genetic prognostic parameters, we determined whether the polymorphisms in the promoter region of the thymidylate synthase (TS) gene that modifies the number of operative binding sites of a transcription factor (USF) could predict the clinical outcome of our patients and complement the EORTC clinical model. Our results indicate that this new genetic parameter (the number of USF-binding sites) could be considered when evaluating the role of TS genotype in the efficacy of the 5-FU-based regimens. Further, confirmatory studies aimed at evaluating the effect of the number of binding sites of transcription factors for selecting 5-FU-treated patients are warranted. PMID:17684476

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

    PubMed

    Parker, Jared B; Stivers, James T

    2011-02-01

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

  12. Mitomycin C with weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract and periampullar carcinomas.

    PubMed

    Chen, J S; Lin, Y C; Jan, Y Y; Liau, C T

    2001-04-01

    We have reported a 33% partial response rate with acceptable toxicity using weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in patients with far advanced biliary tract cancers (BTC). In this study, we added mitomycin (MMC) to 5-FU and LV in an attempt to improve the response rate and survival. From July 1997 to September 1999, 25 chemotherapy-naive patients with pathology-proven far advanced BTC and periampullar cancers were enrolled. The regimen consisted of MMC 10 mg/m(2) every 8 weeks combined with 5-FU 2600 mg/m(2) and LV 150 mg at a schedule of 24-h infusion weekly for 6 weeks followed by a 2 week break. There were 10 males and 15 females with a median age of 57 years (range 40-76). The sites of primary tumor were 15 intrahepatic cholangiocarcinomas (CC), one perihilar CCs, three distal BTC, three gallbladder cancers (GB) and three periampullar cancers. A total of 148 sessions of chemotherapy were given with a mean of 8 (range 2-18). Nineteen patients were evaluable for response. The response rate was: 26% (five of 19) partial response, 42% (eight of 19) stable disease and 32% (six of 19) progressive disease. All of the patients were evaluable for toxicity. Toxicities more than grade III-IV were thrombocytopenia 16% (four of 25), leukopenia 12% (three of 25) and vomiting 4% (one of 25). There were four treatment-related deaths. The median time to disease progression was 3 months. The median survival was 6 months. A combination of MMC with weekly high-dose 5-FU and LV in patients with BTC did not improve the response rate, but produced more toxicity than weekly high-dose 5-FU and LV alone. PMID:11335790

  13. Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort

    PubMed Central

    Mazzuca, Federica; Borro, Marina; Botticelli, Andrea; Mazzotti, Eva; Marchetti, Luca; Gentile, Giovanna; La Torre, Marco; Lionetto, Luana; Simmaco, Maurizio; Marchetti, Paolo

    2016-01-01

    Despite the wide use of 5-fluorouracil-based chemotherapy, development of severe toxicity that follow the treatment is not a rare event. The efforts to establish pretreatment tools for toxicity prediction, led to the development of various pharmacogenetic and biochemical assays, mainly targeted to assess the activity level of dihydropyrimidine dehydrogenase (DPD), the main metabolizing enzyme for 5-fluorouracil. Using peripheral blood mononuclear cells, we developed a biochemical assay, that is not limited to the evaluation of DPD activity, but determines the net result of all the enzymatic transformation of 5FU, in terms of the amount of drug consumed by the cells in a time unit. This parameter, named 5-fluorauracil degradation rate, presents a normal distribution inside the population and highlight the presence of an ultra-rapid metabolizers class of subjects, besides the expected poor metabolizers class. Here we will show that, in a colorectal cancer patient cohort, both poor and ultra-rapid metabolizers have significantly increased the risk of developing severe toxicity (grade3–4). Patient stratification depending on the individual 5-fluorouracil degradation rate allows to identify a 10% of the overall population at high risk of developing severe toxicity, compared to the 1.3% (as assessed in the Italian population) identified by the most commonly employed pharmacogenetic test, including the DPD polymorphism IVS14+1G>A. PMID:26967565

  14. Studies of variation in inherent sensitivities to radiation, 5-fluorouracil and methotrexate in a series of human and murine tumor cell lines in vitro

    SciTech Connect

    Bellamy, A.S.; Whelan, R.D.H.; Hill, B.T.

    1984-01-01

    Clinical studies have reported reduced response rates to subsequent chemotherapy in certain tumors recurring after radiotherapy. These authors have investigated whether there are any correlations between radiation and drug responses in vitro using a range of murine and human tumor cell lines. They have compared sensitivities to X-irradiation and to 24 hr exposures to two widely used antitumor drugs, methotrexate and 5-fluorouracil. The 4 murine lines selected showed a range of radiation responses with Do values of 0.48-0.76 Gy. Methotrexate sensitivities also exhibited an 800-fold difference which appeared to correlate inversely with radiation response. Sensitivity to 5-FU was less variable in these cells and was unrelated to radiation response. In contrast, in the human lines tested, no correlations were observed between drug sensitivities and radiation response. The six lines tested showed a range of radiation responses with Do values of 0.66-1.59 Gy. Methotrexate sensitivities ranged only over a 150-fold concentration but, contrasting with data from the murine cells, no correlation with radiation response was apparent. Similarly, no correlations between response to 5-fluorouracil and radiation or 5-fluorouracil and methotrexate were noted, which is inconsistent with results using murine cells.

  15. Evaluation of the Efficacy of Combined Continuous Arterial Infusion and Systemic Chemotherapy for the Treatment of Advanced Pancreatic Carcinoma

    SciTech Connect

    Ikeda, O. Kusunoki, S.; Kudoh, K.; Takamori, H.; Tsuji, T.; Kanemitsu, K.; Yamashita, Y.

    2006-06-15

    Purpose. To evaluate the effects of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in patients with advanced pancreatic carcinoma. Methods. CTAI was performed in 17 patients with stage IV pancreatic cancer with (n = 11) or without (n = 6) liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The inferior pancreatic artery (IPA) was embolized to achieve delivery of the pancreatic blood supply through only the celiac artery. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. Treatment effects were evaluated based on the primary tumor size, liver metastasis, and survival time and factors such as tumor size, tumor location, and stage of pancreatic carcinoma; the embolized arteries were analyzed with respect to treatment effects and prognosis. Results. A catheter was fixed in the gastroduodenal artery and splenic artery in 10 and 7 patients, respectively. Complete peripancreatic arterial occlusion was successful in 10 patients. CT showed a decrease in tumor size in 6 of 17 (35%) patients and a decrease in liver metastases in 6 of 11 (55%) patients. The survival time ranged from 4 to 18 months (mean {+-} SD, 8.8 {+-} 1.5 months). Complete embolization of arteries surrounding the pancreas was achieved in 10 patients; they manifested superior treatment effects and prognoses (p < 0.05). Conclusion. In patients with advanced pancreatic cancer, long-term CTAI with systemic chemotherapy appeared to be effective not only against the primary tumor but also against liver metastases. Patients with successfully occluded peripancreatic arteries tended to survive longer.

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

    PubMed Central

    Lv, Xing; Xia, Wei-Xiong; Ke, Liang-Ru; Yang, Jing; Qiu, Wen-Zhe; Yu, Ya-Hui; Liang, Hu; Huang, Xin-Jun; Liu, Guo-Yin; Zeng, Qi; Guo, Xiang; Xiang, Yan-Qun

    2016-01-01

    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 were the most common grade 3–4 adverse events in the TC group, and mucositis was the most common in the FC group. Conclusion These data indicate that TC and FC therapies have similar efficacy in treating locally advanced NPC and both are well tolerated. PMID:27574453

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

    SciTech Connect

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

    2005-05-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2014-11-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. Antitumor activity of electrospun polylactide nanofibers loaded with 5-fluorouracil and oxaliplatin against colorectal cancer.

    PubMed

    Zhang, Jiayu; Wang, Xue; Liu, Tongjun; Liu, Shi; Jing, Xiabin

    2016-03-01

    The purpose of this study was to evaluate both in vitro and in vivo anticancer activities against colorectal cancer (CRC) of electrospun polylactide (PLA) nanofibers loaded with 5-fluorouracil (5-Flu) and oxaliplatin. For in vitro evaluation, human CRC HCT8 cells were directly exposed to the drug-loaded fiber mats, followed with MTT and flow cytometry (FCM) assay. For in vivo evaluation, the drug-loaded fiber mats were locally implanted into mouse colorectal CT26 tumor-bearing mice, followed with histological analysis and detection of survival rate. The results showed that the drug-loaded fiber mats was similar to that of the combination of free 5-Flu and oxaliplatin in vitro cytotoxicity but was much superior to intravenous injection of free drug in vivo anticancer activities, presenting with suppressed tumor growth rate and prolonged survival time of mice. In conclusion, anticancer activities of 5-Flu and oxaliplatin against CRC can be significantly improved by using PLA electrospun nanofibers as local drug delivery system. PMID:24870201

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

    PubMed

    Tolba, Mai F; Abdel-Rahman, Sherif Z

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2000-09-01

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

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

    PubMed Central

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

    2014-01-01

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

  7. Second-Line Irinotecan, Leucovorin, and 5-Fluorouracil for Gastric Cancer Patients after Failed Docetaxel and S-1

    PubMed Central

    Jung, Joo Young; Ryu, Min-Hee; Ryoo, Baek-Yeol; Han, Boram; Cho, Ji Woong; Lim, Man Sup; Lim, Hyun; Kang, Ho Suk; Kim, Min-Jeong; Ha, Hong Il; Song, Hunho; Kim, Jung Han; Kim, Hyeong Su; Kang, Yoon-Koo; Zang, Dae Young

    2016-01-01

    Background. This retrospective study aimed to assess the efficacy and toxicities of second-line chemotherapy with irinotecan, leucovorin, and 5-fluorouracil (5-FU) in metastatic gastric cancer (MGC) patients previously treated with docetaxel and S-1 with or without oxaliplatin (DS/DOS). Patients and Methods. We reviewed the data of patients who had previously been treated with first-line DS/DOS and received biweekly irinotecan-based chemotherapy (FOLFIRI/IFL) between October 2004 and November 2011. Results. A total of 209 cycles were administered to 35 patients, with a median of 4 (range, 1–22) cycles each. The overall response rate in 29 response-assessable patients was 17.2%, including 2 complete and 3 partial responses. The median progression-free and overall survivals were 3.81 (95% confidence interval [CI], 1.82–5.80) months and 6.24 (95% CI, 1.44–11.04) months, respectively. The major grade 3/4 toxicity was neutropenia (8.6%). Conclusion. FOLFIRI/IFL chemotherapy showed modest antitumour activity and tolerable toxicities in DS/DOS-treated MGC patients. PMID:26839542

  8. Second-Line Irinotecan, Leucovorin, and 5-Fluorouracil for Gastric Cancer Patients after Failed Docetaxel and S-1.

    PubMed

    Jung, Joo Young; Ryu, Min-Hee; Ryoo, Baek-Yeol; Han, Boram; Cho, Ji Woong; Lim, Man Sup; Lim, Hyun; Kang, Ho Suk; Kim, Min-Jeong; Ha, Hong Il; Song, Hunho; Kim, Jung Han; Kim, Hyeong Su; Kang, Yoon-Koo; Zang, Dae Young

    2016-01-01

    Background. This retrospective study aimed to assess the efficacy and toxicities of second-line chemotherapy with irinotecan, leucovorin, and 5-fluorouracil (5-FU) in metastatic gastric cancer (MGC) patients previously treated with docetaxel and S-1 with or without oxaliplatin (DS/DOS). Patients and Methods. We reviewed the data of patients who had previously been treated with first-line DS/DOS and received biweekly irinotecan-based chemotherapy (FOLFIRI/IFL) between October 2004 and November 2011. Results. A total of 209 cycles were administered to 35 patients, with a median of 4 (range, 1-22) cycles each. The overall response rate in 29 response-assessable patients was 17.2%, including 2 complete and 3 partial responses. The median progression-free and overall survivals were 3.81 (95% confidence interval [CI], 1.82-5.80) months and 6.24 (95% CI, 1.44-11.04) months, respectively. The major grade 3/4 toxicity was neutropenia (8.6%). Conclusion. FOLFIRI/IFL chemotherapy showed modest antitumour activity and tolerable toxicities in DS/DOS-treated MGC patients. PMID:26839542

  9. Discovery and Delivery of Synergistic Chemotherapy Drug Combinations to Tumors

    NASA Astrophysics Data System (ADS)

    Camacho, Kathryn Militar

    Chemotherapy combinations for cancer treatments harbor immense therapeutic potentials which have largely been untapped. Of all diseases, clinical studies of drug combinations are the most prevalent in oncology, yet their effectiveness is disputable, as complete tumor regressions are rare. Our research has been devoted towards developing delivery vehicles for combinations of chemotherapy drugs which elicit significant tumor reduction yet limit toxicity in healthy tissue. Current administration methods assume that chemotherapy combinations at maximum tolerable doses will provide the greatest therapeutic effect -- a presumption which often leads to unprecedented side effects. Contrary to traditional administration, we have found that drug ratios rather than total cumulative doses govern combination therapeutic efficacy. In this thesis, we have developed nanoparticles to incorporate synergistic ratios of chemotherapy combinations which significantly inhibit cancer cell growth at lower doses than would be required for their single drug counterparts. The advantages of multi-drug incorporation in nano-vehicles are many: improved accumulation in tumor tissue via the enhanced permeation and retention effect, limited uptake in healthy tissue, and controlled exposure of tumor tissue to optimal synergistic drug ratios. To exploit these advantages for polychemotherapy delivery, two prominent nanoparticles were investigated: liposomes and polymer-drug conjugates. Liposomes represent the oldest class of nanoparticles, with high drug loading capacities and excellent biocompatibility. Polymer-drug conjugates offer controlled drug incorporations through reaction stoichiometry, and potentially allow for delivery of precise ratios. Here, we show that both vehicles, when armed with synergistic ratios of chemotherapy drugs, significantly inhibit tumor growth in an aggressive mouse breast carcinoma model. Furthermore, versatile drug incorporation methods investigated here can be broadly

  10. CHEMOTHERAPY: A new standard combination for recurrent ovarian cancer?

    PubMed Central

    Bast, Robert C.; Markman, Maurie

    2010-01-01

    Ovarian cancer that recurs more than 6 months following primary chemotherapy can respond to many different drugs, but retreatment with a combination of carboplatin and paclitaxel has become a standard of care. A combination of pegylated liposomal doxorubicin and carboplatin may provide a slightly but significantly greater therapeutic index than carboplatin and paclitaxel. PMID:20877420

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

    PubMed

    Bukkitgar, Shikandar D; Shetti, Nagaraj P

    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(-5)-1×10(-7)M and detection limit and quantification limit were calculated to be 2.04nM and 6.18nM respectively. Further, the sensor was successfully applied in pharmaceutical and biological fluid sample analysis. PMID:27157751

  12. Alteration of the Redox State with Reactive Oxygen Species for 5-Fluorouracil-Induced Oral Mucositis in Hamsters

    PubMed Central

    Wada-Takahashi, Satoko; Takahashi, Shun-suke; Lee, Masaichi Chang-il

    2013-01-01

    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. PMID:24376587

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

    PubMed

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

    2015-02-01

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

  14. [Combined chemotherapy of disseminated skin melanoma].

    PubMed

    Dement'eva, N P; Voznyĭ, E K; Koroleva, L A

    1978-01-01

    The author's experience with nitrosomethylurea+prospidine treatment in 37 patients having disseminated melanoma is described. The mentioned scheme of the combination therapy is proved to be effective. PMID:741699

  15. Prognostic advantage of irinotecan dose escalation according to uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping in patients with metastatic colorectal cancer treated with bevacizumab combined with 5-fluorouracil/leucovorin with irinotecan in a first-line setting.

    PubMed

    Lu, Chien-Yu; Huang, Ching-Wen; Hu, Huang-Ming; Tsai, Hsiang-Lin; Huang, Chun-Ming; Yu, Fang-Jung; Huang, Ming-Yii; Chang, Se-Fen; Huang, Meng-Lin; Wang, Jaw-Yuan

    2014-08-01

    This study compared the clinical responses of patients with metastatic colorectal cancer (mCRC) with 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) plus bevacizumab therapy either with or without uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping and irinotecan dose escalation. Of 107 total patients with mCRC, 79 were classified as the study group and 28 as the control group. The study group received irinotecan dose escalation based on UGT1A1 genotyping whereas the control group did not. Clinicopathologic features, response rates, and survival were compared for the 2 groups. The clinical response rate of patients with mCRC treated with FOLFIRI plus bevacizumab under UGT1A1 genotyping and irinotecan dose escalation was significantly better than that of those without these prospective tests and dose escalation (P = 0.028). Both progression-free survival (PFS) and overall survival were significantly greater in clinical responders than nonresponders (both, P < 0.001), and PFS was significantly greater among the study group patients than among the control group patients, with a median PFS of 12.2 months vs 9.4 months (P = 0.025). Grade 3/4 adverse events were not significantly different between the 2 groups (P = 0.189). Patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan to obtain a better clinical response/outcome with comparable toxicities. PMID:24462762

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

    PubMed Central

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

    2015-01-01

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

  17. Sucralfate mouthwash for prevention and treatment of 5-fluorouracil-induced mucositis: a randomized, placebo-controlled trial.

    PubMed

    Nottage, Michelle; McLachlan, Sue-Anne; Brittain, Mary-Anne; Oza, Amit; Hedley, David; Feld, Ronald; Siu, Lillian L; Pond, Gregory; Moore, Malcolm J

    2003-01-01

    A randomized, double-blind, placebo-controlled trial was conducted to evaluate the effectiveness of a sucralfate mouthwash in preventing and alleviating oral mucositis induced by 5-fluorouracil (5FU). A total of 81 patients with colorectal cancer were enrolled. Patients were studied during their first cycle of chemotherapy with 5FU and leucovorin (LV) daily for 5 days every 4 weeks (Mayo Clinic schedule). Patients were randomly allocated to receive either a sucralfate suspension or a placebo suspension that was identical in appearance. Patients were instructed to use the suspension as a mouthwash four times daily from the beginning of the chemotherapy cycle. All patients received oral cryotherapy. Patients graded the severity of their own symptoms on a daily basis, and this was the primary outcome measure. There was no difference in the frequency or severity of oral mucositis between the sucralfate- and the placebo-treated group. Some mucositis was reported by 79% of the patient group. Assessment of mucositis by trial staff underestimated the incidence of this problem. Results of this trial do not support the hypothesis that a sucralfate mouthwash can prevent or alleviate oral mucositis induced by 5FU. Patient reporting of mucositis is a more sensitive instrument for assessment of mucositis than review by medical staff. PMID:12527953

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

    PubMed

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

    2016-07-01

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

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

    EPA Science Inventory

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

  20. Genotype-phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction.

    PubMed

    Gentile, G; Botticelli, A; Lionetto, L; Mazzuca, F; Simmaco, M; Marchetti, P; Borro, M

    2016-08-01

    5-Fluorouracil is among the most widely used anticancer drug, but a fraction of treated patients develop severe toxicity, with potentially lethal injuries. The predictive power of the available pretreatment assays, used to identify patients at risk of severe toxicity, needs improvements. This study aimed to correlate a phenotypic marker of 5-fluorouracil metabolism (the individual degradation rate of 5-fluorouracil-5-FUDR) with 15 functional polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD). Single SNP (single-nucleotide polymorphism) analysis revealed that the SNPs rs1801160, rs1801265, rs2297595 and rs3918290 (splice site variant IVS14+1G>A) were significantly associated with a decreased value of 5-FUDR, and the rs3918290 causing the larger decrease. Multi-SNP analysis showed that a three-SNP haplotype (Hap7) involving rs1801160, rs1801265 and rs2297595 causes a marked decrease in 5-FUDR, comparable to that caused by the splice site variant rs3918290, which is the main pharmacogenetic marker associated with severe fluorouracil toxicity. The similar effect played by Hap7 and by the splice site variant rs3918290 upon individual 5-FUDR suggests that Hap7 could also represent a similar determinant of fluorouracil toxicity. Haplotype assessment could improve the predictive value of DPYD genetic markers aimed at the pre-emptive identification of patients at risk of severe 5-fluorouracil toxicity.The Pharmacogenomics Journal advance online publication, 28 July 2015; doi:10.1038/tpj.2015.56. PMID:26216193

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

    EPA Science Inventory

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

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

    PubMed Central

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

    1998-01-01

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

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

    SciTech Connect

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

    1985-04-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  6. A phase I/II study of leucovorin, carboplatin and 5-fluorouracil (LCF) in patients with carcinoma of unknown primary site or advanced oesophagogastric/pancreatic adenocarcinomas.

    PubMed Central

    Rigg, A.; Cunningham, D.; Gore, M.; Hill, M.; O'Brien, M.; Nicolson, M.; Chang, J.; Watson, M.; Norman, A.; Hill, A.; Oates, J.; Moore, H.; Ross, P.

    1997-01-01

    Carcinoma of unknown primary site (CUPS) accounts for 5-10% of all malignancies. Forty patients with metastatic CUPS or advanced oesophagogastric/pancreatic adenocarcinomas were recruited. Eligibility included ECOG performance status 0-2, minimum life expectancy of 3 months and measurable disease. The regimen consisted of bolus intravenous 5 fluorouracil (5-FU) and leucovorin (20 mg m-2) days 1-5 and carboplatin (AUC5) on day 3. The leucovorin/carboplatin/5-FU (LCF) was repeated every 4 weeks. The starting dose of 5-FU was 350 mg m-2 day-1 with escalation to 370 and then 400 mg m-2 day -1 after the toxicity at the previous level had been assessed. The maximum tolerated dose (MTD) was defined as the dosage of 5-FU that achieved 60% grade 3/4 toxicity. In addition, objective and symptomatic responses, quality of life and survival were assessed. The MTD of 5-FU in the LCF regimen was 370 mg m-2. The predominant toxicity was asymptomatic marrow toxicity. The 350 mg m-2 level was then expanded. There were two toxic deaths due to neutropenic sepsis, one at 370 mg m-2 after one course and one at 350 mg m-2 after four courses. The objective response rate was 25% with one complete response (CR) and nine partial responses (PRs). The median duration of response was 3.4 months (range 1-10). The CR and eight of the nine PRs were in CUPS patients. Twelve patients developed progressive disease on LCF. Median survival for all 40 patients was 7.8 months (10 months median survival for those treated at 350 mg m-2). The majority of patients described a symptomatic improvement with LCF chemotherapy. The recommended dose of 5-FU for future studies is 350 mg m-2 combined with leucovorin 20 mg m-2 and carboplatin (AUC5). PMID:9000605

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

    PubMed Central

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

    2015-01-01

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

  8. Chemotherapy

    MedlinePlus

    ... saved articles window. My Saved Articles » My ACS » Chemotherapy Chemotherapy (chemo) usually refers to the use of ... better sense of control over your cancer treatment. Chemotherapy Basics How Is Chemotherapy Used to Treat Cancer? ...

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2002-05-01

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

  11. Is there any effect of bolus and/or infusion 5-fluorouracil treatment on microalbuminuria in immediate or long term?

    PubMed

    Tanriverdi, Ozgur

    2014-07-01

    5-Fluorouracil is a widely used cytotoxic chemotherapeutic agent in the treatment settings particularly in patients with gastrointestinal cancer. Various studies on the cardiac adverse effects of 5-fluorouracil, reported the likelihood of altered myocardial contractility and vascular endothelial damage caused by this agent. However, the mechanism underlying 5-fluorouracil-related cardiotoxicity is not clear. In certain experimental studies, thrombotic processes occurring in microvascular field were supposed to play a role in this condition. In the light of this knowledge, the administration of 5-fluorouracil may be considered to cause renal vascular endothelial damage that may result in the altered endothelial permeability. As a result of endothelial dysfunction, increased urinary albumin excretion may be in question and no study investigating this potential direct relationship has been available in medical literature. Based on this evidence, the hypothesis of that 5-fluorouracil might cause renal vascular dysfunction and microalbuminuria, was discussed in this article along with the basic knowledge. PMID:24755457

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

    PubMed Central

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

    2014-01-01

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

  13. Radiochemotherapy With Cisplatin and 5-Fluorouracil After Transurethral Surgery in Patients With Bladder Cancer

    SciTech Connect

    Weiss, Christian . E-mail: Christian.Weiss@strahlen.med.uni-erlangen.de; Engehausen, Dirk G.; Krause, Frens S.; Papadopoulos, Thomas; Dunst, Juergen; Sauer, Rolf; Roedel, Claus

    2007-07-15

    Purpose: To give an update on the long-term outcome of an intensified protocol of combined radiochemotherapy (RCT) with 5-fluorouracil (5-FU) and cisplatin after initial transurethral resection of bladder tumor (TURBT) with selective organ preservation in bladder cancer. Methods and Materials: One hundred twelve patients with muscle-invading or high-risk T1 (G3, associated Tis, multifocality, diameter >5 cm) bladder cancer were enrolled in a protocol of TURBT followed by concurrent cisplatin (20 mg/m{sup 2}/day as 30-min infusion) and 5-FU (600 mg/m{sup 2}/day as 120-h continuous infusion), administered on Days 1-5 and 29-33 of radiotherapy. Response to treatment was evaluated by restaging TURBT 4-6 weeks after RCT. In case of invasive residual tumor or recurrence, salvage cystectomy was recommended. Results: Ninety-nine patients (88.4%) had no detectable tumor at restaging TURBT; 71 patients (72%) have been continuously free from local recurrence or distant metastasis. Superficial relapse occurred in 13 patients and muscle-invasive recurrence in 11 patients. Overall and cause-specific survival rates for all patients were 74% and 82% at 5 years, respectively. Of all surviving patients, 82% maintained their own bladder, 79% of whom were delighted or pleased with their urinary condition. Hematologic Grade 3/4 toxicity occurred in 23%/6% and Grade 3 diarrhea in 21% of patients. One patient required salvage cystectomy due to a shrinking bladder. Conclusion: Concurrent RCT with 5-FU/cisplatin has been associated with acceptable acute and long-term toxicity. Overall and cause-specific survival rates are encouraging. More than 80% of patients preserved their well-functioning bladder.

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2013-06-01

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

  16. Occurrence and severity of alopecia in patients on combination chemotherapy.

    PubMed

    Pai, G S; Vimala, A M; Dinesh, M

    2000-01-01

    The aim of the study was to evaluate the occurrence and severity of alopecia resulting from combination chemotherapy on cancer patients. The study was conducted during the period 1994-1996 on 58 confirmed cases of malignancies attending the Kasturba Medical College Hospital, Mangalore, South India. The treatment regimens followed were standard protocols recommended for those malignancies and which are widely adopted. Specific drug combinations, their dosage and routes and schedules of administration were studied. The influence of 20 different treatment regimens, most of them in combination chemotherapy, were studied. The patients studied were not receiving any other medication which could have caused alopecia as observed in the present study. The pathophysiology of the hair, as influenced by the treatment regimens, were studied by examination of samples of the affected hairs under a Leica compound microscope. Alopecia was the most dominant side effect influencing 35 of the 58 patients undergoing the treatment (60%). The severity of alopecia was assessed by grouping them in four distinct grades. Specific drugs and their combinations causing varying degrees of severity were identified. The initiation of hair loss in different treatment regimens were analysed. It is seen that alopecia is an early manifestation of cutaneous side effects of cancer chemotherapy. In a majority of patients, the manifestation initiated after the first or the second cycle of administration of the rapeutic regimen, indicating a time interval of 1 to 8 weeks after the start of chemotherapy. Single agent drugs, when used alone or in combination with immunomodulator drugs seem to cause much less side effects, including alopecia, when compared to multiple drug regimens. Microscopic examination of the affected hair showed trichorrhexis, fragmentation, decrease in diameter and depigmentation of the hair shaft. PMID:11876617

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

    PubMed Central

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

    2015-01-01

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

  18. 5-Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial.

    PubMed

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

    1996-10-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  20. A Stability-Indicating RP-HPLC Assay Method for 5-Fluorouracil

    PubMed Central

    Sinha, V. R.; Kumar, R. V.; Bhinge, J. R.

    2009-01-01

    The present study describes the development of a validated RP-HPLC method for the determination of 5-fluorouracil in presence of its degradation products or other pharmaceutical excipients. Stress studies were performed on 5-fluorouracil and it was found that it degrades sufficiently in alkaline conditions, while negligible degradation was observed in acidic, neutral, oxidative and photolytic conditions. The peaks of the degradation products were not observed in the chromatogram due to the nonchromophoric nature of the degradation moiety formed. The separations were carried out on a C-18 reversed phase column (Phenomenex; Prodigy ODS3V, 250×4.6 mm, 5 μ) using 50mM KH2PO4 (pH, 5.0) as mobile phase at a flow rate of 1.2 ml/min and temperature of 30°. The wavelength of detection was 254 nm. A retention time of nearly 6 minutes was obtained. Analytical validation parameters such as specificity and selectivity, linearity, accuracy and precision were evaluated. The calibration curve for 5-fluorouracil was linear (r2=0.999±0.0005) from range of 10 μg/ml to 100 μg/ml. Relative standard deviation values for all the key parameters, was less than 2.0 %. The recovery of the drug after standard addition to the degraded sample was found to be 104.69%. Thus, the developed RP-HPLC method was found to be suitable for the determination of 5-fluorouracil in bulk as well as stability samples of the pharmaceutical dosage forms containing various excipients. PMID:20376215

  1. 5-Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells.

    PubMed

    Cottone, Lucia; Capobianco, Annalisa; Gualteroni, Chiara; Perrotta, Cristiana; Bianchi, Marco E; Rovere-Querini, Patrizia; Manfredi, Angelo A

    2015-03-15

    Signals released by leukocytes contribute to tumor growth and influence the efficacy of antineoplastic treatments. The outcome of peritoneal carcinomatosis treatments is unsatisfactory, possibly because chemotherapy activates events that have in the long-term deleterious effects. In this study we offer evidence that 5-fluorouracile (5-FU), besides provoking apoptosis of MC38 colon carcinoma cells, induces a striking attraction of leukocytes both in an orthotopic model of colon carcinomatosis in vivo and in monocyte-migration assays in vitro. Leukocyte attraction depends on the presence of High Mobility Group Box 1 (HMGB1), an endogenous immune adjuvant and chemoattractant released by dying cells. Leukocyte recruitment is prevented in vivo and in vitro using blocking antibodies against HMGB1 and its competitive antagonist BoxA or by interfering with HMGB1 expression. Autophagy is required for leukocyte chemoattraction, since the latter abates upon pharmacological blockade of the autophagic flux while activation of autophagy per se, in the absence of death of colon carcinoma cells, is not sufficient to attract leukocytes. Our results identify autophagy induction and HMGB1 release in colon carcinoma cells as key events responsible for 5-FU elicited leukocyte attraction and define a novel rate-limiting target for combinatorial therapies. PMID:25098891

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

    PubMed

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

    2016-04-01

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

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

    PubMed Central

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

    2016-01-01

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

  4. [18F]2-Fluoro-2-deoxy-D-glucose incorporation by AGS gastric adenocarcinoma cells in vitro during response to epirubicin, cisplatin and 5-fluorouracil

    PubMed Central

    Suttie, S A; Park, K G M; Smith, T A D

    2007-01-01

    Decreased tumour [18F]2-fluoro-2-deoxy-D-glucose (18FDG) incorporation is related to response however its significance at the cell level in gastro-oesophageal cancer and how it relates to cell death is unknown. Here human gastric adenocarcinoma (AGS) cells were treated with lethal dose 10 and 50 (LD10 and LD50), determined by using the MTT assay, of the three drugs, epirubicin, 5-fluorouracil and cisplatin, commonly used in the treatment of patients with gastro-oesophageal cancer. 18FDG incorporation was determined after 48 and 72 h of treatment with each drug and related to drug-induced changes in glucose transport, hexokinase activity, cell cycle distribution and annexin V-PE binding (a measure of apoptosis). Treatment of cells for 48 and 72 h with LD50 doses of cisplatin resulted in reductions in 18FDG incorporation of 27 and 25% respectively and of 5-fluorouracil reduced 18FDG incorporation by 34 and 33% respectively: epirubicin treatment reduced incorporation by 30 and 69% respectively. Cells that had been treated for 72 h with each drug were incubated in drug-free media for a further 6 days to determine their ability to recover. Comparison of the ability to recover from the chemotherapy agent, with 18FDG incorporation before the recovery period allowed an assessment of the predictive ability of 18FDG incorporation. Cells treated with either 5-fluorouracil or cisplatin demonstrated recovery on removal of the drug. In contrast, cells treated with epirubicin did not recover corresponding with the greatest 72 h treatment decrease in 18FDG incorporation. In contrast to adherent cells treated with cisplatin or 5-fluorouracil, adherent epirubicin-treated cells also exhibited very high levels of apoptosis. Glucose transport was decreased after each treatment whilst hexokinase activity was only decreased after 72 h of treatment with each drug. There was no consistent relationship observed between 18FDG incorporation and cell cycle distribution. Our results

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2015-01-01

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

  7. Rituximab in combination with multiagent chemotherapy for pediatric follicular lymphoma.

    PubMed

    Kumar, Riten; Galardy, Paul J; Dogan, Ahmet; Rodriguez, Vilmarie; Khan, Shakila P

    2011-08-01

    Given the rarity of follicular lymphoma (FL) in children, there is limited data on which to base treatment recommendations. Herein, we report our institutional experience of using rituximab with multiagent chemotherapy for pediatric FL. Six pediatric patients were diagnosed with FL from 2000 to 2009. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for varying durations. Five of the six patients remain in remission with a median follow-up of 31 months. Larger randomized trials are indicated to establish the efficacy of this regimen for pediatric FL patients. PMID:21462303

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

    PubMed Central

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

    2015-01-01

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

  9. Oxaliplatin and 5-fluorouracil hepatic infusion with lipiodolized chemoembolization in large hepatocellular carcinoma

    PubMed Central

    Li, Jing-Huan; Xie, Xiao-Ying; Zhang, Lan; Le, Fan; Ge, Ning-Ling; Li, Li-Xin; Gan, Yu-Hong; Chen, Yi; Zhang, Ju-Bo; Xue, Tong-Chun; Chen, Rong-Xin; Xia, Jing-Lin; Zhang, Bo-Heng; Ye, Sheng-Long; Wang, Yan-Hong; Ren, Zheng-Gang

    2015-01-01

    AIM: To investigate transarterial chemoembolization (TACE) with hepatic infusion of oxaliplatin and 5-fluorouracil and Lipiodol chemoembolization in large hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 132 patients with unresectable HCCs larger than 10 cm were treated with hepatic infusion of oxaliplatin and 5-fluorouracil followed by Lipiodol chemoembolization. The primary endpoint was overall survival (OS). Sixteen-week disease-control rate, time to progression (TTP), and major complications were also studied. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP. RESULTS: A total of 319 procedures were performed in the 132 patients. Eleven (8.3%) patients received radical resection following TACE treatment (median time to initial TACE 4.3 ± 2.3 mo). The median OS and TTP were 10.3 and 3.0 mo respectively, with a 50.0% 16-wk disease-control rate. Major complications were encountered in 6.0% (8/132) of patients following TACE and included serious jaundice in 1.5% (2/132) patients, aleukia in 1.5% (2/132), and hepatic failure in 3.0% (4/132). One patient died within one month due to serious hepatic failure and severe sepsis after receiving the second TACE. The risk factor associated with TTP was baseline alpha-fetoprotein level, and vascular invasion was an independent factor related to OS. CONCLUSION: Hepatic infusion of oxaliplatin and 5-fluorouracil followed by lipiodolized-chemoembolization is a safe and promising treatment for patients with HCCs larger than 10 cm in diameter. PMID:25852283

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

    PubMed

    Loprinzi, C L; Dose, A M

    1990-01-01

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

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

    PubMed

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

    2013-06-01

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

  12. 5-Fluorouracil-induced RNA stress engages a TRAIL-DISC-dependent apoptosis axis facilitated by p53

    PubMed Central

    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

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

    PubMed Central

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

    2016-01-01

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

  14. Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma.

    PubMed

    Kataoka, Junro; Shiraha, Hidenori; Horiguchi, Shigeru; Sawahara, Hiroaki; Uchida, Daisuke; Nagahara, Teruya; Iwamuro, Masaya; Morimoto, Hiroki; Takeuchi, Yasuto; Kuwaki, Kenji; Onishi, Hideki; Nakamura, Shinichiro; Takaki, Akinobu; Nouso, Kazuhiro; Yagi, Takahito; Yamamoto, Kazuhide; Okada, Hiroyuki

    2016-05-01

    Runt-related transcription factor 3 (RUNX3) is known to function as a tumor suppressor in gastric cancer and other types of cancers, including hepatocellular carcinoma (HCC). However, its role has not been fully elucidated. In the present study, we aimed to evaluate the role of RUNX3 in HCC. We used the human HCC cell lines Hep3B, Huh7 and HLF; RUNX3 cDNA was introduced into Hep3B and Huh7 cells, which were negative for endogenous RUNX3 expression, and RUNX3 siRNA was transfected into HLF cells, which were positive for endogenous RUNX3. We analyzed the expression of RUNX3 and multidrug resistance-associated protein (MRP) by immunoblotting. MTT assays were used to determine the effects of RUNX3 expression on 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity. Finally, 23 HCC specimens resected from patients with HCC at Okayama University Hospital were analyzed, and correlations among immunohistochemical expression of RUNX3 protein and MRP protein were evaluated in these specimens. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, MRP3 and MRP5 in the RUNX3-negative cells, whereas knockdown of RUNX3 in the HLF cells stimulated the expression of these MRPs. An inverse correlation between RUNX3 and MRP expression was observed in the HCC tissues. Importantly, loss of RUNX3 expression contributed to 5-FU and CDDP resistance by inducing MRP expression. These data have important implications in the study of chemotherapy resistance in HCC. PMID:26985715

  15. Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma

    PubMed Central

    KATAOKA, JUNRO; SHIRAHA, HIDENORI; HORIGUCHI, SHIGERU; SAWAHARA, HIROAKI; UCHIDA, DAISUKE; NAGAHARA, TERUYA; IWAMURO, MASAYA; MORIMOTO, HIROKI; TAKEUCHI, YASUTO; KUWAKI, KENJI; ONISHI, HIDEKI; NAKAMURA, SHINICHIRO; TAKAKI, AKINOBU; NOUSO, KAZUHIRO; YAGI, TAKAHITO; YAMAMOTO, KAZUHIDE; OKADA, HIROYUKI

    2016-01-01

    Runt-related transcription factor 3 (RUNX3) is known to function as a tumor suppressor in gastric cancer and other types of cancers, including hepatocellular carcinoma (HCC). However, its role has not been fully elucidated. In the present study, we aimed to evaluate the role of RUNX3 in HCC. We used the human HCC cell lines Hep3B, Huh7 and HLF; RUNX3 cDNA was introduced into Hep3B and Huh7 cells, which were negative for endogenous RUNX3 expression, and RUNX3 siRNA was transfected into HLF cells, which were positive for endogenous RUNX3. We analyzed the expression of RUNX3 and multidrug resistance-associated protein (MRP) by immunoblotting. MTT assays were used to determine the effects of RUNX3 expression on 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity. Finally, 23 HCC specimens resected from patients with HCC at Okayama University Hospital were analyzed, and correlations among immunohistochemical expression of RUNX3 protein and MRP protein were evaluated in these specimens. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, MRP3 and MRP5 in the RUNX3-negative cells, whereas knockdown of RUNX3 in the HLF cells stimulated the expression of these MRPs. An inverse correlation between RUNX3 and MRP expression was observed in the HCC tissues. Importantly, loss of RUNX3 expression contributed to 5-FU and CDDP resistance by inducing MRP expression. These data have important implications in the study of chemotherapy resistance in HCC. PMID:26985715

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  19. Effects of 5-fluorouracil on the secretory process of the rat parotid gland

    SciTech Connect

    Sandborg, R.R.

    1986-01-01

    Experimental animals were injected intraperitoneally with 100 mg/kg 5-fluorouracil for three days. The total volume, amylase and protein content of cannulated parotid saliva were determined following stimulation with either 5 mg/kg pilocarpine or 5 mg/kg isoproterenol in experimental, pair-fed , and control animals. Saliva from experimental animals was significantly lower in volume, amylase and protein content than both control groups. 5-fluorouracil treatment reduced the total glandular amylase per unit DNA in both unstimulated and isoproterenol-stimulated parotid glands. Decreased protein synthesis may be the mechanism underlying depleted secretory protein stores since the contents of isolated secretory granules from experimental parotid glands contained less radiolabelled protein than either control group and whole gland homogenates showed marked reductions in the activities of three lysosomal enzymes and total RNA content. Experimental animals contained less labelled protein in their secretory granules than controls, but secreted a greater proportion of their total glandular radiolabelled secretory protein into saliva relative to amylase suggesting that newly synthesized secretory proteins are preferentially secreted.

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

    PubMed

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

    2014-01-01

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

  1. [Combination chemotherapy with vincristine, melphalan, CCNA, cyclophosphamide, prednisone in myeloma].

    PubMed

    Le Loët, X; Monconduit, M; Menard, J F; Deshayes, P; Grobois, B; Tanguy, A; Prevost, E; Piguet, H

    1984-05-01

    The authors report the results of a prospective, multi-centre trial involving 87 patients with previously untreated myeloma who were treated by combination chemotherapy consisting of melphalan, cyclophosphamide, CCNU, prednisone and vincristine. 83.1% of patients had a high tumour mass (stage III on Durie and Salmon's classification). The response to treatment could be evaluated in 76 patients and 70% were found to respond. The median actuarial survival of the whole population is 30 months. The survival is significantly longer (p less than 0.001) in responders (median 40 months) than in non-responders (median: 17 months); the survival is significantly shorter (p less than 0.01) in subjects with renal failure (median: 10 months) than in subjects without renal failure (median: 36 months). This treatment is sufficiently well tolerated to be administered on an outpatient basis. One case of acute monoblastic leukaemia was observed. These results are similar to those reported in the literature. PMID:6740189

  2. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

    PubMed Central

    Simpson, Guy R; Relph, Kate; Harrington, Kevin; Melcher, Alan; Pandha, Hardev

    2016-01-01

    Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.

  3. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances.

    PubMed

    Simpson, Guy R; Relph, Kate; Harrington, Kevin; Melcher, Alan; Pandha, Hardev

    2016-01-01

    Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena. PMID:27579292

  4. Tirapazamine has no Effect on Hepatotoxicity of Cisplatin and 5-fluorouracil but Interacts with Doxorubicin Leading to Side Changes in Redox Equilibrium.

    PubMed

    Mandziuk, Slawomir; Matysiak, Wlodzimierz; Korga, Agnieszka; Burdan, Franciszek; Pasnik, Iwona; Hejna, Marcin; Korobowicz-Markiewicz, Agnieszka; Grzycka-Kowalczyk, Luiza; Kowalczyk, Michal; Poleszak, Ewa; Jodlowska-Jedrych, Barbara; Dudka, Jaroslaw

    2016-09-01

    Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the combined anticancer therapy of tirapazamine with a routinely used anticancer drug seems to be a promising solution. Because tirapazamine undergoes redox cycle transformation in this study, the effect of tirapazamine on redox hepatic equilibrium, lipid status and liver morphology was evaluated in rats exposed to cisplatin, doxorubicin and 5-fluorouracil. Rats were intraperitoneally injected with tirapazamine and a particular cytostatic. The animals were killed, and blood and liver were collected. Hepatic glucose, total cholesterol, triglycerides, NADH, NADPH glutathione and the activity of glucose-6-phosphate dehydrogenase were determined. Liver morphology and the immune expression of HMG-CoA-reductase were also assessed. Glucose, total cholesterol, triglycerides, bilirubin concentrations and the activity of aspartate and alanine aminotransferases were determined in the plasma. Tirapazamine displayed insignificant interactions with cisplatin and 5-fluorouracil referring to hepatic morphology and biochemical parameters. However, tirapazamine interacts with doxorubicin, thus leading to side changes in redox equilibrium and lipid peroxidation, but those effects are not severe enough to exclude that drug combination from further studies. Thus, tirapazamine seems to be a promising agent in successive studies on anticancer activity in similar schedules. PMID:26990033

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

    PubMed Central

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

    2015-01-01

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

  6. [Combination Chemotherapy Using Sorafenib and Hepatic Arterial Infusion with a Fine-Powder Formulation of Cisplatin for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis--A Case Report].

    PubMed

    Tsukamoto, Tadashi; Kanazawa, Akishige; Shimizu, Sadatoshi; Murata, Akihiro; Sakae, Masayuki; Kurihara, Shigeaki; Tashima, Tetsuzo; Deguchi, Sota; Nakai, Takashi; Kawasaki, Yasuko; Kioka, Kiyohide

    2015-11-01

    Sorafenib has been a standard therapy for advanced hepatocellular carcinoma (HCC) with portal vein thrombosis. Hepatic arterial infusion chemotherapy (HAIC) is still preferably performed in Japan because of its relatively good tumor-shrinking effect. We report a case of advanced multiple HCC with portal thrombus that responded to combination chemotherapy with sorafenib and repeat hepatic arterial infusion with a fine-powder formulation of cisplatin (IA-call®). A 57-year-old man presented for the treatment of HCC with alcoholic cirrhosis. Multiple HCC were found to be rapidly progressing with portal thrombosis. HAIC with IA-call® was performed, but the tumors progressed. TAE was performed 3 times thereafter and the main tumor shrunk to some extent. A month after the last TAE, the HCC was found to progress again, and oral sorafenib was administered. A reservoir and catheter were placed and HAIC with low-dose 5-fluorouracil and cisplatin was performed for 3 cycles following 1 HAIC cycle with epirubicin and mitomycin C, which was not effective. For 10 months after initial therapy, HAIC using IA-call® has been performed once for 6 weeks. After performing HAIC with IA-call® 5 times, the serum levels of HCC tumor markers AFP and PIVKA-Ⅱdecreased, and the tumors continued to shrink and were not stained on enhanced CT scan. The patient has been alive for 23 months after the initial therapy and has maintained stable disease. PMID:26805203

  7. Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

    PubMed Central

    Hilkens, P. H.; Pronk, L. C.; Verweij, J.; Vecht, C. J.; van Putten, W. L.; van den Bent, M. J.

    1997-01-01

    Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses. PMID:9020489

  8. Surface Molecularly Imprinted Polymer of Chitosan Grafted Poly(methyl methacrylate) for 5-Fluorouracil and Controlled Release

    PubMed Central

    Zheng, Xue-Fang; Lian, Qi; Yang, Hua; Wang, Xiuping

    2016-01-01

    The molecular surface imprinted graft copolymer of chitosan with methyl methacrylate (MIP-CS-g-PMMA) were prepared by free radical polymerization with 5-fluorouracil (5-FU) as the template molecule using initiator of ammonium persulfate as adsorption system. MIPs were characterized by FTIR, X-ray diffraction, thermo-gravimetric analysis, 1H NMR and SEM. The mechanism of graft copolymerization and factors affected graft reaction were studied in details, and the optimum reaction conditions (to the highest %G and %E as the standard) were obtained at [MMA] 1.2 mol/L, [Chitosan] 16.67 mol/L, [initiator] 0.0062 mol/L, temperature 60 °C and reaction time 7 h. MIPs exhibited high recognition selectivity and excellent combining affinity to template molecular. The in vitro release of the 5-FU was highly pH-dependent and time delayed. The release behavior showed that the drugs did not release in simulated gastric fluid (pH = 1.0), and the drug release was small in the simulated small intestinal fluid (pH = 6.8), and drug abrupt release will be produced in the simulated colon fluid (pH = 7.4), indicating excellent colon-specific drug delivery behavior. PMID:26892676

  9. Surface Molecularly Imprinted Polymer of Chitosan Grafted Poly(methyl methacrylate) for 5-Fluorouracil and Controlled Release.

    PubMed

    Zheng, Xue-Fang; Lian, Qi; Yang, Hua; Wang, Xiuping

    2016-01-01

    The molecular surface imprinted graft copolymer of chitosan with methyl methacrylate (MIP-CS-g-PMMA) were prepared by free radical polymerization with 5-fluorouracil (5-FU) as the template molecule using initiator of ammonium persulfate as adsorption system. MIPs were characterized by FTIR, X-ray diffraction, thermo-gravimetric analysis, (1)H NMR and SEM. The mechanism of graft copolymerization and factors affected graft reaction were studied in details, and the optimum reaction conditions (to the highest %G and %E as the standard) were obtained at [MMA] 1.2 mol/L, [Chitosan] 16.67 mol/L, [initiator] 0.0062 mol/L, temperature 60 °C and reaction time 7 h. MIPs exhibited high recognition selectivity and excellent combining affinity to template molecular. The in vitro release of the 5-FU was highly pH-dependent and time delayed. The release behavior showed that the drugs did not release in simulated gastric fluid (pH = 1.0), and the drug release was small in the simulated small intestinal fluid (pH = 6.8), and drug abrupt release will be produced in the simulated colon fluid (pH = 7.4), indicating excellent colon-specific drug delivery behavior. PMID:26892676

  10. 5-Fluorouracil-lipid conjugate: potential candidate for drug delivery through encapsulation in hydrophobic polyester-based nanoparticles.

    PubMed

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

    2014-11-01

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

  11. 5-Fluorouracil sensitizes colorectal tumor cells towards double stranded DNA breaks by interfering with homologous recombination repair

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Hu, Guofang; Wang, Zhehai; Wang, Yuan; Zhang, Qingqing; Tang, Ning; Guo, Jun; Liu, Liyan; Han, Xiao

    2016-01-01

    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 were 17.1% versus 7.2% (P=0.032) and 52.4% versus 30.9% (P=0.042) in group A and B, respectively. Meanwhile, group B was associated with a significantly lower rate of grade 3/4 overall toxicity than group A (P=0.039). Conclusion Our data showed that patients with locally advanced ESCC in group A had longer PFS and OS compared with

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

    PubMed

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

    2001-01-01

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

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

    PubMed

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

    2016-06-01

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

  15. Properties of the surface of a porous polymer modified with 5-fluorouracil, according to data of gas chromatography

    NASA Astrophysics Data System (ADS)

    Gus'kov, V. Yu.; Gainullina, Yu. Yu.; Ivanov, S. P.; Kudasheva, F. Kh.

    2014-06-01

    The effect or modification with 5-fluorouracil on the sorption activity of porous polymeric adsorbent is studied. It is demonstrated that the supramolecular structure formed on the surface is able to addition-ally contribute to the values of the specific retention volumes. It is found that the structure of 5-fluorouracil is capable of size effects corresponding to a molecular window of approximately 7-8 Å. It is concluded that surface polarity diminishes after modification, due to the shielding effect of four fluorine atoms present in the cavity.

  16. Resistance to the quorum-quenching compounds brominated furanone C-30 and 5-fluorouracil in Pseudomonas aeruginosa clinical isolates.

    PubMed

    García-Contreras, Rodolfo; Martínez-Vázquez, Mariano; Velázquez Guadarrama, Norma; Villegas Pañeda, Alejandra Guadalupe; Hashimoto, Takahiro; Maeda, Toshinari; Quezada, Héctor; Wood, Thomas K

    2013-06-01

    The quorum-quenching compounds brominated furanone C-30 and 5-fluorouracil inhibit the pathogenicity of the Pseudomonas aeruginosa laboratory strains PA01 and PA14; however, there is no report studying the effectiveness of these compounds for clinical isolates. Therefore, the effect of both quorum quenchers on the production of pyocyanin, elastase and alkaline protease of eight clinical strains from children was evaluated. Although both compounds were in general effective for the attenuation of these factors, three strains resistant to C-30 were found. For 5-fluorouracil, PA01 and some clinical isolates showed resistance for at least one phenotype. PMID:23620228

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

    PubMed

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

    2002-11-20

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

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

    PubMed

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

    2016-01-01

    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. PMID:27010513

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

    PubMed

    Li, Xin; Xun, Zhe; Yang, Yong

    2016-09-01

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

  20. DFT studies of 5-fluorouracil tautomers on a silicon graphene nanosheet

    NASA Astrophysics Data System (ADS)

    Yaraghi, Afshin; Ozkendir, O. Murat; Mirzaei, Mahmoud

    2015-09-01

    We have performed density functional theory (DFT) calculations to evaluate properties for tautomers of 5-fluorouracil (FU), as an anticancer medicine, in the free form and in the hybridized form with a representative silicon graphene (SiG) nanosheet. All the structures have been fully relaxed to obtain the optimized geometries and energy parameters. The results indicated that the total and binding energies have good clues to determine the properties of tautomers and hybrid structures. Moreover, quadrupole coupling constants (CQ) have been evaluated for the optimized structures to run an atomic level characterization of the investigated structures. The obtained results indicated that the properties for fluorine atoms are characteristically changed through tautomerism and hybridization processes.

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

    NASA Astrophysics Data System (ADS)

    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.

  2. Histopathological and cytochemical studies on the 5-fluorouracil treated gonads of Locusta migratoria (L.).

    PubMed

    Mittal, P K; Sheikher, C; Nath, V

    1978-01-01

    5-Fluorouracil caused necrosis in ovary only whereas testis remained unaffected even with higher doses. In ovary the ooplasm shrank; some follicular epithelial cells became pycnotic, and the nuclei of others showed an abnormal fragmentation of chromatin material; the cytoplasm of follicular epithelial cells was drawn into the peripheral empty space formed by the contraction of the ooplasm, and ultimately the follicular epithelium disintegrated. The interoocytal bridge is some oocytes was lost. The yolk formation was inhibited, and maturation of eggs was prevented. Most of the mature oocytes were also damaged. Inhibition of DNA and RNA synthesis, and decreases in proteins, carbohydrates and lipids was observed. With increased doses and post-treatment periods the effects mentioned above were increased. PMID:755613

  3. Electronic structure of uracil-like nucleobases adsorbed on Si(001): uracil, thymine and 5-fluorouracil

    NASA Astrophysics Data System (ADS)

    Molteni, Elena; Onida, Giovanni; Cappellini, Giancarlo

    2016-04-01

    We study the electronic properties of the Si(001):Uracil, Si(001):Thymine, and Si(001):5-Fluorouracil systems, focusing on the Si dimer-bridging configuration with adsorption governed by carbonyl groups. While the overall structural and electronic properties are similar, with small differences due to chemical substitutions, much larger effects on the surface band dispersion and bandgap show up as a function of the molecular orientation with respect to the surface. An off-normal orientation of the molecular planes is favored, showing larger bandgap and lower total energy than the upright position. We also analyze the localization of gap-edge occupied and unoccupied surface states. Supplementary material in the form of one pdf file available from the Journal web page at http://dx.doi.org/10.1140/epjb/e2016-70011-1

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

    PubMed

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

    2013-01-30

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

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

    PubMed Central

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

    2016-01-01

    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. PMID:27010513

  6. Combined radiotherapy and chemotherapy for high-grade brain tumours

    NASA Astrophysics Data System (ADS)

    Barazzuol, Lara

    Glioblastoma (GBM) is the most common primary brain tumour in adults and among the most aggressive of all tumours. For several decades, the standard care of GBM was surgical resection followed by radiotherapy alone. In 2005, a landmark phase III clinical trial coordinated by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) demonstrated the benefit of radiotherapy with concomitant and adjuvant temozolomide (TMZ) chemotherapy. With TMZ, the median life expectancy in optimally managed patients is still only 12-14 months, with only 25% surviving 24 months. There is an urgent need for new therapies in particular in those patients whose tumour has an unmethylated methylguanine methyltransferase gene (MGMT) promoter, which is a predictive factor of benefit from TMZ. In this dissertation, the nature of the interaction between TMZ and radiation is investigated using both a mathematical model, based on in vivo population statistics of survival, and in vitro experimentation on a panel of human GBM cell lines. The results show that TMZ has an additive effect in vitro and that the population-based model may be insufficient in predicting TMZ response. The combination of TMZ with particle therapy is also investigated. Very little preclinical data exists on the effects of charged particles on GBM cell lines as well as on the concomitant application of chemotherapy. In this study, human GBM cells are exposed to 3 MeV protons and 6 MeV alpha particles in concomitance with TMZ. The results suggest that the radiation quality does not affect the nature of the interaction between TMZ and radiation, showing reproducible additive cytotoxicity. Since TMZ and radiation cause DNA damage in cancer cells, there has been increased attention to the use of poly(ADP-ribose) polymerase (PARP) inhibitors. PARP is a family of enzymes that play a key role in the repair of DNA breaks. In this study, a novel PARP inhibitor, ABT-888

  7. The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer.

    PubMed

    Annels, Nicola E; Shaw, Victoria E; Gabitass, Rachel F; Billingham, Lucinda; Corrie, Pippa; Eatock, Martin; Valle, Juan; Smith, David; Wadsley, Jonathan; Cunningham, David; Pandha, Hardev; Neoptolemos, John P; Middleton, Gary

    2014-02-01

    In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42% of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen. PMID:24292263

  8. 3D Radiotherapy Can Be Safely Combined With Sandwich Systemic Gemcitabine Chemotherapy in the Management of Pancreatic Cancer: Factors Influencing Outcome

    SciTech Connect

    Spry, Nigel Harvey, Jennifer; MacLeod, Craig; Borg, Martin; Ngan, Samuel Y.; Millar, Jeremy L.; Graham, Peter; Zissiadis, Yvonne; Kneebone, Andrew; Carroll, Susan; Davies, Terri; Reece, William H.H.; Iacopetta, Barry; Goldstein, David

    2008-04-01

    Purpose: The aim of this Phase II study was to examine whether concurrent continuous infusion 5-fluorouracil (CI 5FU) plus three-dimensional conformal planning radiotherapy sandwiched between gemcitabine chemotherapy is effective, tolerable, and safe in the management of pancreatic cancer. Methods and Materials: Patients were enrolled in two strata: (1) resected pancreatic cancer at high risk of local relapse (postsurgery arm, n = 22) or (2) inoperable pancreatic cancer in head or body without metastases (locally advanced arm, n = 41). Gemcitabine was given at 1,000 mg/m{sup 2} weekly for 3 weeks followed by 1 week rest then 5-6 weeks of radiotherapy and concurrent CI 5FU (200 mg/m{sup 2}/day). After 4 weeks' rest, gemcitabine treatment was reinitiated for 12 weeks. Results: For the two arms combined, treatment-related Grade 3 and 4 toxicities were reported by 25 (39.7%) and 7 (11.1%) patients, respectively. No significant late renal or hepatic toxicity was observed. In the postsurgery arm (R1 54.5%), median time to progressive disease from surgery was 11.0 months, median time to failure of local control was 32.9 months, and median survival time was 15.6 months. The 1- and 2-year survival rates were 63.6% and 31.8%. No significant associations between outcome and mutations in K-ras or TP53 or microsatellite instability were identified. Post hoc investigation of cancer antigen 19-9 levels found baseline levels and increases postbaseline were associated with shorter survival (p = 0.0061 and p < 0.0001, respectively). Conclusions: This three-dimensional chemoradiotherapy regimen is safe and promising, with encouraging local control for a substantial proportion of patients, and merits testing in a randomized trial.

  9. Combining Chemotherapy with Bevacizumab Improves Outcomes for Ovarian Cancer Patients

    Cancer.gov

    Results from two phase III randomized clinical trials suggest that, at least for some patients with ovarian cancer, adding the antiangiogenesis agent bevacizumab to chemotherapy increases the time to disease progression and may improve survival.

  10. Mediastinal infusion of epirubicin and 5-fluorouracil. A complication of totally implantable central venous systems. Report of a case.

    PubMed

    Rodier, J M; Malbec, L; Lauraine, E P; Batel-Copel, L; Bernadou, A

    1996-01-01

    Perforation of the wall of the superior vena cava by a central venous catheter is reported. The resultant inadvertent infusion of 5-fluorouracil and epirubicin caused a severe acute inflammatory reaction in the right-lobe bronchus, mediastinal infiltration and pleural and pericardial effusions. The patient recovered but has residual mild oesophageal dysfunction. PMID:8781572

  11. [Clinical Investigation of the Effects of Filgrastim BS1 on Neutropenia Following Oral Cancer Chemotherapy (TPF Therapy)].

    PubMed

    Uchiyama, Kimio; Yamada, Manabu; Tamate, Shusuke; Iwasaki, Konomi; Mitomo, Keisuke; Nakayama, Seiichi

    2015-09-01

    The time for the neutrophil count to recover after subcutaneous injection of filgrastim BS1 or lenograstim was studied in patients suffering from neutropenia following preoperative combined chemotherapy using docetaxel, nedaplatin, or cisplatin (in divided doses for 5 days)and 5-fluorouracil for oral cancer. 1. There was no significant difference in the minimum leukocyte and neutrophil counts after chemotherapy. 2. There was no significant difference in the maximum leukocyte and neutrophil counts after chemotherapy. 3. Time for leukocytes to recover from their minimum count(>4,000/mm3)or for neutrophils to recover from their minimum count(>2,000/mm3)and the number of days on which treatment was administered tended to be shorter in the filgrastim BS1 group. Thus, it was concluded that filgrastim BS1 is just as effective as other prior G-CSF agents in treating patients suffering from neutropenia following chemotherapy(TPF therapy). PMID:26469162

  12. Phase I Study of Preoperative Radiation Therapy With Concurrent Infusional 5-Fluorouracil and Oxaliplatin Followed by Surgery and Postoperative 5-Fluorouracil Plus Leucovorin for T3/T4 Rectal Adenocarcinoma: ECOG E1297

    SciTech Connect

    Rosenthal, David I. Catalano, Paul J.; Haller, Daniel G.; Landry, Jerome C.; Sigurdson, Elin R.; Spitz, Francis R.; Benson, Al B.

    2008-09-01

    Purpose: Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. Methods and Materials: Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m{sup 2} per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m{sup 2} during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m{sup 2} per week) with leucovorin (500 mg/m{sup 2} per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. Results: Twenty-one patients were enrolled, 5 at the 55 mg/m{sup 2} oxaliplatin dose level, 5 at 70 mg/m{sup 2}, and 11 at 85 mg/m{sup 2}. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). Conclusions: Oxaliplatin was well tolerated at 85 mg/m{sup 2} given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising.

  13. Water extract of Hedyotis Diffusa Willd suppresses proliferation of human HepG2 cells and potentiates the anticancer efficacy of low-dose 5-fluorouracil by inhibiting the CDK2-E2F1 pathway.

    PubMed

    Chen, Xu-Zheng; Cao, Zhi-Yun; Chen, Tuan-Sheng; Zhang, You-Quan; Liu, Zhi-Zhen; Su, Yin-Tao; Liao, Lian-Ming; Du, Jian

    2012-08-01

    Hedyotis Diffusa Willd (HDW), a Chinese herbal medicine, has been widely used as an adjuvant therapy against various cancers, including hepatocellular carcinoma (HCC). However, the underlying anticancer mechanisms are yet to be elucidated. In the present study, the anticancer effects of HDW were evaluated and the efficacy and safety of HDW combined with low-dose 5-fluorouracil (5-FU) were investigated. HepG2 cells were cultured in vitro and nude mouse xenografts were established in vivo. The proliferation of HepG2 cells was measured using the MTT method and flow cytometry. The mRNA and protein expression levels of cyclin-dependent kinase 2 (CDK2), cyclin E and E2F1 were examined using relative quantitative real-time PCR and western blot analysis, respectively. The results showed that water extract of HDW remarkably inhibited HepG2 cell proliferation in a dose-dependent manner via arrest of HepG2 cells at the G0/G1 phase and induction of S phase delay. This suppression was accompanied by a great decrease of E2F1 and CDK2 mRNA expression. In addition, HDW remarkably potentiated the anticancer effect of low-dose 5-FU in the absence of overt toxicity by downregulating the mRNA and protein levels of CDK2, cyclin E and E2F1. Our findings support the use of HDW as adjuvant therapy of chemotherapy and suggest that HDW may potentiate the efficiency of low-dose 5-FU in treating HCC. PMID:22641337

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  16. Experience with methotrexate, 5-fluorouracil, and leucovorin (MFL): a first line effective, minimally toxic regimen for metastatic breast cancer.

    PubMed

    Auerbach, Michael; Elias, E George; Orford, James

    2002-01-01

    Thirty-two women with untreated metastatic breast cancer were treated with 100 mg/M2 i.v. methotrexate (MTX), 600 mg/M2 5-fluorouracil (5FU) and leucovorin 15 mg orally every 6 hr, 24 hr after MTX (MFL) on days 1 and 8 every 28 days. Stratification was according to sites of metastases (mets), adjuvant (adj), chemotherapy (CTX), and/or hormonal therapy or no adj therapy (Tx). Treatment continued until documented radiographic or clinical disease was in progression. Toxicity was mild, consisting of only minimal elevations of transaminases and mild cytopenias. There was no pulmonary toxicity. There were no hospitalizations, treatment delays or cessations for toxicity. One patient with skeletal mets had a complete response and 7 had partial responses. The overall median progression free survival (PFS) was 13.8 months (mos). Eighteen patients with skeletal mets had PFS from 7-70 mos (median 15.9). Five patients with lung mets only had PFS from 6-20 mos (median 9.8 mos). Patients with liver alone or with other visceral mets showed progression within 2-5 mos. However, patients with bone and visceral mets without liver involvement had PFS from 8-50 mos (median 20.5). Of 21 adj Tx failures the median PFS was 8.8 mos (2-94). Six who received adj CTX had a median PFS of 7.6 mos (3-12) and 4 tamoxifen (tam) failures a median PFS of 11 mos (8-15). Eleven patients who received adj CTX+tam had a median PFS of 8.5 mos (2-94). Six patients received tam at adj failure and MFL at progression. These six had a median PFS of 19.8 mos (8-50). The patients (six, who received no prior adj Tx) had a median PFS of 24.3 (8-70). MFL is as effective in achieving clinical remissions in metastatic breast cancer, is inexpensive and is far less toxic than other CTX regimes. MFL should strongly be considered as first line Tx. PMID:11852998

  17. 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins.

    PubMed Central

    Nita, M. E.; Nagawa, H.; Tominaga, O.; Tsuno, N.; Fujii, S.; Sasaki, S.; Fu, C. G.; Takenoue, T.; Tsuruo, T.; Muto, T.

    1998-01-01

    Recently, apoptosis has been implicated as one of the end points of cells exposed to chemotherapeutic agents. The p53 and Bcl-2 family of proteins are involved in chemotherapy-induced apoptosis, but in a cell type-dependent manner. We sought to determine the roles played by the p53 and Bcl-2 family of proteins in 5-fluorouracil (5-FU)-induced apoptosis of human colon cancer cell lines. We first studied the p53 genetic and functional status, and then 5-FU, at inhibitory concentration of 50% (IC50) doses, was used to induce apoptosis, which was confirmed by morphological analysis and enzyme-linked immunosorbent assay (ELISA). Bcl-2, Bcl-X(L), Bax, Bad, Bak and p53 protein expression was analysed by Western blotting. Using five human colon cancer cell lines, we found that equitoxic (IC50) doses of 5-FU induced apoptosis in both wild-type p53 and mutant p53 cells. Analysis of the steady-state levels of Bcl-2 family proteins showed high expression of Bcl-X(L) in all of the cell lines except Colo320. Bcl-2 was expressed in two of them. Bax presented with the lowest basal expression and Bad showed homogeneous expression. On the other hand, Bak expression varied more than fivefold among these cells. In cells containing wild-type p53 (e.g. LoVo), 5-FU-induced apoptosis was accompanied by increased expression of Bax and Bak without consistent modulation of other bcl-2 family proteins. In contrast in cells containing mutant p53 (e.g. DLD1), Bak expression was remarkably increased. There was a significant correlation between chemosensitivity and Bcl-X(L) to Bax ratio, rather than Bcl-2 to Bax. In conclusion, these results suggest that some members of the Bcl-2 family of proteins, in human colon cancer cell lines, are modulated by 5-FU and that the ratio of Bcl-X(L) to Bax may be related to chemosensitivity to 5-FU. Images Figure 1 Figure 2 Figure 3 PMID:9792140

  18. 5-Fluorouracil as an enhancer of aminolevulinate-based photodynamic therapy for skin cancer: New use for a venerable agent?

    NASA Astrophysics Data System (ADS)

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

    2011-02-01

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

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

    PubMed

    Shirasaka, T; Shimamoto, Y; Fukushima, M

    1993-09-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  2. Factorial designed 5-fluorouracil-loaded microsponges and calcium pectinate beads plugged in hydroxypropyl methylcellulose capsules for colorectal cancer

    PubMed Central

    Gupta, Ankita; Tiwari, Gaurav; Tiwari, Ruchi; Srivastava, Rishabh

    2015-01-01

    Introduction: The work was aimed to develop an enteric-coated hydroxypropyl methylcellulose (HPMC) capsules (ECHC) plugged with 5-fluorouracil (5-FU)-loaded microsponges in combination with calcium pectinate beads. Materials and Methods: The modified quasi-emulsion solvent diffusion method was used to prepare microsponges. A 32 factorial design was employed to study the formulation and the effects of independent variables (volume of organic solvent and Eudragit-RS100 content) on dependent variables (particle size, %entrapment efficiency, and %cumulative drug release). The optimized microsponge (F4) was characterized by scanning electron microscopy, powder X-ray diffraction, and thermogravimetric analysis. F4 was plugged along with the calcium pectinate beads in HPMC capsules coated with enteric polymer Eudragit-L100 (Ed-L100) and/or Eudragit-S100 (Ed-S100) in different proportions. An in vitro release study of ECHC was performed in simulated gastric fluid for 2 h, followed by simulated intestinal fluid for next 6 h and then in simulated colonic fluid (in the presence and absence of pectinase enzyme for further 16 h). The optimized formulation was subjected to in vivo roentgenographic and pharmacokinetic studies in New Zealand white rabbits to analyze the in vivo behavior of the developed colon-targeted capsules. Results: Drug release was retarded on coating with Ed-S100 in comparison to a blend of Ed-S100:Ed-L100 coating. The percentage of 5-FU released at the end of 24 h from ECHC3 was 97.83 ± 0.12% in the presence of pectinase whereas in the control study, it was 40.08 ± 0.02%. Conclusion: Thus, enteric-coated HPMC capsules plugged with 5-FU-loaded microsponges and calcium pectinate beads proved to be a promising dosage form for colon targeting. PMID:26682194

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

    PubMed Central

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

    2016-01-01

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

  4. Numerical simulation of a mathematical model of combination of immunotherapy and chemotherapy of cancer

    NASA Astrophysics Data System (ADS)

    Wei, Hsiu-Chuan; Hwang, Shin-Feng; Chen, Yuh-Yih; Chen, Tze-Jang

    2013-10-01

    In this study, a mathematical model of tumor growth with a combination of immunotherapy and chemotherapy is considered. A numerical simulation using human data in clinical literature is conducted. A numerical method based on the continuation technique is employed to locate the unstable fixed-point curve as the dosage varies. A combination of chemotherapy and immunotherapy can employ low dosages of drugs. The effect of the combined dosages is also investigated in this work.

  5. Curcumin and 5-Fluorouracil-loaded, folate- and transferrin-decorated polymeric magnetic nanoformulation: a synergistic cancer therapeutic approach, accelerated by magnetic hyperthermia

    PubMed Central

    Balasubramanian, Sivakumar; Girija, Aswathy Ravindran; Nagaoka, Yutaka; Iwai, Seiki; Suzuki, Masashi; Kizhikkilot, Venugopal; Yoshida, Yasuhiko; Maekawa, Toru; Nair, Sakthikumar Dasappan

    2014-01-01

    The efficient targeting and therapeutic efficacy of a combination of drugs (curcumin and 5-Fluorouracil [5FU]) and magnetic nanoparticles encapsulated poly(D,L-lactic-co-glycolic acid) nanoparticles, functionalized with two cancer-specific ligands are discussed in our work. This multifunctional, highly specific nanoconjugate resulted in the superior uptake of nanoparticles by cancer cells. Upon magnetic hyperthermia, we could harness the advantages of incorporating magnetic nanoparticles that synergistically acted with the drugs to destroy cancer cells within a very short period of time. The remarkable multimodal efficacy attained by this therapeutic nanoformulation offers the potential for targeting, imaging, and treatment of cancer within a short period of time (120 minutes) by initiating early and late apoptosis. PMID:24531392

  6. A Case of Metastatic Urachal Carcinoma Treated With FOLFIRI (irinotecan and 5-Fluorouracil/leucovorin) Plus Bevacizumab

    PubMed Central

    Kanamaru, Tomohiro; Iguchi, Taro; Yukimatsu, Nao; Shimizu, Yasuomi; Kohyama, Yuki; Tachibana, Hirokazu; Kato, Minoru; Yamasaki, Takeshi; Tamada, Satoshi; Nakatani, Tatsuya

    2014-01-01

    A 68-year-old man was introduced to our hospital for the treatment of lung and mediastinum lymph node metastases that originated from an urachal carcinoma 4 years after a partial cystectomy. First-line chemotherapy with an S-1 and cisplatin combination was ineffective. The patient received FOLFIRI plus bevacizumab chemotherapy as salvage chemotherapy. Stability was achieved after eight cycles of FOLFIRI plus bevacizumab therapy. We conducted a biopsy of the metastatic tumor, and the pathology of the biopsy tissue was partially necrotic. To our knowledge, this case represents the first report of a metastatic urachal carcinoma treated with FOLFIRI plus bevacizumab. PMID:26793485

  7. Anti-HepG-2 cell properties of rare earth tungstosilicic polyoxometalates containing 5-fluorouracil.

    PubMed

    Liu, Xia; Wang, Shuai-Shuai; Feng, Chang-Gen

    2012-12-01

    Two novel rare earth tungstosilicic polyoxometalate containing 5-fluorouracil, K26 (C4 H4 FN2O2)8Pr (SiW11 O39)4 x 10H2O (FPSW) and K26(C4H4FN2O2)8Sm(SiW11O39)4 x 9H2O (FSSW), were synthesized and their structure were characterized by using elemental analysis, FTIR spectra, X-ray powder diffraction and TG. The antitumor activity tests of the compounds FPSW and FSSW were carried out by the methyl thiazolyl tetrazolium method in hepatocellular carcinoma cell HepG-2. The results showed that FPSW and FSSW could inhibit the HepG-2 cells in vitro significantly. The EC50 of FPSW and FSSW is 1.94 x 10(-5) and 1.32 x 10(-5) mol x L(-1) respectively. The therapeutic index of FPSW and FSSW is 0.76 and 1.58 respectively. PMID:23427558

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2001-01-01

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

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

    SciTech Connect

    von der Maase, H.

    1984-01-01

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

  11. 5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Comprehensive Review of the Literature.

    PubMed

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

    2016-06-01

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

  12. Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil.

    PubMed

    Ardalan, B; Cooney, D A; Jayaram, H N; Carrico, C K; Glazer, R I; Macdonald, J; Schein, P S

    1980-05-01

    The biochemical basis for the resistance of murine leukemia P388 to 5-fluorouracil (FUra) was systematically investigated by examining the transport and metabolism of FUra, or its anabolites, as well as the inhibition of enzymes and processes known to be affected by the drug. Of these parameters, only three were found to be altered significantly in the resistant line: (a) the enzyme required for the phosphorylation of uridine 5'-monophosphate to uridine 5'-diphosphate was present at a significantly lower specific activity in the resistant line than in its sensitive counterpart; (b) the rates of generation and persistance of 5-fluoro-2'-deoxyuridine 5'-monophosphate were significantly lower and shorter in the variant; and (c) there was a 1.6- and 3-fold decrease in the incorporation of FUra into polyadenylic acid-containing RNA and polyadenylic acid-lacking RNA, respectively, in resistant versus sensitive cells. Taken together, these findings suggest a dual mechanism for resistance to FUra in these leukemic cells, namely, a depressed capacity to generate di- and triphosphates of the riboside and deoxyriboside of the drug leading to lower pools of the proximate antimetabolite, fluorouridine 5'-triphosphate, and accelerated excretion of 5-fluoro-2'-deoxyuridine 5'-monophosphate, so that thymidylate synthetase is perturbed in a less than lethal way. PMID:6245793

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

    PubMed

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

    2016-08-01

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

  14. Supercritical CO2 foamed polycaprolactone scaffolds for controlled delivery of 5-fluorouracil, nicotinamide and triflusal.

    PubMed

    Salerno, Aurelio; Saurina, Javier; Domingo, Concepción

    2015-12-30

    The manufacture of porous polycaprolactone (PCL) scaffolds containing three different drugs, namely 5-fluorouracil, nicotinamide and triflusal, was investigated in this work with the aim of obtaining bioactive systems with controlled drug delivery capabilities. The scaffolds were prepared by means of a supercritical CO2 (scCO2) foaming technique by optimizing the drug loading process. This was achieved by dissolving the drugs in organic solvents miscible with scCO2 and by mixing these drug/solvent solutions with PCL powder. The as prepared mixtures were further compressed to eliminate air bubbles and finally processed by the scCO2 foaming technique. ScCO2 saturation and foaming conditions were optimized to create the porosity within the samples and to allow for the concomitant removal of the organic solvents. Physical and chemical properties of porous scaffolds, as well as drug content and delivery profiles, were studied by HPLC. The results of this study demonstrated that the composition of the starting PCL/drug/solvent mixtures affected polymer crystallization, scaffold morphology and pore structure features. Furthermore, it was found that drug loading efficiency depended on both initial solution composition and drug solubility in scCO2. Nevertheless, in the case of highly scCO2-soluble drugs, such as triflusal, loading efficiency was improved by adding a proper amount of free drug inside of the pressure vessel. The drug delivery study indicated that release profiles depended mainly upon scaffolds composition and pore structure features. PMID:26570986

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-09-20

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

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

    PubMed

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

    2015-08-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    1996-01-01

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

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

    PubMed

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

    2014-08-01

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

  3. Retrospective evaluation of 5-fluorouracil-interferon-a aTreatment of advanced colorectal cancer patients.

    PubMed

    András, C; Csiki, Z; Gál, I; Takács, I; Antal, L; Szegedi, G

    2000-01-01

    The authors describe the retrospective analysis of treatment by 5-fluorouracil and interferon-a aof 34 patients with advanced colorectal cancer. An average of 4.6 treatment cycles (3 12) was applied. Complete remission was not observed; partial remission was observed in 8 patients; in 13 patients no change occurred and progression was detected in 14 cases. Remission rate was 22.8%, mean response time was 5.2 (3 12) months, mean progress-free survival 5.6 (0 22) months. Mean survival from the start of treatment was 11.9 (1 42) months and from the establishment of the diagnosis 26.1 (3 60) months. Severe life-threatening side-effects did not occur; other side-effects such as fever, nausea, diarrhea, leucopenia, and anemia responded to drugs. Treatment by 5-FU and interferon, in accordance with other authors findings, improved survival and well-being of patients but no breakthrough has been achieved. PMID:11033456

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Jin, Qiao; Mitschang, Fabian; Agarwal, Seema

    2011-10-10

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

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

    NASA Astrophysics Data System (ADS)

    Majrad, Mohamed Saleh

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

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

    PubMed

    Wu, Jing; Hu, Dong; Zhang, Rongbo

    2012-10-01

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

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

    PubMed

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

    2011-08-15

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

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

    PubMed

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

    2010-08-01

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

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

    PubMed Central

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

    2014-01-01

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

  12. 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation

    PubMed Central

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

    2016-01-01

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

  13. Effect of unsaturated menthol analogues on the in vitro penetration of 5-fluorouracil through rat skin.

    PubMed

    Chen, Yang; Wang, Jian; Cun, Dongmei; Wang, Manli; Jiang, Juan; Xi, Honglei; Cui, Hongxia; Xu, Yongnan; Cheng, Maosheng; Fang, Liang

    2013-02-25

    To explore the structure-activity relationship for terpenes as transdermal penetration enhancers, unsaturated menthol analogues were synthesized in our study, including p-menth-1-en-3-ol (Compd 1), p-menth-4-en-3-ol (Compd 2), p-menth-4(8)-en-3-ol (Compd 3) and p-menth-8-en-3-ol (Compd 4). Their enhancing activity on the penetration of 5-fluorouracil through rat skin was evaluated by in vitro experiments. Attenuated total reflection-Fourier transform infrared spectroscopy, molecular modeling and transepidermal water loss (TEWL) were introduced to investigate the enhancer induced alteration in different skin lipid domains. The results indicated that Compd 3 achieved the highest enhancement ability with an enhancement ratio of 3.08. Other analogues were less effective than Compd 3, and no significant difference was found between them and menthol. Treatment of rat skin with these enhancers did not produce any shift in the stretching vibration of the methylene in hydrophobic lipid chains, but significantly improved the polar pathway across the rat skin as suggested by the increased TEWL. Molecular modeling results suggested that polar head groups of the skin lipids provided the main binding site for enhancer action. These findings indicated that the studied compounds enhanced drug transport by interacting with the polar domain of the skin lipid, instead of by affecting the arrangement of the hydrophobic chains. PMID:23333756

  14. Comparison of Intrahepatic and Pancreatic Perfusion on Fusion Images Using a Combined SPECT/CT System and Assessment of Efficacy of Combined Continuous Arterial Infusion and Systemic Chemotherapy in Advanced Pancreatic Carcinoma

    SciTech Connect

    Ikeda, Osama Tamura, Yoshitaka; Nakasone, Yutaka; Shiraishi, Shinya; Kawanaka, Kouichi; Tomiguchi, Seiji; Yamashita, Yasuyuki; Takamori, Hiroshi; Kanemitsu, Keiichiro; Baba, Hideo

    2007-09-15

    Purpose. The purpose of this study was to compare intrahepatic and pancreatic perfusion on fusion images using a combined single-photon emission computed tomography (SPECT)/CT system and to evaluate the efficacy of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in the treatment of advanced pancreatic carcinoma. Materials and Methods. CTAI was performed in 33 patients (22 men, 11 women; age range, 35-77 years; mean age, 60 years) with stage IV pancreatic cancer with liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. In all patients we obtained fusion images using a combined SPECT/CT system. Pancreatic perfusion on fusion images was classified as perfusion presence or as perfusion absent in the pancreatic cancer. Using WHO criteria we recorded the tumor response after 3 months on multislice helical CT scans. Treatment effects were evaluated based on the pancreatic cancer, liver metastasis, and factors such as intrahepatic and pancreatic perfusion on fusion images. For statistical analysis we used the chi-square test; survival was evaluated by the Kaplan Meier method (log-rank test). Results. On fusion images, pancreatic and intrahepatic perfusion was recorded as hot spot and as homogeneous distribution, respectively, in 18 patients (55%) and as cold spot and heterogeneous distribution, respectively, in 15 (45%). Patients with hot spot in the pancreatic tumor and homogeneous distribution in the liver manifested better treatment results (p < 0.05 and p < 0.01, respectively). Patients with hot spot both in the pancreatic cancer and in the liver survived longer than those with cold spot in the pancreatic cancer and heterogeneous distribution in the liver (median {+-} SD, 16.0 {+-} 3.7 vs. 8.0 {+-} 1.4 months; p < 0.05). Conclusions. We conclude that in patients with advanced

  15. Efficacy of Sucralfate Mouth Wash in Prevention of 5-fluorouracil Induced Oral Mucositis: A Prospective, Randomized, Double-Blind, Controlled Trial.

    PubMed

    Ala, Shahram; Saeedi, Majid; Janbabai, Ghasem; Ganji, Reza; Azhdari, Elham; Shiva, Afshin

    2016-04-01

    Sucralfate has been used for the prevention and treatment of radiotherapy- and chemotherapy-induced stomatitis and mucositis in a number of studies, but the results are contradictory. To answer such discrepancies, the present study was designed to evaluate the efficacy of sucralfate mouthwash in prevention of 5-fluorouracil (5-FU)-induced oral mucositis in patients with gastrointestinal malignancies. Patients with gastrointestinal cancers receiving 5-FU-based chemotherapy regimens were included in this randomized, blinded, controlled trial and were randomly allocated to either sucralfate mouthwash (every 6 h) or placebo. The patients were visited at fifth and tenth day of trial; the presence and severity of oral mucositis and the intensity of pain were assessed. The patients receiving sucralfate experienced lower frequency and severity of mucositis (76% vs. 38.5%, P = 0.005 and 84 vs. 38.5%, P < 0.001, respectively) and less intense pain (2.5 ± 2.2 vs. 5.08 ± 3.82, P = 0.004 and 1.33 ± 0.86 vs. 4.12 ± 3.5, P = 0.001, respectively) compared with the placebo group both at day 5 and day 10. Within the sucralfate group, a decrease in frequency and severity of mucositis was observed throughout the trial period, while in the placebo group no such effect was observed. Sucralfate mouthwash reduced the frequency and severity of 5-FU-induced oral mucositis in patients with gastrointestinal malignancies compared with placebo, indicating its efficacy in the prevention of chemotherapy-induced mucositis. PMID:27007594

  16. Clinical, biochemical and histological study of the effect of antimicrobial photodynamic therapy on oral mucositis induced by 5-fluorouracil in hamsters.

    PubMed

    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. PMID:25612464

  17. Clofarabine-based combination chemotherapy for relapse and refractory childhood acute lymphoblastic leukemia.

    PubMed

    Arakawa, Yuki; Koh, Katsuyoshi; Aoki, Takahiro; Kubota, Yasuo; Oyama, Ryo; Mori, Makiko; Hayashi, Mayumi; Hanada, Ryoji

    2014-11-01

    Clofarabine, one of the key treatment agents for refractory and relapsed acute lymphoblastic leukemia (ALL), achieves a remission rate of approximately 30% with single-agent clofarabine induction chemotherapy. However, a remission rate of approximately 50% was reported with a combination chemotherapy regimen consisting of clofarabine, etoposide, and cyclophosphamide. We treated two cases with refractory and relapsed ALL with combination chemotherapy including clofarabine; one was an induction failure but the other achieved remission. Both cases developed an infectious complication (NCI-CTCAE grade 3) and body pain with infusion. Prophylactic antibiotic and opioid infusions facilitated avoiding septic shock and pain. Further investigation of such cases is required. PMID:25501414

  18. The effects of 5-fluorouracil and doxorubicin on expression of human immunodeficiency virus type 1 long terminal repeat

    SciTech Connect

    Panozzo, J.; Akan, E.; Griffiths, T.D.; Woloschak, G.E.

    1996-03-01

    Previous work by many groups has documented induction of the HIV-LTR following exposure of cells to ultraviolet light and other DNA damaging agents. Our experiments set out to determine the relative activation or repression of the HIV-LTR in response to two classes of chemotherapeutic agents: Doxorubicin is a DNA-damage inducing agent, and 5-fluorouracil has an antimetabolic mode of action. Using HeLa cells stably transfected with a construct in which HIV-LTR drives expression of the chloramphenicol acetyl transferase reporter gene, we demonstrated an up to 10-fold induction following doxorubicin treatment in 24 h post-treatment. This induction was repressed by treatment with salicylic acid, suggesting a role for prostaglandin/cyclo-oxygenase pathways and/or NFKB in the inductive response. Induction by 5-fluorouracil, in contrast, was more modest (two-fold at most) though it was consistently elevated over controls.

  19. Design, synthesis and biological evaluation of 5-fluorouracil-derived benzimidazoles as novel type of potential antimicrobial agents.

    PubMed

    Fang, Xue-Jie; Jeyakkumar, Ponmani; Avula, Srinivasa Rao; Zhou, Qian; Zhou, Cheng-He

    2016-06-01

    A series of 5-fluorouracil benzimidazoles as novel type of potential antimicrobial agents were designed and synthesized for the first time. Bioactive assay manifested that some of the prepared compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains in comparison with reference drugs norfloxacin, chloromycin and fluconazole. Noticeably, 3-fluorobenzyl benzimidazole derivative 5c gave remarkable antimicrobial activities against Saccharomyces cerevisiae, MRSA and Bacillus proteus with MIC values of 1, 2 and 4μg/mL, respectively. Experimental research revealed that compound 5c could effectively intercalate into calf thymus DNA to form compound 5c-DNA complex which might block DNA replication and thus exert antimicrobial activities. Molecular docking indicated that compound 5c should bind with DNA topoisomerase IA through three hydrogen bonds by the use of fluorine atom and oxygen atoms in 5-fluorouracil with the residue Lys 423. PMID:27117429

  20. Cardiac arrhythmia and ischaemic events after combination chemotherapy for testicular cancer.

    PubMed

    Villani, F; Misrachi, D; Galimberti, M

    1994-11-01

    The aim of the present investigation was to evaluate the type and the incidence of cardiac arrhythmias and ischaemic events in patients suffering from testicular cancer and submitted to combination chemotherapy with cisplatin, bleomycin and vinblastine (PVB) or etoposide (PEB). Forty-seven patients took part in the study; 23 were treated with PVB and 24 with PEB. Holter monitoring was performed in each patient before chemotherapy and on the 1st, 2nd and 5th day of the first cycle of drug administration. The results showed that combination chemotherapy with PVB or PEB was accompanied by the appearance of, or an increase in, the incidence of supraventricular ectopic beats. No significant difference was found between the two groups. No significant conduction disturbances were recorded. These results show that combination chemotherapy with PVB or PEB, at least during the first cycle, has no significant ventricular arrhythmogenic or ischaemic potency in young people with no history of cardiac disease. PMID:7530660

  1. [R0 Resection of Locally Advanced Pancreatic Cancer after Combination Chemotherapy with Gemcitabine and S-1].

    PubMed

    Kametaka, Hisashi; Makino, Hironobu; Fukada, Tadaomi; Seike, Kazuhiro; Koyama, Takashi; Hasegawa, Akio

    2015-11-01

    A 68-year-old female was referred to our institution in October 2014 for additional therapy for cancer of the head of the pancreas. Utilizing a computed tomography scan, he was initially diagnosed with locally advanced unresectable cancer because of massive invasion to the superior mesenteric artery (SMA). Combination chemotherapy consisting of gemcitabine and S-1 was administrated for 10 months. Since the tumor was remarkably reduced after chemotherapy, pancreaticoduodenectomy combined with portal vein resection was performed. Since the histopathological findings indicated few residual cancer tissues, our chemotherapy was considered dramatically effective. The postoperative course was uneventful and the patient remains well and without any recurrences 14 months after the surgery. We therefore report a case of locally unresectable pancreatic cancer, which achieved R0 resection after combination chemotherapy with gemcitabine and S-1. PMID:26805123

  2. Synthesis, structural elucidation, biological, antioxidant and nuclease activities of some 5-Fluorouracil-amino acid mixed ligand complexes

    NASA Astrophysics Data System (ADS)

    Shobana, Sutha; Subramaniam, Perumal; Mitu, Liviu; Dharmaraja, Jeyaprakash; Arvind Narayan, Sundaram

    2015-01-01

    Some biologically active mixed ligand complexes (1-9) have been synthesized from 5-Fluorouracil (5-FU; A) and amino acids (B) such as glycine (gly), L-alanine (ala) and L-valine (val) with Ni(II), Cu(II) and Zn(II) ions. The synthesized mixed ligand complexes (1-9) were characterized by various physico-chemical, spectral, thermal and morphological studies. 5-Fluorouracil and its mixed ligand complexes have been tested for their in vitro biological activities against some pathogenic bacterial and fungal species by the agar well diffusion method. The in vitro antioxidant activities of 5-Fluorouracil and its complexes have also been investigated by using the DPPH assay method. The results demonstrate that Cu(II) mixed ligand complexes (4-6) exhibit potent biological as well as antioxidant activities compared to 5-Fluorouracil and Ni(II) (1-3) and Zn(II) (7-9) mixed ligand complexes. Further, the cleaving activities of CT DNA under aerobic conditions show moderate activity with the synthesized Cu(II) and Ni(II) mixed ligand complexes (1-6) while no activity is seen with Zn(II) complexes (7-9). Binding studies of CT DNA with these complexes show a decrease in intensity of the charge transfer band to the extent of 5-15% along with a minor red shift. The free energy change values (Δ‡G) calculated from intrinsic binding constants indicate that the interaction between mixed ligand complex and DNA is spontaneous.

  3. Orotate phosphoribosyltransferase localizes to the Golgi complex and its expression levels affect the sensitivity to anti-cancer drug 5-fluorouracil.

    PubMed

    Hozumi, Yasukazu; Tanaka, Toshiaki; Nakano, Tomoyuki; Matsui, Hirooki; Nasu, Takashi; Koike, Shuji; Kakehata, Seiji; Ito, Tsukasa; Goto, Kaoru

    2015-01-01

    Orotate phosphoribosyltransferase (OPRT) is engaged in de novo pyrimidine synthesis. It catalyzes oronitine to uridine monophosphate (UMP), which is used for RNA synthesis. De novo pyrimidine synthesis has long been known to play an important role in providing DNA/RNA precursors for rapid proliferative activity of cancer cells. Furthermore, chemotherapeutic drug 5-fluorouracil (5-FU) is taken up into cancer cells and is converted to 5-fluoro-UMP (FUMP) by OPRT or to 5-fluoro-dUMP (FdUMP) through intermediary molecules by thymidine phosphorylase. These 5-FU metabolites are misincorporated into DNA/RNA, thereby producing dysfunction of these information processing. However, it remains unclear how the subcellular localization of OPRT and how its variable expression levels affect the response to 5-FU at the cellular level. In this study, immunocytochemical analysis reveals that OPRT localizes to the Golgi complex. Results also show that not only overexpression but also downregulation of OPRT render cells susceptible to 5-FU exposure, but it has no effect on DNA damaging agent doxorubicin. This study provides clues to elucidate the cellular response to 5-FU chemotherapy in relation to the OPRT expression level. PMID:26700594

  4. 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

    SciTech Connect

    Clavel, Sebastien; Nguyen, David H.A.; Fortin, Bernard; Despres, Philippe; Khaouam, Nader; Donath, David; Soulieres, Denis; Guertin, Louis; Nguyen-Tan, Phuc Felix

    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.

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

    PubMed Central

    Liu, Shuai; Yang, Xuesong

    2014-01-01

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

  6. Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection.

    PubMed

    Liaw, C C; Wang, H M; Wang, C H; Yang, T S; Chen, J S; Chang, H K; Lin, Y C; Liaw, S J; Yeh, C T

    1999-03-01

    From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma ammonium level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of dehydration. Higher plasma ammonium levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma ammonium levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. PMID:10327032

  7. A review of hyperthermia combined with radiotherapy/chemotherapy on malignant tumors.

    PubMed

    Rao, Wei; Deng, Zhong-Shan; Liu, Jing

    2010-01-01

    Therapeutic hyperthermia is a procedure that involves heating tissues to a higher temperature level, typically ranging from 41 degrees C to 45 degrees C. Its combination with radiotherapy and/or chemotherapy has been performed for many years, with remarkable success in treating advanced and recurrent cancers. The current hyperthermia strategies generally include local, regional, and whole-body hyperthermia, which can be implemented by many heating methods, such as microwave, radiofrequency, laser, and ultrasound. There are several hyperthermic treatment modalities in conjunction with radiotherapy/chemotherapy. Numerous studies have attempted to explain the mechanisms of thermosensitization from radiation and chemotherapy; however, a generalized standard for determining an optimal hyperthermia modality combined with radiotherapy/chemotherapy has not been established, so more research is needed. Fortunately, phase II/III clinical trials have demonstrated that hyperthermia combination therapy is beneficial for local tumor control and survival in patients with high-risk tumors of different types. The aim of this article is to present a comprehensive review of the latest advances in tumor hyperthermia combined with radiotherapy and/ or chemotherapy. We specifically focus on synergistic cellular and molecular mechanisms, thermal dose, treatment sequence, monitoring and imaging, and clinical outcomes of the combination therapy. The role of nanoparticles in sensitization during radio-/chemotherapy is also evaluated. Finally, research challenges and future trends in the related areas are presented. PMID:21175406

  8. Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs.

    PubMed

    Ooyama, Akio; Okayama, Yoshihiro; Takechi, Teiji; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu

    2007-04-01

    Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response. PMID:17425594

  9. Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer

    SciTech Connect

    Kim, Dae Yong; Jung, Kyung Hae . E-mail: khjung@ncc.re.kr; Kim, Tae Hyun; Kim, Duck-Woo; Chang, Hee Jin; Jeong, Jun Yong; Kim, Young Hoon; Son, Seok-Hyun; Yun, Tak; Hong, Chang Won; Sohn, Dae Kyung; Lim, Seok-Byung; Choi, Hyo Seong; Jeong, Seung-Yong; Park, Jae-Gahb

    2007-02-01

    Purpose: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Methods: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n = 145) or capecitabine (n = 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. Results: Radiologic examination showed that tumor volume decreased by 68.2% {+-} 20.5% in the FL group and 68.3% {+-} 22.3% in the capecitabine group (p = 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p = 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p = 0.758). Conclusion: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.

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

    PubMed

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

    1995-05-17

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

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

    PubMed

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

    1993-12-15

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

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Cornwell, P A; Barry, B W

    1994-04-01

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

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

    PubMed

    Eftekhar, Ebrahim; Jaberie, Hajar; Naghibalhossaini, Fakhraddin

    2016-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  17. Effect of adenosine on the supramolecular architecture and activity of 5-fluorouracil

    NASA Astrophysics Data System (ADS)

    Singh, Udai P.; Kashyap, Sujata; Singh, Hari Ji; Mishra, Bhupesh Kumar; Roy, Partha; Chakraborty, Ajanta

    2012-04-01

    The reactions of adenosine (Ad) with 5-halouracils (5XU where X = F for 1, Cl for 2, Br for 3 and I for 4) resulted in the formation of co-crystals 1-4 in monoclinic with P21 space group. Despite of great variation in the halo substituent at the 5th position of the uracil, each structure contains the same number and same type of non-covalent interactions i.e., primary N-H⋯N, N-H⋯O, O-H⋯N, O-H⋯O hydrogen bonds and secondary C-H⋯O and X⋯O interactions within these motifs as well as with neighboring molecules. As compared to Ad the size of cavity increases in co-crystal 1 to accommodate the 5FU as a guest. With the variation of halogen from fluoro to iodo on the uracil, the orientation of the molecules remains the same with a slight difference in the dihedral angle in all the co-crystals 1-4. This study demonstrates that hydrogen-bonded interactions between adenosine and halouracils provide a supramolecular assembly to these co-crystals. Computational studies illustrate that the size of the halo substituents on uracil has no effect on the hydrogen bond interaction energy. It further reveals that the orientation of molecules remain same in both solid phase as well as in the gaseous phase. The antitumor and DNA cleavage activity studies show that the antitumor activity of 5-fluorouracil against MCF-7 breast cancer decreases in the presence of adenosine.

  18. Effect of dietary boron on 5-fluorouracil induced oral mucositis in rats

    PubMed Central

    Aras, Mutan Hamdi; Sezer, Ufuk; Erkilic, Suna; Demir, Tuncer; Dagli, Seyda Nur

    2013-01-01

    Objective: The aim of this study was to evaluate the effect of boron on 5-fluorouracil (5-FU)–induced oral mucositis in rats. Materials and Methods: Sixty-four male Wistar albino rats were injected with 5-FU on days 1 and 3. The right cheek pouch mucosa was scratched with the tip of an 18-G needle, dragged twice in a linear movement, on days 3 and 5. The animals were randomly divided into two groups of 32: boron group (BG) and control group (CG). Rats in the CG did not receive any treatment, whereas the others were fed boron (3 mg·kg-1·day-1) by gavage. The animals were sacrificed on day 3 (n = 8), 6 (n = 8), 9 (n = 8), and 12 (n = 8), and the cheek pouch was removed for histopathological analysis. Results: On day 3, both groups showed necrosis and active inflammation, but the inflammation was mild in CG and moderate in BG. On day 6, both BG and CG showed necrosis; in the CG, there was moderate inflammation, and in the BG, there was severe inflammation and granulation tissue around the necrotic area. On day 9, re-epithelization began in both groups, and there were no differences between groups. Re-epithelization was complete in both groups on day 12. Conclusion: We found no beneficial effect of boron in healing oral mucositis. Additional research is warranted to elucidate the pathogenic inflammatory mechanisms involved in mucositis and the prophylactic and therapeutic roles of antioxidants. PMID:24926211

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

    SciTech Connect

    Lawrence, T.S.; Davis, M.A.; Maybaum, J. )

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

    PubMed

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

    2011-11-28

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

  1. Radiation and concurrent chemotherapy for the treatment of Lewis lung tumor and B16 melanoma tumor in C57/BL mice

    SciTech Connect

    Pedersen, J.E.; Barron, G.

    1984-08-01

    C57/BL mice bearing either Lewis lung tumor or B16 melanoma tumor were treated with radiation and concurrent chemotherapy. The treatment results were determined in vivo by tumor regrowth delay assay. When continuous infusion of either Cyclophosphamide (CYCLO) or 5-Fluorouracil (5-FU) or Adriamycin (ADRIA) or Mitomycin-C (MITO-C) was used in combination with continuous radiation at 1 cGy/min, no increase in tumor regrowth delay was observed over that of radiation alone. When multiple drug chemotherapy, FAM (5-FU, ADRIA, MITO-C) was administered in combination with radiation at 80 cGy/min, no increase in tumor regrowth delay was observed over that of radiation alone. In these two murine tumor models, when clinically relevant concentrations of commonly used chemotherapy agents were combined with radiation, no therapeutic advantage was observed.

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

    NASA Astrophysics Data System (ADS)

    Weiss, Jason; Fraser, Craig; Rubio-Ruiz, Belén; Myers, Samuel; Crispin, Richard; Dawson, John; Brunton, Valerie; Patton, E.; Carragher, Neil; Unciti-Broceta, Asier

    2014-07-01

    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.

  3. N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture

    PubMed Central

    Weiss, Jason T.; Fraser, Craig; Rubio-Ruiz, Belén; Myers, Samuel H.; Crispin, Richard; Dawson, John C.; Brunton, Valerie G.; Patton, E. Elizabeth; Carragher, Neil O.; Unciti-Broceta, Asier

    2014-01-01

    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 Pd0, has been proposed by our group as a way to reach therapeutic levels of the active drug in the affected tissue/organ while reducing its systemic toxicity. 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 Pd0-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- vs. 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. PMID:25121087

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

    PubMed Central

    2016-01-01

    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. PMID:27087736

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

    PubMed Central

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

    2005-01-01

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

  6. AB058. Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

    PubMed Central

    Zhang, Yu; Hu, Hailong; Tian, Dawei; Wu, Changli

    2016-01-01

    Objective The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after TURBT (P<0.001). The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003). Kaplan-Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and

  7. Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

    PubMed Central

    Zhang, Yu; Xie, Linguo; Chen, Tao; Xie, Wanqin; Wu, Zhouliang; Xu, Hao; Xing, Chen; Sha, Nan; Shen, Zhonghua; Qie, Yunkai; Liu, Xiaoteng; Hu, Hailong; Wu, Changli

    2016-01-01

    Objective The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after TURBT (P<0.001). The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003). Kaplan–Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P-value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and

  8. Efficacy of Olanzapine Combined Therapy for Patients Receiving Highly Emetogenic Chemotherapy Resistant to Standard Antiemetic Therapy

    PubMed Central

    Abe, Masakazu; Kasamatsu, Yuka; Kado, Nobuhiro; Kuji, Shiho; Tanaka, Aki; Takahashi, Nobutaka; Takekuma, Munetaka; Hirashima, Yasuyuki

    2015-01-01

    Objective. Olanzapine is proved to be effective for chemotherapy induced nausea and vomiting (CINV). But its efficacy in combination with standard antiemetic therapy is unknown. The purpose of this study is to prove the preventive effect of olanzapine for the prevention of CINV caused by highly emetogenic chemotherapy when used with standard antiemetic therapy. Method. Gynecologic cancer patients receiving cisplatin-based chemotherapy who had grade 2 or 3 nausea in overall phase (0–120 h after chemotherapy) despite standard therapy were assigned to this study. From the next cycles to cycles in which patients developed grade 2 or 3 nausea, they received olanzapine with standard therapy. 5 mg oral olanzapine was administered for 7 days from the day before chemotherapy. The effectiveness of preventive administration of olanzapine was evaluated retrospectively. The primary endpoint was nausea control rate (grade 0 or 1) with olanzapine. Results. Fifty patients were evaluable. The nausea control rate with olanzapine was improved from 58% to 98% in acute phase (0–24 h after chemotherapy) and 2% to 94% in delayed phase (24–120 h after chemotherapy). In overall phase, the nausea control rate improved from 0% to 92%, and it was statistically significant (P < 0.001). Conclusion. Preventive use of olanzapine combined with standard antiemetic therapy showed improvement in control of refractory nausea. PMID:26425564

  9. Postoperative Chemoradiotherapy Combined with Epirubicin-Based Triplet Chemotherapy for Locally Advanced Adenocarcinoma of the Stomach or Gastroesophageal Junction

    PubMed Central

    Li, Guichao; Zhang, Zhen; Ma, Xuejun; Zhu, Ji; Cai, Gang

    2013-01-01

    Background Due to low tolerance to chemotherapy, the maximum number of cycles of postoperative adjuvant chemotherapy is 4 in adjuvant gastric clinical trials. The aim of this study is to retrospectively evaluate the safety and efficacy of adjuvant epirubicin-based triplet chemotherapy and radiotherapy in the treatment of resected locally advanced stomach or gastroesophageal junction adenocarcinoma. Methodology/Principal Findings From January 2004 to July 2008, ninety-seven consecutive gastric or gastroesophageal junction adenocarcinoma patients in stages T3–4/N+ were treated with postoperative radiotherapy and chemotherapy. The recommended treatment plan was radical resection followed by 1–2 cycles of adjuvant chemotherapy (ACT), postoperative chemoradiotherapy (CRT), and, finally, 4–5 cycles of ACT. The patients were classified into two groups depending on the number of cycles of ACT: group 1 received 4–6 cycles (n = 59), and group 2 received 0–3 cycles (n = 38). The detailed grouping is as follows: RT alone, 2; RT and CT, 18; concurrent RTCT and CT, 41; and CRT, 36. Of the 97 patients, 77 patients received concurrent therapy (CRT, (5-fluorouracil or capecitabine), and 20 received radiotherapy alone because of patient refusal (n = 15) or treatment toxicity (n = 5). After a median follow-up of 44 months, the 3-year disease free survival(DFS) and overall survival (OS) were 66.5% and 69.5% for group 1 and 45.5% and 50% for group 2, respectively (p = 0.005 and p = 0.024). Multivariate analysis revealed that 4–6 cycles of ACT, lymphovascular invasion, or peritoneal metastasis were independent prognostic factors for disease-free survival or overall survival (p<0.05). Conclusions/Significance This study demonstrates that concurrent chemoradiation with adjuvant epirubicin-based triplet chemotherapy is feasible and tolerable for gastric or gastroesophageal junction carcinoma patients. Patients can benefit from more cycles of ACT. PMID

  10. FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional Selective Internal Radiation Therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer

    PubMed Central

    2014-01-01

    Background Colorectal cancer (CRC) is the second most common malignancy in Europe and a leading cause of cancer-related death. Almost 50% of patients with CRC develop liver metastases, which heralds a poor prognosis unless metastases can be downsized to surgical resection or ablation. The FOXFIRE trial examines the hypothesis that combining radiosensitising chemotherapy (OxMdG: oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia) as a first-line treatment for liver-dominant metastatic CRC will improve clinical outcomes when compared to OxMdG chemotherapy alone. Methods/Design FOXFIRE is an open-label, multicentre, randomised controlled trial of OxMdG with or without the addition of SIRT (1:1 randomisation). Eligible adult patients have histologically confirmed colorectal adenocarcinoma, liver metastases measurable on computed tomography scan and untreatable by either surgical resection or local ablation, and they may have limited extra-hepatic disease, defined as ≤5 nodules in the lung and/or one other metastatic site which is amenable to future definitive treatment. Eligible patients may have received adjuvant chemotherapy following resection of the primary tumour, but are not permitted to have previously received chemotherapy for metastatic disease, and must have a life expectancy of ≥3 months and a WHO performance status of 0–1. The primary outcome is overall survival. Secondary outcomes include progression free survival (PFS), liver-specific PFS, patient-reported outcomes, safety, response rate, resection rate and cost-effectiveness. FOXFIRE shares a combined statistical analysis plan with an international sister trial called SIRFLOX. Discussion This trial is establishing a network of SIRT centres and ‘feeder’ chemotherapy-only centres to standardise the delivery of SIRT across the whole of

  11. Stereotactic Body Radiation Therapy (SBRT) combined with chemotherapy for unresected pancreatic adenocarcinoma

    PubMed Central

    Gurka, Marie K.; Kim, Christine; He, Ruth; Charabaty, Aline; Haddad, Nadim; Johnson, Lynt; Jackson, Patrick; Weiner, Louis; Marshall, John L; Collins, Sean P.; Pishvaian, Michael J.; Unger, Keith

    2015-01-01

    Introduction The role of conventionally fractionated radiation therapy in the management of unresectable pancreatic cancer is controversial. One concern about concurrent chemoradiation relates to the timing of chemotherapy. In contrast to conventional radiation therapy, SBRT delivers high doses in a shorter duration resulting in minimal disruption in chemotherapy. Here we report our results of patients treated with SBRT and chemotherapy for inoperable pancreatic cancer. Methods Thirty-eight consecutive patients treated with SBRT and chemotherapy for locally advanced, borderline resectable, and medically inoperable at our institution from January 2008 to December 2012 were included in this retrospective analysis. Treatment was delivered in 5 fractions of 5 or 6 Gy per fraction over five days. Median time from diagnosis to SBRT was 1.9 months. Toxicities were scored using the CTCAE v.3. Survival was calculated using the Kaplan-Meier method. Results The median age was 70 years (range 45 – 90). ECOG performance status ranged from 0 – 3. Thirty-four patients received concurrent chemotherapy. Four other patients received sequential chemotherapy. Median OS was 14.3 months and median PFS was 9.2 months from diagnosis. From radiation, OS and PFS were 12.3 months and 6.8 months, respectively. The overall local control rate was 79%. Acute toxicity was minimal. Severe late SBRT-related toxicities included one grade 3 gastric outlet obstruction, one grade 4 biliary stricture and a grade 5 gastric hemorrhage. Conclusions SBRT combined with chemotherapy for unresectable pancreatic cancer is convenient, feasible and generally well tolerated. The outcomes of SBRT combined with chemotherapy compare favorably to the results of treatment with chemotherapy and conventional radiation therapy. PMID:25171298

  12. Conversion Chemotherapy for Technically Unresectable Colorectal Liver Metastases: A Retrospective, STROBE-Compliant, Single-Center Study Comparing Chemotherapy Alone and Combination Chemotherapy With Cetuximab or Bevacizumab.

    PubMed

    Basso, Michele; Dadduzio, Vincenzo; Ardito, Francesco; Lombardi, Pasquale; Strippoli, Antonia; Vellone, Maria; Orlandi, Armando; Rossi, Sabrina; Cerchiaro, Eleonora; Cassano, Alessandra; Giuliante, Felice; Barone, Carlo

    2016-05-01

    The response rate of patients with unresectable liver-limited metastases of colorectal cancer can be improved by converting inoperable disease to operable disease. However, the benefits of conversion chemotherapy for survival are still controversial.Patients considered to have technically inoperable disease by a multidisciplinary team were retrospectively analyzed. Patients were stratified based on the treatment they received, into the chemotherapy only (G1), chemotherapy plus bevacizumab (G2), or chemotherapy plus cetuximab (G3) groups. The primary endpoint was the resection rate. The secondary endpoint was the overall survival (OS), according to both the treatment received and liver surgery status.In total, 104 patients were included: 30 in the G1, 39 in the G2, and 35 in the G3 groups. All G3 patients had the wild-type KRAS exon 2. The surgical resection rates for patients in the G1, G2, and G3 groups were 43.3% (13/30), 30.7% (12/39), and 51.4% (18/35), respectively. Disease-free survival did not show significant differences among the 3 groups. The median OS was 35.2 months in the G1, 28.8 months in the G2, and 42.1 months in the G3 (P = 0.25) groups. The OS was significantly higher in patients who underwent surgical resection than those who did not. The median OS was 28.4 months in patients who did not undergo resection, whereas it had not been reached after a median follow-up period of 37.5 months for patients who underwent surgical resection (events: 21/43).Our data confirmed that the conversion of initially inoperable disease to operable disease conferred a survival benefit, even in patients who relapsed after surgery. The addition of cetuximab to chemotherapy improved the objective response and resection rates, conferring a potential survival benefit even in patients whose diseases were not converted to operable disease, compared to chemotherapy alone or in combination with bevacizumab. PMID:27196492

  13. Observations of the incidence of metastasis following laser hyperthermia in combination with chemotherapy, PDT, and excision

    NASA Astrophysics Data System (ADS)

    Wang, Mianjing; Gao, Menglin; Gao, Jin; Xue, Kexun; Xu, Zuyan; Zhang, Jingyuan; Li, Qongru; Geng, Zifan; Gong, Zhuo; Ye, Qing; Gu, Pei; Xao, Jing-Lian

    1993-03-01

    Our early observations have confirmed that laser hyperthermia or PDT alone does not promote the tumor metastasis. In order to evaluate the combined effect of local tumor laser hyperthermia on the distant metastasis, transplantable forestomach carcinoma (Fc) in 615 line mice was treated by Nd:YAG laser hyperthermia (45 degree(s)C/20 min) combined with PDT (HpD 5 mg/kg, 480 J/cm2, 20 min), chemotherapy (Cyclophosphamide 28.8 mg/kg) and excision, respectively. The results show that (1) the tumor growth inhibition by various treatment was significant compared with a control group; (2) no statistics different in metastasis rate were observed in laser hyperthermia combined with PDT, chemotherapy, or scalpel excision separately. It is suggested that laser hyperthermia combined with PDT, chemotherapy, or excision does not increase the incidence of the tumor metastasis.

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

    PubMed

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

    2015-06-01

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

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

    PubMed Central

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

    2015-01-01

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

  16. Experimental studies of combination of PDT and tumor chemotherapy or 60Co irradiation

    NASA Astrophysics Data System (ADS)

    Didziapetriene, Janina; Prasmickiene, Grazina; Sukeliene, Dalija; Rotomskis, Ricardas; Streckyte, Giedre; Atkocius, Vydmantas; Staciokiene, Laima; Smilgevicius, Valerijus

    1995-01-01

    We present experimental results obtained by combining photodynamic therapy (PDT) with tumor chemotherapy or radiotherapy. Dimethoxyhematoporphyrin (DMHp) and photosan (PS) were used as photosensitizers, pharanoxi and vincristine as antitumor drugs. The therapeutic effect of the combination of PDT and antitumor drugs (pharanoxi, vincristine) slightly increases as compared to the treatment of PDT or antitumor drug alone. The additive therapeutic effect is achieved under the combination of PDT and 60Co irradiation. It seems that the sensitizers DMHp and PS regulate lipid peroxidation in blood serum of experimental animals, which becomes more active under the influence of alkylating antitumor drugs. Therefore, they could protect an organism from negative influence of tumor chemotherapy.

  17. Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy

    PubMed Central

    Spencer, Drew A; Young, Jacob S; Kanojia, Deepak; Kim, Julius W; Polster, Sean P; Murphy, Jason P; Lesniak, Maciej S

    2015-01-01

    Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future. PMID:25996044

  18. Magnetic nanoparticle-conjugated polymeric micelles for combined hyperthermia and chemotherapy

    NASA Astrophysics Data System (ADS)

    Kim, Hyun-Chul; Kim, Eunjoo; Jeong, Sang Won; Ha, Tae-Lin; Park, Sang-Im; Lee, Se Guen; Lee, Sung Jun; Lee, Seung Woo

    2015-10-01

    Magnetic nanoparticle-conjugated polymeric micelles (MNP-PMs) consisting of poly(ethylene glycol)-poly(lactide) (PEG-PLA) and iron oxide nanoparticles were prepared and used as nanocarriers for combined hyperthermia and chemotherapy. Doxorubicin (DOX) was encapsulated in MNP-PMs, and an alternating magnetic field (AMF) resulted in an increase to temperature within a suitable range for inducing hyperthermia and a higher rate of drug release than observed without AMF. In vitro cytotoxicity and hyperthermia experiments were carried out using human lung adenocarcinoma A549 cells. When MNP-PMs encapsulated with an anticancer drug were used to treat A549 cells in combination with hyperthermia under AMF, 78% of the cells were killed by the double effects of heat and the drug, and the combination was more effective than either chemotherapy or hyperthermia treatment alone. Therefore, MNP-PMs encapsulated with an anticancer drug show potential for combined chemotherapy and hyperthermia.Magnetic nanoparticle-conjugated polymeric micelles (MNP-PMs) consisting of poly(ethylene glycol)-poly(lactide) (PEG-PLA) and iron oxide nanoparticles were prepared and used as nanocarriers for combined hyperthermia and chemotherapy. Doxorubicin (DOX) was encapsulated in MNP-PMs, and an alternating magnetic field (AMF) resulted in an increase to temperature within a suitable range for inducing hyperthermia and a higher rate of drug release than observed without AMF. In vitro cytotoxicity and hyperthermia experiments were carried out using human lung adenocarcinoma A549 cells. When MNP-PMs encapsulated with an anticancer drug were used to treat A549 cells in combination with hyperthermia under AMF, 78% of the cells were killed by the double effects of heat and the drug, and the combination was more effective than either chemotherapy or hyperthermia treatment alone. Therefore, MNP-PMs encapsulated with an anticancer drug show potential for combined chemotherapy and hyperthermia. Electronic

  19. A comparative study of 5-Fluorouracil release from chitosan/silver and chitosan/silver/MWCNT nanocomposites and their cytotoxicity towards MCF-7.

    PubMed

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

    2016-09-01

    5-Fluorouracil encapsulated chitosan/silver and chitosan/silver/multiwalled carbon nanotubes were synthesized to comparatively study the release profile and cytotoxicity of the systems towards MCF-7 cell line. The triclinic structure of 5-Fluorouracil, face centered cubic structure of silver and the semi-crystalline nature of chitosan were elucidated using the XRD pattern. The XRD pattern of Chitosan/silver/multiwalled carbon nanotube consisted of (002) reflection of graphitic carbon from carbon nanotube. The evident splitting of NH2 and NH3(+) and a variation in the intensity of OH peaks in the FTIR pattern were indicative of the binding of moieties like silver, carbon nanotube and 5-Fluorouracil to chitosan. The encapsulation of 5-Fluorouracil was evident from elemental mapping and from the presence of reflections corresponding to 5-Fluorouracil in the SAED pattern. The release profile showed a prolonged release for 5-Fluorouracil encapsulated Chitosan/silver/multiwalled carbon nanotube and a better cytotoxicity with a IC50 of 50μg/ml was observed for the same. PMID:27207060

  20. Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer.

    PubMed

    Swain, S M; Sorace, R A; Bagley, C S; Danforth, D N; Bader, J; Wesley, M N; Steinberg, S M; Lippman, M E

    1987-07-15

    We have treated 76 patients with locally advanced breast cancer, 31 with stage IIIA, 41 with stage IIIB, and 4 with stage IV disease, with primary induction chemotherapy including an attempted hormonal synchronization in 70 patients. All were treated to maximum objective clinical response before proceeding to any local therapy. Patients achieving a complete response with a negative repeat biopsy generally received radiation therapy while patients with residual disease, partial response (PR) or no change (NC) status received debulking surgery prior to radiation therapy. Regardless of response to induction chemotherapy, patients received at least 6 additional months of chemotherapy following local therapy. Initial doses of combination chemotherapy were escalated to targeted myelosuppression. The objective response rate to induction chemotherapy was 93% with 49% complete response (CR), 44% PR, and 7% NC. The median numbers of cycles of chemotherapy to achieve a CR, PR, or NC were 5, 3, and 5, respectively. Three patients who currently have PRs are still on chemotherapy with continued tumor regression. Of 37 patients achieving a CR to chemotherapy, 35 were assessed by biopsies to determine pathological evidence of response. Twenty-three of the 37 patients (62%) were proven to be complete responders with negative biopsies. Twenty-four patients have relapsed, 6 with stage IIIA, 16 with stage IIIB, and 2 with stage IV. Five patients have had locoregional relapses alone, 4 locoregional and distant, and 15 distant alone. Median time to progression is 35.9 months for stage IIIA and 34.2 months for stage IIIB. Median survival is 35.3 months for stage IIIB and is indeterminate for stage IIIA. This aggressive primary chemotherapy regimen with hormonal synchronization followed by local therapy appears to provide excellent local control and encouraging early results on systemic disease control. PMID:3036348

  1. Hepatic metastasis from esophageal cancer treated by surgical resection and hepatic arterial infusion chemotherapy.

    PubMed

    Hanazaki, K; Kuroda, T; Wakabayashi, M; Sodeyama, H; Yokoyama, S; Kusama, J

    1998-01-01

    We herein describe a successful surgical resection of esophageal cancer with syncronous liver metastasis and report the first case of a partial response to hepatic arterial infusion chemotherapy for recurrence of esophageal hepatic metastasis after hepatectomy. Hepatectomy and subsequent hepatic arterial infusion chemotherapy with cisplatin and 5-fluorouracil is thus recommended as an effective treatment for liver metastasis from esophageal cancer. PMID:9496513

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

    PubMed

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

    2005-03-10

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

  3. The role of chemotherapy in managing chronic lymphocytic leukemia: optimizing combinations with targeted therapy.

    PubMed

    Nastoupil, Loretta J; Sinha, Rajni; Flowers, Christopher R

    2013-09-01

    For many years, alkylating agents were the standard treatment for chronic lymphocytic leukemia (CLL). The advent of purine analogs improved response rates, but not overall survival, and although the monoclonal antibody rituximab is generally active against B-cell malignancies, it has demonstrated limited benefits as monotherapy for the treatment of CLL. However, specific combinations of chemotherapy, antibodies and targeted therapies have demonstrated additive or synergistic activity in CLL cells and deliver substantial clinical benefits. A greater understanding of the actions of chemotherapies and targeted agents on cellular pathways will advance the development of rationally designed combinations corresponding to individual patients' disease profiles. PMID:23919536

  4. Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma

    PubMed Central

    Banavali, Shripad; Pasquier, Eddy; Andre, Nicolas

    2015-01-01

    We report here a case of a 69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. The beta blockers were added since the tumour was positive for betaadrenergic receptor. A complete response was quickly obtained and lasted for 20 months. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies and illustrates the potential of metronomics to generate innovative yet inexpensive targeted therapies for both high-income and low-/middle-income countries. PMID:25624880

  5. Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma.

    PubMed

    Banavali, Shripad; Pasquier, Eddy; Andre, Nicolas

    2015-01-01

    We report here a case of a 69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. The beta blockers were added since the tumour was positive for betaadrenergic receptor. A complete response was quickly obtained and lasted for 20 months. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies and illustrates the potential of metronomics to generate innovative yet inexpensive targeted therapies for both high-income and low-/middle-income countries. PMID:25624880

  6. Evaluation of the therapeutic results of actinic keratosis treated with topical 5% fluorouracil by reflectance confocal laser microscopy: preliminary study*

    PubMed Central

    Ishioka, Priscila; Maia, Marcus; Rodrigues, Sarita Bartholomei; Marta, Alessandra Cristina; Hirata, Sérgio Henrique

    2015-01-01

    Topical treatment for actinic keratosis with 5% fluorouracil has a recurrence rate of 54% in 12 months of follow-up. This study analyzed thirteen actinic keratoses on the upper limbs through confocal microscopy, at the time of clinical diagnosis and after 4 weeks of treatment with fluorouracil. After the treatment was established and evidence of clinical cure was achieved, in two of the nine actinic keratoses, confocal microscopy enabled visualization of focal areas of atypical honeycomb pattern in the epidermis indicating therapeutic failure. Preliminary data suggest the use of confocal microscopy as a tool for diagnosis and therapeutic control of actinic keratosis. PMID:26131881

  7. Two Half-Sandwiched Ruthenium (II) Compounds Containing 5-Fluorouracil Derivatives: Synthesis and Study of DNA Intercalation

    PubMed Central

    Li, Zhao-Jun; Hou, Yong; Qin, Da-An; Jin, Zhi-Min; Hu, Mao-Lin

    2015-01-01

    Two novel coordination compounds of half-sandwiched ruthenium(II) containing 2-(5-fluorouracil)-yl-N-(pyridyl)-acetamide were synthesized, and their intercalation binding modes with calf thymus DNA were revealed by hyperchromism of ultraviolet-visible spectroscopy; the binding constants were determined according to a Langmuir adsorption equation that was deduced on the base of careful cyclic voltammetry measurements. The two compounds exhibited DNA intercalation binding activities with the binding constants of 1.13×106 M-1 and 5.35 ×105 M-1, respectively. PMID:25789618

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

    PubMed

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

    2006-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    1998-05-01

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

  11. A combined model of human erythropoiesis and granulopoiesis under growth factor and chemotherapy treatment

    PubMed Central

    2014-01-01

    Background Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. Results To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in

  12. Regional hyperthermia combined with chemotherapy in paediatric, adolescent and young adult patients: current and future perspectives.

    PubMed

    Seifert, Georg; Budach, Volker; Keilholz, Ulrich; Wust, Peter; Eggert, Angelika; Ghadjar, Pirus

    2016-01-01

    Here we evaluate the current status of clinical research on regional hyperthermia (RHT) in combination with chemotherapy or radiation therapy in paediatric oncology.Data were identified in searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using medical subject headings including hyperthermia, cancer, paediatric oncology, children, radiation therapy and chemotherapy. Currently, only two RHT centres exist in Europe which treat children. Clinical RHT research in paediatric oncology has as yet been limited to children with sarcomas and germ cell tumours that respond poorly to or recur after chemotherapy. RHT is a safe and effective treatment delivering local thermic effects, which may also stimulate immunological processes via heat-shock protein reactions. RHT is used chiefly in children and adolescents with sarcomas or germ cell tumours located in the abdomino-pelvic region, chest wall or extremities to improve operability or render the tumour operable. It could potentially be combined with radiation therapy in a post-operative R1 setting where more radical surgery is not possible or combined with chemotherapy instead of radiation therapy in cases where the necessary radiation dose is impossible to achieve or would have mutilating consequences. RHT might also be an option for chemotherapy intensification in the neoadjuvant first-line treatment setting for children and adolescents, as was recently reflected in the promising long-term outcome data in adults with high-risk soft tissue sarcomas (EORTC 62961/ESHO trial).The limited data available indicate that combining RHT with chemotherapy is a promising option to treat germ cell tumours and, potentially, sarcomas. RHT may also be beneficial in first-line therapy in children, adolescents and young adults. The research should focus on optimising necessary technical demands and then initiate several clinical trials incorporating RHT into interdisciplinary treatment of children

  13. Chemotherapy for colorectal cancer in the elderly

    PubMed Central

    Kim, Jung Han

    2015-01-01

    Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the elderly. However, elderly patients with CRC tend to be under-presented in clinical trials and undertreated in clinical practice. Advanced age alone should not be the only criteria to preclude effective therapy in elderly patients with CRC. The best guide about optimal cancer treatment can be provided by comprehensive geriatric assessment. Elderly patients with stage III colon cancer can enjoy the same benefit from adjuvant chemotherapy with 5-fluorouracil/leucovorin or capecitabine as younger patients, without a substantial increase in toxicity. With conflicting results of retrospective studies and a lack of data available from randomized studies, combined modality treatment should be used with great caution in elderly patients with locally advanced rectal cancer. Combination chemotherapy can be considered for older patients with metastatic CRC. For elderly patients who are frail or vulnerable, however, monotherapy or a stop-and-go strategy may be desirable. The use of targeted therapies in older patients with metastatic CRC appears to be promising in view of their better efficacy and toxicity. Treatment should be individualized based on the nature of the disease, the physiologic or functional status, and the patient’s preference. PMID:25954089

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed

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

    2000-07-01

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

  16. l-carnosine dipeptide overcomes acquired resistance to 5-fluorouracil in HT29 human colon cancer cells via downregulation of HIF1-alpha and induction of apoptosis.

    PubMed

    Iovine, Barbara; Guardia, Francesca; Irace, Carlo; Bevilacqua, Maria Assunta

    2016-08-01

    Hypoxia-inducible factor (HIF-1α) protein is over-expressed in many human cancers and is a major cause of resistance to drugs. HIF-1α up-regulation decreases the effectiveness of several anticancer agents, including 5-fluorouracil (5-FU), because it induces the expression of drug efflux transporters, alters DNA repair mechanisms and modifies the balance between pro- and antiapoptotic factors. These findings suggest that inhibition of HIF-1α activity may sensitize cancer cells to cytotoxic drugs. We previously reported that l-carnosine reduces HIF-1α expression by inhibiting the proliferation of colon cancer cells. In the present study we investigated the effect of l-carnosine on HT29 colon cancer cells with acquired resistance to 5-FU. We found that l-carnosine reduces colon cancer cell viability, decreases HIF-1α and multi-drug resistant protein MDR1-pg expression, and induces apoptosis. Moreover, the l-carnosine/5-FU combination lowers the expression of some chemoresistance markers. The combination index evaluated in vitro on the HT29-5FU cell line by median drug effect analysis reveals a significant synergistic effect. PMID:27234614

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

    SciTech Connect

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

    1984-05-01

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

  18. Prognostic significance of p16 in locoregionally advanced head and neck cancer treated with concurrent 5-fluorouracil, hydroxyurea, cetuximab and intensity-modulated radiation therapy.

    PubMed

    Tong, Charles C L; Lau, K H Vincent; Rivera, Michael; Cannan, David; Aguirre-Ghiso, Julio; Sikora, Andrew G; Gupta, Vishal; Forsythe, Kevin; Ko, Eric C; Misiukiewicz, Krzysztof; Gurudutt, Vivek; Teng, Marita S; Packer, Stuart H; Genden, Eric M; Kao, Johnny

    2012-05-01

    A phase II trial was conducted to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) into a well-described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen. Patients with stage IVa-IVb or high-risk stage III squamous cell carcinomas were enrolled. Prior organ-conserving surgery or induction chemotherapy was allowed. IMRT was administered in 1.5 Gy fractions twice daily on days 1-5 of weeks 1, 3, 5, 7±9 for a total dose of 60-73.5 Gy. Concurrent systemic therapy consisted of 5-FU (600 mg/m2), HU (500 mg BID) and cetuximab (250 mg/m2). p16INK4A expression was assessed by immunohistochemistry. From January 2007 to January 2010, 65 patients (61 with stage IV disease; 31 with oropharyngeal primaries) were enrolled. At a median follow-up of 28 months, 2-year locoregional control, distant control, progression-free survival, event-free survival and overall survival were 79, 83, 72, 63 and 80%, respectively. In 48 patients with available pre-treatment tissue, p16 overexpression was associated with significantly increased distant control (p=0.03), progression-free survival (p=0.02), event-free survival (p=0.007) and overall survival (p=0.03). The most common grade 3-4 toxicities were mucositis (46%), leukopenia (18%), anemia (18%) and dermatitis (17%). Concurrent 5-FU, HU, cetuximab and SIB-IMRT is a highly active regimen, particularly in patients with p16-positive disease. PMID:22322320

  19. Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

    SciTech Connect

    Kato, Ken; Muro, Kei; Minashi, Keiko; Ohtsu, Atsushi; Ishikura, Satoshi; Boku, Narikazu; Takiuchi, Hiroya; Komatsu, Yoshito; Miyata, Yoshinori; Fukuda, Haruhiko

    2011-11-01

    Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m{sup 2}/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m{sup 2}) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m{sup 2}/day) on Days 1-5 and CDDP (80 mg/m{sup 2}) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.

  20. The Effect of Analogues of 1α,25-Dihydroxyvitamin D₂ on the Regrowth and Gene Expression of Human Colon Cancer Cells Refractory to 5-Fluorouracil.

    PubMed

    Neska, Jacek; Swoboda, Paweł; Przybyszewska, Małgorzata; Kotlarz, Agnieszka; Bolla, Narasimha Rao; Miłoszewska, Joanna; Grygorowicz, Monika Anna; Kutner, Andrzej; Markowicz, Sergiusz

    2016-01-01

    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. PMID:27314328

  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

    PubMed Central

    Neska, Jacek; Swoboda, Paweł; Przybyszewska, Małgorzata; Kotlarz, Agnieszka; Bolla, Narasimha Rao; Miłoszewska, Joanna; Grygorowicz, Monika Anna; Kutner, Andrzej; Markowicz, Sergiusz

    2016-01-01

    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. PMID:27314328

  2. Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha

    PubMed Central

    Braybrooke, J P; Propper, D J; O’Byrne, K J; Koukourakis, M I; Patterson, A V; Houlbrook, S; Love, S D; Varcoe, S; Taylor, M; Ganesan, T S; Talbot, D C; Harris, A L

    2000-01-01

    Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNα), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m–2, 9 MIU m–2and 18 MIUm–2. IFNα was administered on day 0 cycle two, day –1 and day 0 cycle three and day –2, day –1 and day 0 cycle four. A fourth cohort was treated with IFNα 9 MIU m–2three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNα. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNα led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P = 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNα. A single dose of IFNα as low as 3 MIU m–2can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNα for biomodulation of 5-FU. © 2000 Cancer Research Campaign PMID:10901374

  3. Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade.

    PubMed

    Zhang, Binhao; Leng, Chao; Wu, Chao; Zhang, Zhanguo; Dou, Lei; Luo, Xin; Zhang, Bixiang; Chen, Xiaoping

    2016-03-01

    5-Fluorouracil (5-FU), a cell cycle-specific antimetabolite, is one of the most commonly used chemotherapeutic agents for colorectal cancer (CRC). Yet, resistance to 5-FU-based chemotherapy is still an obstacle to the treatment of this malignancy. Mutation or loss of Smad4 in CRC is pivotal for chemoresistance. However, the mechanism by which Smad4 regulates the chemosensitivity of CRC remains unclear. In the present study, we investigated the role of Smad4 in the chemosensitivity of CRC to 5-FU, and whether Smad4-regulated cell cycle arrest is involved in 5-FU chemoresistance. We used Smad4-expressing CT26 and Smad4-null SW620 cell lines as experimental models, by knockdown or transgenic overexpression. Cells or tumors were treated with 5-FU to determine chemosensitivity by cell growth, tumorigenicity assay and a mouse model. Cell cycle distribution was examined with flow cytometric analysis, and cell cycle-related proteins were examined by western blotting. Smad4 deficiency in CT26 and SW620 cells induced chemoresistance to 5-FU both in vitro and in vivo. Smad4 deficiency attenuated G1 or G2 cell cycle arrest by activating the PI3K/Akt/CDC2/survivin pathway. The PI3K inhibitor, LY294002, reversed the activation of the Akt/CDC2/survivin cascade in the Smad4-deficient cells, while it had little effect on cells with high Smad4 expression. In conclusion, we discovered a novel mechanism mediated by Smad4 to trigger 5-FU chemosensitivity through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade. The present study also implies that LY294002 has potential therapeutic value to reverse the chemosensitivity of CRC with low Smad4 expression. PMID:26647806

  4. Preoperative Chemoradiotherapy for Rectal Cancer: Randomized Trial Comparing Oral Uracil and Tegafur and Oral Leucovorin Vs. Intravenous 5-Fluorouracil and Leucovorin

    SciTech Connect

    Torre, Alejandro de la Garcia-Berrocal, Maria Isabel; Arias, Fernando; Marino, Alfonso; Valcarcel, Francisco; Magallon, Rosa; Regueiro, Carlos A.; Romero, Jesus; Zapata, Irma; Fuente, Cristina de la; Fernandez-Lizarbe, Eva; Vergara, Gloria; Belinchon, Belen; Veiras, Maria; Moleron, Rafael; Millan, Isabel

    2008-01-01

    Purpose: To compare, in a randomized trial, 5-fluorouracil (FU) plus leucovorin (LV) (FU+LV) vs. oral uracil and tegafur (UFT) plus LV (UFT+LV) given concomitantly with preoperative irradiation in patients with cT3-4 or N+ rectal cancer. Methods and Materials: A total of 155 patients were entered onto the trial. Patients received pelvic radiotherapy (4500-5,040 cGy in 5 to 6 weeks) and chemotherapy consisting of two 5-day courses of 20 mg/m{sup 2}/d LV and 350 mg/m{sup 2}/d FU in the first and fifth weeks of radiotherapy (77 patients) or one course of 25 mg/d oral LV and 300 mg/m{sup 2}/d UFT for 4 weeks beginning in the second week of radiotherapy (78 patients). The primary endpoints were pathologic complete response (pCR) and resectability rate. Secondary endpoints included downstaging rate, toxicity, and survival. Results: Grade 3-5 acute hematologic toxicity occurred only with FU+LV (leukopenia 9%; p = 0.02). There were no differences in resectability rates (92.1% vs. 93.4%; p = 0.82). The pCR rate was 13.2% in both arms. Tumor downstaging was more frequent with UFT+LV (59.2% vs. 43.3%; p = 0.04). Three-year overall survival was 87% with FU+LV and 74% with UFT+LV (p = 0.37). The 3-year cumulative incidences of local recurrence were 7.5% and 8.9%, respectively (p = 0.619; relative risk, 1.46; 95% confidence interval 0.32-6.55). Conclusion: Although this study lacked statistical power to exclude clinically significant differences between both groups, the outcome of patients treated with UFT+LV did not differ significantly from that of patients treated with FU+LV, and hematologic toxicity was significantly lower in the experimental arm.

  5. Combinational strategies of metformin and chemotherapy in cancers.

    PubMed

    Zhang, Hui-Hui; Guo, Xiu-Li

    2016-07-01

    Chemotherapeutic regimens are the most common treatment to inhibit tumor growth, but there is great variability in clinical responses of cancer patients; cancer cells often develop resistance to chemotherapeutics which results in tumor recurrence and further progression. Metformin, an extensively prescribed and well-tolerated first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer adjuvant drug combined with chemotherapeutic drugs to improve treatment efficacy and lower doses. In this review, we summarized the molecular mechanisms underlying anticancer effects of metformin, which included insulin- and AMPK-dependent effects, selectively targeting cancer stem cells, reversing multidrug resistance, inhibition of the tumor metastasis and described the antineoplastic effects of metformin combined with chemotherapeutic agents in digestive system cancers (colorectal, gastric, hepatic and pancreatic cancer), reproductive system cancers (ovarian and endometrial cancer), prostate cancer, breast cancer, lung cancer, etc. Moreover, the clinical trials regarding metformin in combination of chemotherapeutic drugs were presented and the clinical obstacle or limitation related to the potential role of metformin in cancer treatment was also discussed in this review. PMID:27118574

  6. Can thymidine phosphorylase be a predictive marker for gemcitabine and doxifluridine combination chemotherapy in cholangiocarcinoma?: case series.

    PubMed

    Kang, Myoung Hee; Lee, Won Sup; Go, Se-Il; Kim, Moon Jin; Lee, Un Seok; Choi, Hye Jung; Kim, Dong Chul; Lee, Jeong-Hee; Kim, Hoon-Gu; Bae, Kyung Soo; Cho, Jae Min

    2014-12-01

    Unresectable cholangiocarcinoma is poorly responded to chemotherapy, especially for the case refractory to gemcitabine and cisplatin. Here, we tested whether high expression of thymidine phosphorylase (TP) can be a predictive biomarker for the indicator for gemcitabine and doxifluridine combination chemotherapy in the cholangiocarcinoma refractory to gemcitabine and cisplatin. Immunohistochemical staining for TP was performed with a biopsy specimen. We accepted the result as positive when more than 10% of cancer cells were stained with moderate intensity. Here, we report 2 cases of TP-positive cholangiocarcinoma well controlled with gemcitabine and doxifluridine combination chemotherapy, which had been refractory to the first line treatment with gemcitabine and cisplatin combination chemotherapy. PMID:25526478

  7. When Combined with Chemotherapy, Bevacizumab Is Associated with Increased Risk of Death

    Cancer.gov

    Cancer patients who receive the targeted therapy bevacizumab (Avastin) in combination with chemotherapy are at increased risk of serious side effects that may lead to death, according to a meta-analysis of 16 clinical trials that was published February 2,

  8. Synergistic chemotherapy by combined moderate hyperthermia and photochemical internalization

    PubMed Central

    Christie, Catherine; Molina, Stephanie; Gonzales, Jonathan; Berg, Kristian; Nair, Rohit Kumar; Huynh, Khoi; Madsen, Steen J.; Hirschberg, Henry

    2016-01-01

    Combination therapies of photochemical internalization (PCI) and moderate hyperthermia (MHT) were investigated in an in vitro system consisting of human and rat glioma spheroids. PCI using the amphiphilic photosensitizer, AlPcS2a and two anti cancer agents BLM or 5-FU were used. Spheroids were irradiated with λ = 670 nm laser light in an incubator at temperatures ranging from 37 to 44°C. For each temperature investigated, spheroids were divided into 4 groups: control, drug-only, photodynamic therapy (PDT), and PCI. PDT and PCI spheroids were exposed to radiant exposures ranging from 0.3 to 2.5 J cm−2 using an irradiance of 5 mW cm−2. Toxicity was evaluated from spheroid growth kinetics. The combination of PCI and MHT resulted in significant increases in BLM efficacy at 44°C for both cell line derived spheroids compared to controls at 37°C over the range of radiant exposures examined. 5-FU PCI was ineffective for the human cell line at both 37 and 44°C. PMID:27446650

  9. Synergistic chemotherapy by combined moderate hyperthermia and photochemical internalization.

    PubMed

    Christie, Catherine; Molina, Stephanie; Gonzales, Jonathan; Berg, Kristian; Nair, Rohit Kumar; Huynh, Khoi; Madsen, Steen J; Hirschberg, Henry

    2016-04-01

    Combination therapies of photochemical internalization (PCI) and moderate hyperthermia (MHT) were investigated in an in vitro system consisting of human and rat glioma spheroids. PCI using the amphiphilic photosensitizer, AlPcS2a and two anti cancer agents BLM or 5-FU were used. Spheroids were irradiated with λ = 670 nm laser light in an incubator at temperatures ranging from 37 to 44°C. For each temperature investigated, spheroids were divided into 4 groups: control, drug-only, photodynamic therapy (PDT), and PCI. PDT and PCI spheroids were exposed to radiant exposures ranging from 0.3 to 2.5 J cm(-2) using an irradiance of 5 mW cm(-2). Toxicity was evaluated from spheroid growth kinetics. The combination of PCI and MHT resulted in significant increases in BLM efficacy at 44°C for both cell line derived spheroids compared to controls at 37°C over the range of radiant exposures examined. 5-FU PCI was ineffective for the human cell line at both 37 and 44°C. PMID:27446650

  10. Multifunctional hybrid materials for combined photo and chemotherapy of cancer.

    PubMed

    Botella, Pablo; Ortega, Ilida; Quesada, Manuel; Madrigal, Roque F; Muniesa, Carlos; Fimia, Antonio; Fernández, Eduardo; Corma, Avelino

    2012-08-21

    Combined chemo and photothermal therapy in in vitro testing has been achieved by means of multifunctional nanoparticles formed by plasmonic gold nanoclusters with a protecting shell of porous silica that contains an antitumor drug. We propose a therapeutic nanoplatform that associates the optical activity of small gold nanoparticles aggregates with the cytotoxic activity of 20(S)-camptothecin simultaneously released for the efficient destruction of cancer cells. For this purpose, a method was used for the controlled assembly of gold nanoparticles into stable clusters with a tailored absorption cross-section in the vis/NIR spectrum, which involves aggregation in alkaline medium of 15 nm diameter gold colloids protected with a thin silica layer. Clusters were further encapsulated in an ordered homogeneous mesoporous silica coating that provides biocompatibility and stability in physiological fluids. After internalization in 42-MG-BA human glioma cells, these protected gold nanoclusters were able to produce effective photothermolysis under femtosecond pulse laser irradiation of 790 nm. Cell death occurred by combination of a thermal mechanism and mechanical disruption of the membrane cell due to induced generation of micrometer-scale bubbles by vaporizing the water inside the channels of the mesoporous silica coating. Moreover, the incorporation of 20(S)-camptothecin within the pores of the external shell, which was released during the process, provoked significant cell death increase. This therapeutic model could be of interest for application in the treatment and suppression of non-solid tumors. PMID:22555652

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

    PubMed Central

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

    2015-01-01

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

  12. Combination chemotherapy and radiation therapy for small cell carcinoma.

    PubMed

    Holoye, P Y; Samuels, M L; Lanzotti, V J; Smith, T; Barkley, H T

    1977-03-21

    A three-drug combination of the chemotherapeutic agents cyclophosphamide, vincristine sulfate, and doxorubicin hydrochloride was given to 45 patients with small cell bronchogenic carcinoma. In addition, patients with limited disease received radiation therapy to the primary tumor. The complete response rate was 44%, with a median survival of 50 weeks. The partial response rate was 29%, with a median survival of 35 weeks. Patients who did not respond to therapy showed a median survival of only 12 weeks. Twenty percent of the patients had their first recurrence in the brain, and the median survival from the time of disease recurrence was ten weeks. Bone marrow metastasis was encountered in 24% of the patient population, but this did not adversely affect survival. PMID:190427

  13. Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma. A randomized study

    SciTech Connect

    Trovo, M.G.; Minatel, E.; Veronesi, A.; Roncadin, M.; De Paoli, A.; Franchin, G.; Magri, D.M.; Tirelli, U.; Carbone, A.; Grigoletto, E. )

    1990-02-01

    Between June 1980 and December 1983, 111 patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were entered into a randomized trial comparing radiotherapy alone versus radiotherapy and combination chemotherapy with cyclophosphamide, Adriamycin (doxorubicin), methotrexate, and procarbazine. Thirty-five of 62 (56.4%) patients treated with 4500 rad in 15 fractions in 3 weeks and 19 of 49 (38.8%) patients treated with the same radiation treatment and chemotherapy had an objective response. The difference in response rate was not significant (P = 0.900). Median time to progression was 5.9 and 7.02 months, respectively, for the radiation treatment and the combined treatment. Median survival was 11.74 and 10.03 months, respectively, without statistically significant differences between the two groups of patients. The toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant superiority of combined radiotherapy and chemotherapy treatment over radiation therapy alone was evidenced. Whether different chemotherapy regimens may prove more effective in this context should be clarified by further studies.

  14. A Reactive 1O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

    2016-07-01

    The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen (1O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of 1O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this 1O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency.

  15. A Reactive (1)O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer.

    PubMed

    Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

    2016-01-01

    The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen ((1)O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of (1)O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this (1)O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency. PMID:27443831

  16. A Reactive 1O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer

    PubMed Central

    Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

    2016-01-01

    The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen (1O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of 1O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this 1O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency. PMID:27443831

  17. [Rectal cancer and adjuvant chemotherapy: which conclusions?].

    PubMed

    Bachet, J-B; Rougier, P; de Gramont, A; André, T

    2010-01-01

    Adenocarcinoma of the rectum represents about a third of cases of colorectal cancer, with an annual incidence of 12,000 cases in France. On the contrary of colon cancer, the benefice of adjuvant chemotherapy in rectal cancer has not been definitively proved, more because this question was assessed in few recent studies than because negative results. Preoperative radiochemotherapy is now the reference treatment for mid and lower rectal cancers, and allow to increase the local control without improvement of progression free survival and overall survival. The data of the "historical studies" of adjuvant treatment in rectal cancer published before 1990, of the meta-analysis of adjuvant trials in rectal cancer and of the QUASAR study suggest that adjuvant chemotherapy with fluoropyrimidines (intravenous or oral), in absence of pre-operative treatment, decrease the risk of metastatic relapse after curative surgery for a rectal cancer of stage II or III. This benefice seems similar to the one observed in colon cancer. In the EORTC radiotherapy group trial 22921, an adjuvant chemotherapy with 5-fluorouracil and low dose of leucovorin was not associated with a significantly improvement of overall survival but, despite the fact that only 42.9% of patients received all planed cycles, the progression free survival was increased (not significantly) in groups receiving adjuvant chemotherapy. The French recommendations are to discuss the indication of adjuvant chemotherapy by fluoropyrimidines in cases of stage III rectal cancer on histopathologic reports and no chemotherapy in case of stade II. Despite the fact that none study have assessed a combination of fluoropyrimidines and oxaliplatin in adjuvant setting in rectal cancer, like in colon cancer, the Folfox4, modified Folfox6 or Xelox regimens are valid options in stage III (experts opinion). In cases of pathologic complete remission or in absence of involved nodes, the benefice of adjuvant chemotherapy is not assessed. In

  18. Thermosensitive gemcitabine-magnetoliposomes for combined hyperthermia and chemotherapy

    NASA Astrophysics Data System (ADS)

    Ferreira, Roberta V.; da Mata Martins, Thaís Maria; Goes, Alfredo Miranda; Fabris, José D.; Cavalcante, Luis Carlos D.; Eugenio Fernandez Outon, Luis; Domingues, Rosana Z.

    2016-02-01

    The combination of magnetic hyperthermia therapy with the controlled release of chemotherapeutic agents in tumors may be an efficient therapeutic with few side effects because the bioavailability, tolerance and amount of the drug can be optimized. Here, we prepared magnetoliposomes consisting of magnetite nanoparticle cores and the anticancer drug gemcitabine encapsulated by a phospholipid bilayer. The potential of these magnetoliposomes for controlled drug release and cancer treatment via hyperthermic behavior was investigated. The magnetic nanoparticle encapsulation efficiency was dependent on the initial amount of magnetite nanoparticles present at the encapsulation stage; the best formulation was 66%. We chose this formulation to characterize the physicochemical properties of the magnetoliposomes and to encapsulate gemcitabine. The mean particle size and distribution were determined by dynamic light scattering (DLS), and the zeta potential was measured. The magnetoliposome formulations all had acceptable characteristics for systemic administration, with a mean size of approximately 150 nm and a polydispersity index <0.2. The magnetoliposomes were stable in aqueous suspension for at least one week, as determined by DLS. Temperature increases due to the dissipation energy of magnetoliposome suspensions subjected to an applied alternating magnetic field (AMF) were measured at different magnetic field intensities, and the values were appropriated for cancer treatments. The drug release profile at 37 °C showed that 17% of the gemcitabine was released after 72 h. Drug release from magnetoliposomes exposed to an AMF for 5 min reached 70%.

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

    PubMed Central

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

    2013-01-01

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

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

    SciTech Connect

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

    2006-10-15

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

  1. Treatment of advanced pancreatic cancer with 5-fluorouracil, folinic acid and interferon alpha-2A: results of a phase II trial.

    PubMed Central

    Bernhard, H.; Jäger-Arand, E.; Bernhard, G.; Heike, M.; Klein, O.; Riemann, J. F.; Meyer zum Büschenfelde, K. H.; Dippold, W.; Knuth, A.

    1995-01-01

    Interferon alpha-2a (IFN-alpha) and folinic acid (FA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. A phase II study was initiated to evaluate the effect of a combination of 5-FU/FA/IFN-alpha in patients with advanced pancreatic cancer. Sixty previously untreated patients with advanced adenocarcinoma of the pancreas were treated with 500 mg m-2 FU via an intravenous bolus 1 h after the initiation of a 2 h infusion of 500 mg m-2 FA. Before starting the FA infusion, 6 million units (MU) of IFN-alpha was administered subcutaneously. The treatment was repeated once a week. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR) and 28 (49%) no change of disease (NC). Thirteen patients (23%) had progressive disease (PD). The median survival time was 10 months for all patients, 22 months for patients with partial remission and 5 months for patients with progressive disease. Many patients with tumour-related pain whose tumours were affected in terms of PR, MR, NC were free of pain during treatment with this regimen (22/36 patients). The common toxicities observed were fever (56%), nausea (37%) and diarrhoea (33%). These data suggest that biochemical modulation of 5-FU with FA and IFN-alpha has some positive effects in the treatment of pancreatic cancer of moderate toxicity. PMID:7819023

  2. A phase I trial of docetaxel and 5-day continuous infusion of 5-fluorouracil in patients with advanced or recurrent breast cancer.

    PubMed Central

    Ando, M.; Watanabe, T.; Sasaki, Y.; Ying, D. F.; Omuro, Y.; Katsumata, N.; Narabayashi, M.; Tokue, Y.; Fujii, H.; Igarashi, T.; Wakita, H.; Ohtsu, T.; Itoh, K.; Adachi, I.; Taguchi, T.

    1998-01-01

    To determine the maximum-tolerated doses (MTDs), the dose-limiting toxicities (DLTs) and the recommended doses for further trials of docetaxel in combination with a 5-day continuous infusion of 5-fluorouracil (5-FU) in advanced or recurrent breast cancer patients who had been treated previously with at least one chemotherapeutic regimen, patients were treated with docetaxel as a 1-h infusion on day 1 followed by 5-FU as a continuous infusion on days 1 through 5 every 3-4 weeks. Three or six patients were assessed at the following escalating dose levels of docetaxel/5-FU per day: 40/150, 40/300, 50/300, 50/500 and 60/500 mg m(-2). Nineteen patients entered this trial, of whom 18 could be assessed for adverse event and therapeutic efficacy. The DLTs were neutropenia and diarrhoea. The MTDs were 60 mg m(-2) of docetaxel on day 1 and 500 mg m(-2) per day of 5-day continuous infusion of 5-FU. One of 18 patients achieved a complete response and eight achieved partial response (over all response rate: 50%). The recommended doses of docetaxel and 5-day continuous infusion of 5-FU for a phase II trial are 50 mg m(-2) and 500 mg m(-2) per day every 3 or 4 weeks. PMID:9667671

  3. Effects on platelet function of combination etoposide and carboplatin chemotherapy in pediatric oncology patients.

    PubMed

    Pignatelli, P; Properzi, E; Pisani, M; Clerico, A; Schiavetti, A; Lenti, L; Pulcinelli, F M; Ferroni, P; Gazzaniga, P P

    1998-01-01

    The effects of a therapeutic course of the combination of carboplatin and etoposide on platelet function have been evaluated in 10 pediatric patients with brain tumors. Platelet count, in vitro aggregation tests, P-selectin expression and agonist-induced ATP release were evaluated before, and 7 and 15 days after one cycle of chemotherapy. The analysis of the results demonstrated the presence of an in vitro platelet aggregation defect in response to collagen and arachidonic acid in all patients 7 days after therapy. A concomitant decrease of collagen- and arachidonic acid-induced ATP release was also observed. Both platelet aggregation and ATP release returned to baseline values 15 days after chemotherapy administration. Conversely, in vitro platelet aggregation and secretion induced by ADP and epinephrine were unaltered by carboplatin and etoposide administration. Furthermore, P-selectin expression was negative at baseline and did not change after chemotherapy. These results support the hypothesis that combination etoposide and carboplatin chemotherapy in pediatric patients is responsible for possible disturbances in biochemical pathways required for platelet secretion and aggregation. PMID:16793755

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

    PubMed

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

    2016-05-01

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

  5. Outcome of Neoadjuvant Chemotherapy on Local Recurrence and Distant Metastasis of Oral Squamous Cell Carcinoma: A Retrospective Study

    PubMed Central

    Tabrizi, Reza; Garajei, Ata; Shafie, Ehsan; Jamshidi, Samira

    2016-01-01

    Statement of the Problem Neoadjuvant chemotherapy (NCH) is controversial in the treatment of oral squamous cell carcinoma (OSCC). Purpose The aim of this study was to evaluate the efficacy of NCH on OSCC prognosis. Materials and Method In this retrospective cohort study, 94 patients were studied in two groups. The patients in group 1 received NCH before the surgery, and those in group 2 underwent resection without any chemotherapy prior to surgery. The employed NCH agents consisted of cisplatin in combination with 5-fluorouracil in two treatment courses. Tumor size, lymph node involvement, age, and follow-up time were considered as variable factors of the study. Local recurrence (LR) and distant metastasis (DM) were outcomes of the study. Results Comparison of LR and DM in various tumor sizes demonstrated no significant difference between the two groups (p> 0.05). Analysis of the data did not show any statistically significant difference between the groups for LR in subjects with N0, N1 and N2. Each one-year increase in age was associated with 10% increase in the hazard ratio (HR) (HR distance metastasis Y/N = 1.10, p= 0.05). In the same analysis, when considering LR as a dependent factor, LR risk in N2 was 3 times more than in N1 (p= 0.02). LR risk in N3 was 5 times more than in N1 [HR local recurrence (p= 0.006). Conclusion Based on our results, neoadjuvant chemotherapy with combination of cisplatin and 5-fluorouracil may not improve prognosis of OSCC. However, further studies are suggested to assess other neoadjuvant chemotherapy protocols in OSCC patients. PMID:27602396

  6. Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecologic cancers as compared to cisplatin alone.

    PubMed

    Merouani, A; Davidson, S A; Schrier, R W

    1997-01-01

    To investigate the increased nephrotoxicity of taxol and cisplatin combination chemotherapy in gynecologic cancers as compared to cisplatin alone, the medical records of 25 patients with gynecological cancers were reviewed for evaluation of nephrotoxicity after chemotherapy treatment. The data included age, serum creatinine, calculated creatinine clearance, initial and cumulative dose of cisplatin and taxol, primary site of the cancer, renal ultrasound and hydration protocols. Renal function was evaluated before, during and 6 months after chemotherapy. Renal dysfunction was defined as a greater than 25% decrease in creatinine clearance. Comparing 11 patients treated with taxol and cisplatin versus 14 treated with cisplatin alone, there was a significant difference in effect on renal function. Nine of 11 patients (81%) treated with the combination chemotherapy had a greater than 25% decrease in creatinine clearance while only 4 of the 14 patients (29%) treated with cisplatin alone had such a decrease in creatinine clearance (p < 0.004). The patients treated with the combination chemotherapy, however, received a higher dose of cisplatin (80.4 vs. 66.4 mg/m2, p < 0.02) and were treated longer (6.7 vs. 4.3 months, p < 0.002). Nevertheless, when the patients were matched for age, initial dose and cumulative dose of cisplatin, a higher frequency of nephrotoxicity persisted in patients treated with taxol and cisplatin as compared to cisplatin alone (72 as compared to 20%, p < 0.02). The patients in both groups were comparably hydrated; prerenal failure and urinary tract obstruction were excluded in all patients. Six months after completion of chemotherapy, a significantly lower creatinine clearance was still observed in patients treated with taxol and cisplatin combination therapy (46 vs. 76 ml/min, p < 0.01). In summary, a retrospective analysis of renal function in patients with gynecological cancers showed an increased nephrotoxicity in patients treated with taxol and

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

    SciTech Connect

    Tentes, I.K.; Schmidt, W.M.; Krupitza, G.; Steger, G.G.; Mikulits, W.; Kortsaris, A.; Mader, R.M.

    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.

  8. Colon Cancer Cells Gene Expression Signature As Response to 5- Fluorouracil, Oxaliplatin, and Folinic Acid Treatment

    PubMed Central

    Negrei, Carolina; Hudita, Ariana; Ginghina, Octav; Galateanu, Bianca; Voicu, Sorina Nicoleta; Stan, Miriana; Costache, Marieta; Fenga, Concettina; Drakoulis, Nikolaos; Tsatsakis, Aristidis M.

    2016-01-01

    5-FU cytotoxicity mechanism has been assigned both to the miss-incorporation of fluoronucleotides into RNA and DNA and to the inhibition of thymidylate synthase. 5-FU is one of the most widely used chemotherapeutic drugs, although it has severe side effects that may vary between patients. Pharmacogenetic studies related to 5-FU have been traditionally focused on the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase that breaks 80–85% of 5-FU into its inactive metabolite. Choosing the right dosing scheme and chemotherapy strategy for each individual patient remains challenging for personalized chemotherapy management. In the general effort toward reduction of colorectal cancer mortality, in vitro screening studies play a very important role. To accelerate translation research, increasing interest has been focused on using in vivo-like models such as three-dimensional spheroids. The development of higher throughput assays to quantify phenotypic changes in spheroids is an active research area. Consequently, in this study we used the microarray technology to reveal the HT-29 colorectal adenocarcinoma cells gene expression signature as response to 5-FU/OXP/FA treatment in a state of the art 3D culture system. We report here an increased reactive oxygen species production under treatment, correlated with a decrease in cell viability and proliferation potential. With respect to the HT-29 cells gene expression under the treatment with 5-FU/OXP/FA, we found 15.247 genes that were significantly differentially expressed (p < 0.05) with a fold change higher that two-fold. Among these, 7136 genes were upregulated and 8111 genes were downregulated under experimental conditions as compared to untreated cells. The most relevant and statistic significant (p < 0.01) pathways in the experiment are associated with the genes that displayed significant differential expression and are related to intracellular signaling, oxidative stress, apoptosis, and cancer. PMID

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

    PubMed Central

    Aitini, Enrico; Rossi, Anna; Morselli, Patrizia; Vivorio, Beatrice; Bruschi, Alessandra; Bottura, Chiara; Colombo, Giorgio L

    2012-01-01

    Background Colorectal cancer is one of the most frequent and lethal cancers. The aim of this study was to analyze the costs relating to treatment of colorectal cancer between Xelox and Folfox-4 at a regional level according to the clinical experience at an Italian hospital in Lombardy. Methods A cost analysis was carried out regarding resource consumption by patients suffering from colorectal cancer based on data collected over a 12-month period between 2010 and 2011. The analysis involved 40 patients who attended the Department of Medical Oncology and Hematology at Carlo Poma Hospital to undergo adjuvant therapy for colorectal cancer. A chart was created for each patient containing their medical history, their pharmacological therapy indicating the number and duration of chemotherapy cycles, dose in mg administered for each cycle, number of day hospital visits for each cycle, number of days spent in hospital to position the central vein catheter, type of infusion pump used, any subsequent supportive therapy, and any side effects and outpatient visits connected with side effects. Results The cost analysis shows the savings involved in using Xelox for a single cycle of treatment, ie, approximately €1414.00 per patient (53% compared with Folfox-4). For each single cycle of treatment, the savings generated by using capecitabine compared with 5-FU can be attributed mostly to the fact that oral administration of chemotherapy requires fewer resources and does not require use of a central vein catheter (approximately 70% of overall cost) which amply compensates for the higher cost of capecitabine compared with 5-FU-LV. Sensibility analysis confirms the results of the base-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. PMID

  10. Paclitaxel combined with capecitabine as first-line chemotherapy for advanced or recurrent gastric cancer.

    PubMed

    Yuan, Meiqin; Yang, Yunshan; Lv, Wangxia; Song, Zhengbo; Zhong, Haijun

    2014-07-01

    Chemotherapy is of crucial importance in advanced gastric cancer (AGC) patients, in order to obtain palliation of symptoms and improve survival. To date, no standard chemotherapy regimen has been established for AGC. The purpose of the present study was to evaluate the efficacy and toxicity of the combination regimen of paclitaxel and capecitabine (PX) as first-line chemotherapy in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated with PX as first-line chemotherapy between January 2001 and December 2012 at the Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. In total, 36 patients were enrolled, with a median age of 53.5 years and a Karnofsky performance status (KPS) score of ≥80. A median of 4 PX cycles were administered (range, 2-8 cycles). The median progression-free survival time was 3.7 months [95% confidence interval (CI), 2.9-4.5 months) and the median overall survival time was 12.0 months (95% CI, 9.8-14.1 months). From the 36 patients evaluated, one (2.8%) achieved a complete response, seven (19.4%) achieved a partial response, 24 (66.7%) exhibited stable disease and four (11.1%) exhibited progressive disease. The objective response rate was 22.2% (8/36), and the disease control rate was 88.9% (32/36). All 36 patients were assessed for treatment toxicity. Grade 3 or 4 adverse events included neutropenia (2.8% of patients), hand-foot syndrome (2.8%) and vomiting (2.8%). No neutropenic fever or treatment-related mortalities were observed. PX combination chemotherapy may be a valuable first-line therapy for advanced or recurrent gastric cancer. PMID:24959275

  11. Combination chemotherapy with docetaxel and carboplatin for elderly patients with endometrial cancer

    PubMed Central

    YOSHIDA, HIROYUKI; IMAI, YUICHI; FUJIWARA, KEIICHI

    2016-01-01

    Approximately half of all endometrial cancer cases are diagnosed in patients aged >65 years. The objective of this study was to compare the tolerability and effectiveness of combination chemotherapy with docetaxel and carboplatin between endometrial cancer patients older and younger than 65 years of age. Chemotherapy-naive patients with endometrial cancer were enrolled in this retrospective study between April, 2008 and March, 2015. The patients received docetaxel (60 mg/m2) and carboplatin (area under the curve of 6 mg/ml/min) on day 1 of a 3-week cycle. The tolerability and effectiveness of this regimen were analyzed. A total of 41 patients with endometrial cancer were enrolled in this study, of whom 26 (63%) were aged <65 years and 15 (37%) were aged ≥65 years. There were no significant differences with regard to Eastern Cooperative Oncology Group performance status score and disease stage between the two groups. Patients aged >65 years were significantly more likely to have serous or clear-cell histology and high-grade tumors compared with the younger group (P=0.014 and 0.012, respectively). Although the number of chemotherapy cycles, cycle delays and treatment interruptions were comparable between older and younger patients, there was a trend toward more dose reductions in the older group (P=0.12). The incidence of hematological toxicities did not differ significantly between the two groups. The incidence of grade 3/4 diarrhea was significantly higher in the older group (P=0.014) and hypersensitivity was significantly more frequent in the younger group (P=0.035). Patients aged ≥65 years had equivalent response rates, progression-free survival and overall survival compared with those aged <65 years. These results suggest that combination chemotherapy with docetaxel and carboplatin was tolerable and effective for the treatment of elderly chemotherapy-naive patients with endometrial cancer. PMID:27123279

  12. Concurrent radio-chemotherapy with docetaxel and cisplatinum in inoperable or relapsed head and neck cancer.

    PubMed

    Mencoboni, M; Rebella, L; Tredici, S; Bergaglio, M; Delle Piane, M; Salami, A; Bavazzano, M; Ghio, R; Grimaldi, A; Scarpati, D

    2005-01-01

    Usually head and neck cancer is treated with combined therapy, applying surgery, if possible, and then radiotherapy and chemotherapy in a sequential or concomitant way. Sequential approach seems to be preferred, because of the high toxicity rate of concomitant therapy. Platinum compounds and 5-fluorouracil are the standard drugs, but new drugs are entering therapeutic arena: gemcitabine and taxanes are the most promising ones. The efficacy of these drugs, especially in association with radiotherapy, must be assessed; moreover it is essential to ascertain how to associate these drugs to radiotherapy and to evaluate drug toxicity when combined with the latter. End point of the study here presented is a preliminar assessment of toxicity and feasibility of concurrent radio-chemoterapy with docetaxel and cisplatinum in patients with head and neck cancer. The number of enrolled patients and the relatively short time of follow up do not allow to evaluate treatment efficacy. PMID:16437998

  13. Modeling Combined Chemotherapy and Particle Therapy for Locally Advanced Pancreatic Cancer

    PubMed Central

    Durante, Marco; Tommasino, Francesco; Yamada, Shigeru

    2015-01-01

    Pancreatic ductal adenocarcinoma is the only cancer for which deaths are predicted to increase in 2014 and beyond. Combined radiochemotherapy protocols using gemcitabine and hypofractionated X-rays are ongoing in several clinical trials. Recent results indicate that charged particle therapy substantially increases local control of resectable and unresectable pancreas cancer, as predicted from previous radiobiology studies considering the high tumor hypoxia. Combination with chemotherapy improves the overall survival (OS). We compared published data on X-ray and charged particle clinical results with or without adjuvant chemotherapy calculating the biological effective dose. We show that chemoradiotherapy with protons or carbon ions results in 1 year OS significantly higher than those obtained with other treatment schedules. Further hypofractionation using charged particles may result in improved local control and survival. A comparative clinical trial using the standard X-ray scheme vs. the best current standard with carbon ions is crucial and may open new opportunities for this deadly disease. PMID:26217585

  14. Salvage chemotherapy for ovarian cancer recurrence: weekly cisplatin in combination with epirubicin or etoposide.

    PubMed

    Zanaboni, F; Scarfone, G; Presti, M; Maggi, R; Borello, C; Bolis, G

    1991-10-01

    From December 1986 to April 1990, 40 consecutive ovarian cancer patients who relapsed after response to cisplatin-based chemotherapy regimens were treated with seven courses of weekly cisplatin, in combination with epirubicin or etoposide. The overall response rate obtained with the intensive schedule was 60% and the complete response rate was 25%; median duration of response was 7 months and median survival time, 13.5 months. Responsive cases seem to have longer survival; a prognostic factor for response to salvage treatment and longer survival is the disease-free interval after the first-line chemotherapy. Weekly cisplatin as intensive treatment was very well tolerated and showed acceptable toxicity in both the combination protocols with epirubicin or etoposide. PMID:1959783

  15. Cytoxan, epirubicin, methotrexate and 5-fluorouracil with hormonal synchronization (tamoxifen/premarin) in advanced breast cancer. Preliminary results.

    PubMed

    Zaniboni, A; Simoncini, E; Marpicati, P; Gorni, F; Cervi, G C; Marini, G

    1986-10-01

    Thirty-three patients with advanced breast cancer were treated with combination chemotherapy and hormonal synchronization in an attempt to increase the overall response rate generally obtained with traditional modalities of treatment. Among the 31 evaluable patients 1 complete (3%), 7 partial (22%), 13 stable disease (42%) and 10 progression of disease (53%) were obtained. Side effects were quite manageable although there were two episodes of life-threatening hematological toxicity. Taking into account the poor prognostic characteristics of our patients (high percentage of dominant visceral disease, 21/31 previously treated patients), our preliminary results with this regimen are interesting and the treatment deserves further evaluation. PMID:3024851

  16. 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

    PubMed Central

    Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

    2015-01-01

    Background Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Methods Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Results Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. Conclusion While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. PMID:26109878

  17. Chondroitin sulphate decorated nanoparticulate carriers of 5-fluorouracil: development and in vitro characterization.

    PubMed

    Yadav, Awesh K; Agarwal, Abhinav; Jain, Sanyog; Mishra, Anil K; Bid, Hemant; Rai, Gopal; Agrawal, Hirnanshu; Agrawal, Govind P

    2010-08-01

    The present study investigates prospective of tailored nanoparticles as vectors to provide improved therapeutic efficacy of encapsulated anti-cancer drug 5-FU. Condritin Sulphate (CS) conjugated PLGA nanoparticles were prepared using PEG-bis-amine and adipic dihydrazide as spacers and loaded with an anti-cancer drug 5-FU (CS-PEG-PLGA-FU and CS-ADH-PLGA-FU). The formulations were then compared with non CS-anchored monomethoxy(polyethylene glycol) (MPEG-PLGA-FU) nanoparticles. Nanoparticlulate systems were further characterized by FTIR, NMR, TEM studies and particle size/polydispersity index (PDI) analysis. DSC and XRD were also performed to assess the nature of 5-FU inside the nanoparticles. The nanoparticles prepared using amphiphilic block copolymer CS-PEG-PLGA were able to sustain the release of 5-FU up to 48 h whereas those of CS-ADH-PLGA and MPEG-PLGA released the drug up to 24 h. The CS-PEG-PLGA-FU nanoparticles were found to be least haemolytic when compared to free drug, CS-ADH-PLGA-FU and MPEG-PLGA-FU nanoparticles. Cytotoxicity studies were performed on MCF-7/MDA-MD 231 breast cancer cells. PLGA nanoparticles exhibited more potent cytotoxic effect on MCF-7/MDA-MD 231 cells than free doxorubicin. Further, enhanced cytotoxicity and lower hemolytic potential of CS-PEG-PLGA-FU nanoparticles suggest a potential application in cancer chemotherapy. PMID:21323107

  18. Capecitabine Induced Multifocal Leukoencephalopathy: Do We Have Always to Switch off the Chemotherapy?

    PubMed

    Bougea, Anastasia; Voskou, Panagiota; Kilidireas, Constantinos; Andreadou, Elisabeth

    2016-01-01

    Capecitabine is a well tolerated and safe 5-fluorouracil agent for adjuvant, neoadjuvant chemotherapy or metastatic cases. Neurological side effects require discontinuation of chemotherapy. We report this unique case of a 50-year-old female, who presented an isolated episode of dysarthria and ataxia under bevacizumab, capecitabine, and oxaliplatin treatment due to reversible multifocal leukoencephalopathy that did not recur after readministration of chemotherapy. PMID:26966603

  19. Modified irinotecan and infusional 5-fluorouracil (mFOLFIRI) in patients with refractory advanced pancreas cancer (APC): a single-institution experience

    PubMed Central

    Bupathi, M.; Ahn, D. H.; Wu, C.; Ciombor, K. K.; Stephens, J. A.; Reardon, J.; Goldstein, D. A.; Bekaii-Saab, T.

    2016-01-01

    Pancreatic adenocarcinoma is the fourth leading cause of cancer death. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in outcome measures with acceptable toxicities when combined with 5-fluorouracil (5-FU)/leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in advanced pancreas cancer (APC). We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs), and Kaplan–Meier methods were used to calculate the median progression-free survival (PFS) and overall survival (OS). Forty patients were included in this analysis. Patients received 1–5 lines of prior therapy (25 % with more than 3 lines of prior therapy). The mean age at diagnosis was 60, and 98 % had ECOG of 1. The mean CA 19-9 at the start of therapy was 33,169 U/ml. The median PFS was 2.59 months [95 % confidence interval (CI) (1.90, 3.54)], and OS was 4.75 months [95 % CI (3.14, 8.98)]. The most common AEs included fatigue (98 %), neuropathy (83 %), anorexia (68 %), nausea (60 %) and constipation (55 %). Grade 3 toxicities included fatigue (13 %) and rash (3 %). There were no observed grade 4 toxicities. In this single-institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in a heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC. PMID:26995224

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

    PubMed

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

    2016-06-01

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

  1. Polymer-Caged Nanobins for Synergistic Cisplatin-Doxorubicin Combination Chemotherapy

    PubMed Central

    Lee, Sang-Min

    2013-01-01

    Multicomponent chemotherapy has increasingly become a strategy of great importance in clinical cancer treatments. However, this type of chemotherapy has not been demonstrated in nanoscale delivery vehicles where two cytotoxic agents can be packaged together, potentially leading to synergistic drug activities. Herein, we present the co-delivery of doxorubicin and cisplatin via a single polymer-caged nanobin (PCN) and show that co-packaging can yield strong synergy in the efficacy of these agents. Such a PCN comprises of a doxorubicin-encapsulated liposomal core protected by a pH-responsive cisplatin prodrug-loaded polymer shell with tunable drug ratios and surface charge potentials. This dual-agent Pt-PCNDXR formulation dramatically enhances the overall cytotoxicity of each drug against cancer cells at reduced doses and exhibits higher synergy than combinations of either the free drugs or separately nano-packaged drugs. These results clearly indicate that the polymer-caged nanobin platform can offer new means for building synergy into combination chemotherapy regimens. PMID:21077673

  2. Malignant Esophagogastric Junction Obstruction: Efficacy of Balloon Dilation Combined with Chemotherapy and/or Radiation Therapy

    SciTech Connect

    Ko, Gi-Young; Song, Ho-Young Hong, Heuk-Jin; Sung, Kyu-Bo; Seo, Tae-Seok; Yoon, Hyun-Ki

    2003-04-15

    Purpose: To assess the efficacy of balloon dilation combined with chemotherapy and/or radiation therapy for palliation of dysphagia due to malignant esophagogastric junction strictures. Methods: Fluoroscopically guided balloon dilation was attempted in 20 patients. The causes of strictures were gastric adenocarcinoma (n = 10) and esophageal squamous cell carcinoma (n = 10). Scheduled chemotherapy and/or radiation therapy followed balloon dilation in all patients. Results: There were no technical failures or major complications. After balloon dilation, 15 (75%) patients showed improvement of dysphagia. No patient complained of reflux esophagitis during the follow-up period. Among the 15 patients, seven needed no further treatment for palliation of dysphagia until their deaths. The remaining eight patients underwent repeat balloon dilation(n = 4) or stent placement (n = 4)3-43 weeks (mean 15 weeks) after the initial balloon dilation because of recurrent dysphagia. Conclusion: Balloon dilation combined with chemotherapy and/or radiation therapy seems to be an easy and reasonably effective palliative treatment for malignant esophagogastric strictures.

  3. Advanced epithelial ovarian cancer: toxicity of whole abdominal irradiation after operation, combination chemotherapy, and reoperation

    SciTech Connect

    Schray, M.F.; Martinez, A.; Howes, A.E.; Ballon, S.C.; Podratz, K.C.; Sikic, B.I.; Malkasian, G.D.

    1986-05-01

    Thirty-five patients with advanced ovarian cancer have received, as salvage therapy, irradiation consisting of 30 Gy to the entire abdominal contents with partial liver/kidney shielding and boosts to 42 and 51 Gy for the paraaortic/diaphragmatic and pelvic regions, respectively. These patients had received 6 to 25 cycles (median, 11 cycles) of prior combination chemotherapy (included cisplatin in 30), with second-look laparotomy performed in 33; 24 (68%) had three or more laparotomies. Acute gastrointestinal toxicity was generally mild. Significant hematologic toxicity (leukocytes less than 2000/mm3; or platelets less than 100,000/mm3) was seen in 19 (54%); platelet suppression occurred in 18 of these 19. Nine patients failed to complete the prescribed course of therapy; in seven, this was secondary to hematologic toxicity. Amount of prior chemotherapy and advanced age correlated with degree of hematologic toxicity. Five patients without evidence of disease (laparotomy confirmed) have developed treatment-related bowel obstruction. No other chronic toxicity of clinical significance has been observed. Seven patients have developed bowel obstruction associated with progressive neoplasm. Irradiation was well tolerated symptomatically, but hematologic toxicity associated with prior chemotherapy prevented its completion in 20% of patients. Clinical manifestations of radiation bowel toxicity have been moderate to date and should be interpreted in the context of the aggressive combined modality program.

  4. Comparing Intra-Arterial Chemotherapy Combined With Intravesical Chemotherapy Versus Intravesical Chemotherapy Alone: A Randomised Prospective Pilot Study for T1G3 Bladder Transitional Cell Carcinoma After Bladder-Preserving Surgery

    SciTech Connect

    Chen, Junxing Yao, Zhijun Qiu, Shaopeng Chen, Lingwu; Wang, Yu Yang, Jianyong Li, Jiaping

    2013-12-15

    Purpose: To compare the efficacy of intra-arterial chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder transitional cell carcinoma (BTCC) followed by bladder-preserving surgery. Materials and Methods: Sixty patients with T1G3 BTCC were randomly divided into two groups. After bladder-preserving surgery, 29 patients (age 30-80 years, 24 male and 5 female) received intra-arterial chemotherapy in combination with intravesical chemotherapy (group A), whereas 31 patients (age 29-83 years, 26 male and 5 female) were treated with intravesical chemotherapy alone (group B). Twenty-nine patients were treated with intra-arterial epirubicin (50 mg/m{sup 2}) + cisplatin (60 mg/m{sup 2}) chemotherapy 2-3 weeks after bladder-preserving surgery once every 4-6 weeks. All of the patients received the same intravesical chemotherapy: An immediate prophylactic was administered in the first 6 h. After that, therapy was administered one time per week for 8 weeks and then one time per month for 8 months. The instillation drug was epirubicin (50 mg/m{sup 2}) and lasted for 30-40 min each time. The end points were tumour recurrence (stage Ta, T1), tumour progression (to T2 or greater), and disease-specific survival. During median follow-up of 22 months, the overall survival rate, tumour-specific death rate, recurrence rate, progression rate, time to first recurrence, and adverse reactions were compared between groups. Results: The recurrence rates were 10.3 % (3 of 29) in group A and 45.2 % (14 of 31) in group B, and the progression rates were 0 % (0 of 29) in group A and 22.6 % (7 of 31) in group B. There was a significant difference between the two groups regarding recurrence (p = 0.004) and progression rates (p = 0.011). Median times to first recurrence in the two groups were 15 and 6.5 months, respectively. The overall survival rates were 96.6 and 87.1 %, and the tumour-specific death rates were 0 % (0 of 29) and 13.5 % (4 of 31

  5. Postoperative Chemotherapy Followed by Conformal Concomitant Chemoradiotherapy in High-Risk Gastric Cancer

    SciTech Connect

    Quero, Laurent; Bouchbika, Zineb; Kouto, Honorine; Baruch-Hennequin, Valerie; Gornet, Jean-Marc; Munoz, Nicolas; Cojean-Zelek, Isabelle; Houdart, Remi; Panis, Yves; Valleur, Patrice; Aparicio, Thomas; Maylin, Claude; Hennequin, Christophe

    2012-06-01

    Purpose: To analyze the efficacy, toxicity, and pattern of relapse after adjuvant cisplatin-based chemotherapy followed by three-dimensional irradiation and concomitant LV5FU2 chemotherapy (high-dose leucovorin and 5-fluorouracil bolus plus continuous infusion) in the treatment of completely resected high-risk gastric cancer. Methods and Materials: This was a retrospective analysis of 52 patients with high-risk gastric cancer initially treated by total/partial gastrectomy and lymphadenectomy between January 2002 and June 2007. Median age was 54 years (range, 36-75 years). Postoperative treatment consisted of 5-fluorouracil and cisplatin chemotherapy. Adjuvant chemotherapy was followed by three-dimensional conformal radiotherapy in the tumor bed and regional lymph nodes at 4500 cGy/25 fractions in association with concomitant chemotherapy. Concomitant chemotherapy consisted of a 2-h infusion of leucovorin (200 mg/m Superscript-Two ) followed by a bolus of 5-fluorouracil (400 mg/m Superscript-Two ) and then a 44-h continuous infusion of 5-fluorouracil (2400-3600 mg/m Superscript-Two ) given every 14 days, for three cycles (LV5FU2 protocol). Results: Five-year overall and disease-free survival were 50% and 48%, respectively. Distant metastases and peritoneal spread were the most frequent sites of relapse (37% each). After multivariate analysis, only pathologic nodal status was significantly associated with disease-free and overall survival. Acute toxicities were essentially gastrointestinal and hematologic. One myocardial infarction and one pulmonary embolism were also reported. Eighteen patients had a radiotherapy program interruption because of acute toxicity. All patients but 2 have completed radiotherapy. Conclusion: Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-fluorouracil seemed to be feasible and resulted in successful locoregional control.

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

    PubMed Central

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

    2014-01-01

    Epithelial-to-mesenchymal transition (EMT) has been associated with poor treatment outcomes in various malignancies and is inversely associated with miRNA-145 expression. Therefore, we hypothesized that SNAI2 (Slug) may mediate 5FU chemotherapy resistance through inhibition of miR-145 in colorectal cancer (CRC) and thus, represents a novel therapeutic target to enhance current CRC treatment strategies. Compared to parental DLD1 colon cancer cells, 5FU-resistant (5FUr) DLD1 cells demonstrated features of EMT, including >2-fold enhanced invasion (p<0.001) and migration, suppressed E-Cadherin expression, and 2-fold increased SNAI2 expression. DLD1 and HCT116 cells with stable expression of SNAI2 (DLD1/SNAI2; HCT116/SNAI2) also demonstrated EMT features such as the decreased E-Cadherin, as well as significantly decreased miR-145 expression, as compared to control empty vector cells. Based on a miR-145 luciferase promoter assay, we demonstrated that SNAI2 repressed activity of the miR-145 promoter in the DLD1 and HCT116 cells. In addition, the ectopic expressing SNAI2 cell lines demonstrated decreased 5FU sensitivity and conversely, miR-145 replacement significantly enhanced 5FU sensitivity. In the parental SW620 colon cancer cell line with high SNAI2 and low miR-145 levels, inhibition of SNAI2 directly with short hairpin sequence for SNAI2 and miR-145 replacement therapy both decreased Vimentin expression and increased in vitro 5FU sensitivity. In pre-treatment rectal cancer patient biopsy samples, low miR-145 expression levels correlated with poor response to neoadjuvant 5FU based chemoradiation. These results suggested that the SNAI2:miR-145 pathway may represent a novel clinical therapeutic target in CRC and may serve as a response predictor to chemoradiation therapy. PMID:25249558

  7. Docetaxel combined with intraperitoneal hyperthermic perfusion chemotherapy and hyperthermia in the treatment of advanced ovarian cancer

    PubMed Central

    ZHANG, TING; PAN, QIONG; XIAO, SONGSHU; LI, LIJIE; XUE, MIN

    2016-01-01

    Ovarian cancer is a clinical type of gynecological malignant tumor with poor prognosis and a high mortality rate. At present, the primary treatment method used is surgery, with chemotherapy as an ajdunctive therapy. Thus, new short-term treatments should be identified. The aim of the present study was to investigate the short-term curative effects and safety of docetaxel combined with intraperitoneal cisplatin chemotherapy and hyperthermia treatment of advanced ovarian cancer. A total of 112 cases of advanced (stage III–IV) ovarian cancer patients confirmed by clinical diagnosis between October 2014 and December 2015 were included in the study. The patients were randomly divided into the study and control groups (n=56 cases). The control group was treated with docetaxel and intraperitoneal cisplatin hyperthermic perfusion chemotherapy, while the study group was treated with docetaxel venous chemotherapy and intraperitoneal cisplatin cyclical hyperthermic perfusion chemotherapy with BR-TRG-1 body cavity hyperthermic perfusion treatment system. Clinical treatment results for short-term curative effects and adverse reactions were compared and analyzed 8 weeks after treatment. The total effective rate of the study and control groups were 87.5 and 62.5%, respectively, and the difference was statistically significant (P<0.05). The controlled rate of ascites, remission rate of tumor and descent rate of CA125 of patients in the study group were better than patients in the control group (P<0.05). The rate of adverse reactions of patients in the study group was 39.3%, and the grade of toxicity was from I to II, while the rate of adverse reactions of patients in the control group was 55.4%, and the grade of toxicity was from II to III. The difference between the two groups was statistically significant (P<0.05). In conclusion, applying the combination of docetaxel, intraperitoneal cisplatin hyperthermic perfusion chemotherapy and hyperthermia to treat advanced ovarian

  8. An observation on combined use of chemotherapy and traditional Chinese medicine to relieve cancer pain.

    PubMed

    Lin, C; Lin, X; Yang, J

    1996-12-01

    We have treated 50 patients with stage III, VI malignant tumors confirmed by pathology. The patients were divided into two groups. One group was treated by combination of chemotherapy and traditional Chinese medicine (treatment group); the other only by chemotherapy (control group). The effect of cancer treatment was evaluated according to the criteria of WHO. The results showed that the effective rate was 80% in treatment group and 52% in control group. The pain relieving rate was 68% in treatment group and 40% in control group (P < 0.01). This fact demonstrates that the application of traditional Chinese medicine can invigorate blood circulation, eliminate blood stasis, soften hardness and dissolve the mass, nourish blood and increase vigor. This kind of application can not only enhance the effect of cancer treatment but also increase the cancer pain relieving rate. PMID:9389100

  9. Ginseng and Anticancer Drug Combination to Improve Cancer Chemotherapy: A Critical Review

    PubMed Central

    Chen, Shihong; Huang, Ying; O'Barr, Stephen A.; Wong, Rebecca A.; Chow, Moses Sing Sum

    2014-01-01

    Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer. PMID:24876866

  10. Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Oxaliplatin on Human Colorectal and Gastric Cancer Xenografts.

    PubMed

    Nukatsuka, Mamoru; Nakagawa, Fumio; Takechi, Teiji

    2015-09-01

    TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride (at a molar ratio of 1:0.5) that was approved in Japan in 2014 for the treatment of unresectable advanced or recurrent colorectal cancer. In the present study, the enhancement of therapeutic efficacy using a combination of TAS-102 and oxaliplatin was evaluated in a xenograft-bearing nude mouse model of colorectal and gastric cancer. TAS-102 was orally administered twice-a-day from day 1 to 14, and oxaliplatin was administered intravenously on days 1 and 8. The in vivo growth-inhibitory activity was evaluated based on the tumor volume and the growth-delay period, was estimated based on the period required to reach a tumor volume five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and RTV5 in mice administered TAS-102 with oxaliplatin were significantly superior to those associated with either monotherapy in mice with colorectal (HCT 116, SW-48; p<0.001) and gastric cancer (SC-2, MKN74; p<0.001). MKN74/5FU, a 5-fluorouracil-resistant MKN74 sub-line, was sensitive to both FTD and oxaliplatin in vitro. In vivo, TAS-102 alone was effective in MKN74/5FU, and its anti-tumor activity was significantly enhanced in combination with oxaliplatin (p<0.001). No significant decrease in body weight or toxicity was observed compared to either monotherapy. The present pre-clinical findings indicate that combination of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, and can be utilized in both chemo-naïve tumors and recurrent tumors after 5-fluorouracil treatment. PMID:26254349

  11. Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin–paclitaxel doublet chemotherapy

    PubMed Central

    Roulstone, V; Twigger, K; Zaidi, S; Pencavel, T; Kyula, JN; White, C; McLaughlin, M; Seth, R; Karapanagiotou, EM; Mansfield, D; Coffey, M; Nuovo, G; Vile, RG; Pandha, HS; Melcher, AA; Harrington, KJ

    2016-01-01

    Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin—taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin—paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin—taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication. PMID:22895509

  12. Concurrent Chemoradiotherapy With 5-Fluorouracil and Mitomycin C for Invasive Anal Carcinoma in Human Immunodeficiency Virus-Positive Patients Receiving Highly Active Antiretroviral Therapy

    SciTech Connect

    Fraunholz, Ingeborg

    2010-04-15

    Purpose: To report the clinical outcomes of chemoradiotherapy (CRT) for anal carcinoma in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy. Patients and Methods: Between 1997 and 2008, 21 HIV-positive patients who were receiving highly active antiretroviral therapy were treated with CRT (50.4 Gy at 1.8 Gy/fraction plus a 5.4-10.8-Gy external boost; 5-fluorouracil, 1,000 mg/m{sup 2}, Days 1-4 and 29-32; and mitomycin C, 10 mg/m{sup 2}, Days 1 and 29). A retrospective analysis was performed with respect to the tumor response, local control, cancer-specific and overall survival, and toxicity. The immunologic parameters, including pre- and post-treatment CD4 count, viral load, and acquired immunodeficiency syndrome-specific morbidity was recorded during follow-up (median, 53 months; range, 10-99). Results: CRT could be completed in all 21 patients with a reduction in the chemotherapy dose and/or interruption of radiotherapy in 5 and 5 cases, respectively. Acute Grade 3 toxicity occurred in 8 (38%) of the 21 patients. A complete response was achieved in 17 patients (81%), and tumor persistence or early progression was noted in 4 (19%). Six patients (29%) died, 5 of cancer progression and 1 of treatment-related toxicity. The 5-year local control, cancer-specific, and overall survival rate was 59%, 75%, and 67%, respectively. The median CD4 count significantly decreased from 347.5 cells/muL before CRT to 125 cells/muL 3-7 weeks after CRT completion (p <.001). In 6 (32%) of 19 patients, an increase of the HIV viral load was noted. Both parameters returned to the pretreatment values with additional follow-up. Conclusion: Our data have confirmed that in the highly active antiretroviral therapy era, HIV-related anal cancer can be treated with standard CRT without dose reductions. Close surveillance of the immunologic parameters is necessary.

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

    PubMed Central

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

    1991-01-01

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

  14. Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer

    PubMed Central

    Blaszkowsky, L. S.; Ryan, D. P.; Szymonifka, J.; Borger, D. R.; Zhu, A. X.; Clark, J. W.; Kwak, E. L.; Mamon, H. J.; Allen, J. N.; Vasudev, E.; Shellito, P. C.; Cusack, J. C.; Berger, D. L.; Hong, T. S.

    2014-01-01

    Background To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer. Patients and methods Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6–9 weeks following the completion of chemoradiation. Results Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3–4 toxicity occurred in 46.9% of patients. Grade 3–4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1–87.6%). Conclusions Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR. Clinicaltrials.gov NCT00307736. PMID:24356623

  15. Synergistic therapeutic effects of Schiff's base cross-linked injectable hydrogels for local co-delivery of metformin and 5-fluorouracil in a mouse colon carcinoma model.

    PubMed

    Wu, Xilong; He, Chaoliang; Wu, Yundi; Chen, Xuesi

    2016-01-01

    In situ formed hydrogels based on Schiff base reaction were formulated for the co-delivery of metformin (ME) and 5-fluorouracil (5FU). The reactive aldehyde-functionalized four-arm polyethylene glycol (PFA) was synthesized by end-capping of 4-arm PEG with 4-formylbenzoic acid (FA) and used as a cross-linking agent. The injectable hydrogels are designed through the quick gelation induced by the formation of covalent bonds via Schiff-base reaction of PFA with 4-arm poly (ethylene glycol)-b-poly (L-lysine) (PPLL). This formulation eliminated the need for metal catalysts and complicated processes in the preparation of in situ-forming hydrogels. In vitro degradation and drug release studies demonstrated that both ME and 5FU were released through PFA/PPLL hydrogels in a controlled and pH-dependent manner. When incubated with mouse colon adenocarcinoma cells (C26), the ME/5FU-incorporated PFA/PPLL hydrogels had synergistic inhibitory effects on the cell cycle progression and cell proliferation in colon cancer cells. After a single subcutaneous injection of the hydrogel containing ME/5FU beside the tumors of BALB/c mice inoculated with C26 cells, the dual-drug-loaded hydrogels displayed superior therapeutic activity resulted from a combination of p53-mediated G1 arrest and apoptosis in C26 cells. Hence, the Schiff's base cross-linked hydrogels containing ME and 5FU may have potential therapeutic applications in the treatments of colon cancer. PMID:26497429

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

    PubMed Central

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

    2009-01-01

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

  17. Application of 5-Fluorouracil-Polycaprolactone Sustained-Release Film in Ahmed Glaucoma Valve Implantation Inhibits Postoperative Bleb Scarring in Rabbit Eyes.

    PubMed

    Bi, Xiu-Zeng; Pan, Wei-Hua; Yu, Xin-Ping; Song, Zong-Ming; Ren, Zeng-Jin; Sun, Min; Li, Cong-Hui; Nan, Kai-Hui

    2015-01-01

    This study was designed to investigate whether 5-fluorouracil (5-Fu)-polycaprolactone sustained-release film in Ahmed glaucoma valve implantation inhibits postoperative bleb scarring in rabbit eyes. Eighteen New Zealand white rabbits were randomly divided into three groups (A, B and C; n = 6 per group). Group A received combined 5-Fu-polycaprolactone sustained-release film application and Ahmed glaucoma valve implantation, group B received local infiltration of 5-Fu and Ahmed glaucoma valve implantation, and group C received Ahmed glaucoma valve implantation. Postoperative observations were made of the anterior segment, intraocular pressure, central anterior chamber depth, blebs, drainage tube, and accompanying ciliary body detachment. The pathology of the blebs and surrounding tissues were observed at month 3 postoperatively. We revealed that the 5-Fu-polycaprolactone sustained-release film maintained a release concentration range of 13.7 ± 0.12 to 37.41 ± 0.47 μg/ml over three months in vitro. Postoperatively, diffuse blebs with ridges were found in all eyes in group A, two blebs were observed in group B, and no bleb formation was present in group C. The postoperative central anterior chamber depth in group A was significantly less than that of the other two groups. The postoperative intraocular pressure of group A stabilized at 6.33-8.67 mmHg, whereas that of group C gradually remained at 7.55-10.02 mmHg. The histopathology showed that the fibrous tissue thickness of the blebs in group A was significantly thinner than that of the other groups. We conclude that the 5-Fu-polycaprolactone sustained-release film had a sustained drug release effect, which promoted the inhibition of bleb scarring after Ahmed glaucoma valve implantation. PMID:26579716

  18. Application of 5-Fluorouracil-Polycaprolactone Sustained-Release Film in Ahmed Glaucoma Valve Implantation Inhibits Postoperative Bleb Scarring in Rabbit Eyes

    PubMed Central

    Bi, Xiu-Zeng; Pan, Wei-Hua; Yu, Xin-Ping; Song, Zong-Ming; Ren, Zeng-Jin; Sun, Min; Li, Cong-Hui; Nan, Kai-Hui

    2015-01-01

    This study was designed to investigate whether 5-fluorouracil (5-Fu)-polycaprolactone sustained-release film in Ahmed glaucoma valve implantation inhibits postoperative bleb scarring in rabbit eyes. Eighteen New Zealand white rabbits were randomly divided into three groups (A, B and C; n = 6 per group). Group A received combined 5-Fu-polycaprolactone sustained-release film application and Ahmed glaucoma valve implantation, group B received local infiltration of 5-Fu and Ahmed glaucoma valve implantation, and group C received Ahmed glaucoma valve implantation. Postoperative observations were made of the anterior segment, intraocular pressure, central anterior chamber depth, blebs, drainage tube, and accompanying ciliary body detachment. The pathology of the blebs and surrounding tissues were observed at month 3 postoperatively. We revealed that the 5-Fu-polycaprolactone sustained-release film maintained a release concentration range of 13.7 ± 0.12 to 37.41 ± 0.47 μg/ml over three months in vitro. Postoperatively, diffuse blebs with ridges were found in all eyes in group A, two blebs were observed in group B, and no bleb formation was present in group C. The postoperative central anterior chamber depth in group A was significantly less than that of the other two groups. The postoperative intraocular pressure of group A stabilized at 6.33–8.67 mmHg, whereas that of group C gradually remained at 7.55–10.02 mmHg. The histopathology showed that the fibrous tissue thickness of the blebs in group A was significantly thinner than that of the other groups. We conclude that the 5-Fu-polycaprolactone sustained-release film had a sustained drug release effect, which promoted the inhibition of bleb scarring after Ahmed glaucoma valve implantation. PMID:26579716

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    2013-01-01

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

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

    PubMed

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

    2012-12-01

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

  2. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial.

    PubMed

    Del Mastro, Lucia; Levaggi, Alessia; Michelotti, Andrea; Cavazzini, Giovanna; Adami, Francesca; Scotto, Tiziana; Piras, Margherita; Danese, Saverio; Garrone, Ornella; Durando, Antonio; Accortanzo, Valeria; Bighin, Claudia; Miglietta, Loredana; Pastorino, Simona; Pronzato, Paolo; Castiglione, Federico; Landucci, Elisabetta; Conte, PierFranco; Bruzzi, Paolo

    2016-01-01

    The study was designed to compare an anthracycline-containing regimen to a regimen combining both anthracycline and paclitaxel as adjuvant therapy for high-risk breast cancer patients. In this multicenter, randomized phase-III trial, node-positive early breast cancer patients were randomly assigned to receive either 6 cycles of FEC (5-fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2), day 1, every 3 weeks) or 4 cycles of EP (epirubicin 90 mg/m(2) and paclitaxel 175 mg/m(2), day 1, every 3 weeks). The primary endpoint was overall survival (OS). Secondary endpoints included toxicity and event-free survival (EFS). From 1996 to 2001, 1055 patients were enrolled. At a median follow-up of 12.8 years, 335 deaths had been recorded. The 10-year OS was 73 % (95 % CI 69-77) in the FEC arm and 74 % (95 % CI 70-78) in the EP arm (p = 0.405). The 10-year EFS was 51 % (95 % CI 45-56) in the FEC arm and 49 % (95 % CI 44-55) in the EP arm (p = 0.572). No difference in the hazard of death was observed (HR for EP 0.85, 95 % CI 0.68-1.06, p = 0.15). Patients treated with FEC experienced more frequently nausea and vomiting, stomatitis, and leukopenia as compared to patients treated with EP. Toxicities which occurred more frequently with EP were anemia, fever, myalgias, and neurotoxicity. Our study failed to demonstrate a superiority of an adjuvant treatment with four EP as compared to six FEC in node-positive breast cancer patients. PMID:26661403

  3. Demonstration in vitro of inhibition in normal rat tissues yet stimulation in Jensen sarcoma cells of 5-fluorouracil anabolism by purine nucleosides

    SciTech Connect

    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.

  4. Therapeutic and scintigraphic applications of polymeric micelles: combination of chemotherapy and radiotherapy in hepatocellular carcinoma.

    PubMed

    Shih, Ying-Hsia; Peng, Cheng-Liang; Chiang, Ping-Fang; Lin, Wuu-Jyh; Luo, Tsai-Yueh; Shieh, Ming-Jium

    2015-01-01

    This study evaluated a multifunctional micelle simultaneously loaded with doxorubicin (Dox) and labeled with radionuclide rhenium-188 ((188)Re) as a combined radiotherapy and chemotherapy treatment for hepatocellular carcinoma. We investigated the single photon emission computed tomography, biodistribution, antitumor efficacy, and pathology of (188)Re-Dox micelles in a murine orthotopic luciferase-transfected BNL tumor cells hepatocellular carcinoma model. The single photon emission computed tomography and computed tomography images showed high radioactivity in the liver and tumor, which was in agreement with the biodistribution measured by γ-counting. In vivo bioluminescence images showed the smallest size tumor (P<0.05) in mice treated with the combined micelles throughout the experimental period. In addition, the combined (188)Re-Dox micelles group had significantly longer survival compared with the control, (188)ReO4 alone (P<0.005), and Dox micelles alone (P<0.01) groups. Pathohistological analysis revealed that tumors treated with (188)Re-Dox micelles had more necrotic features and decreased cell proliferation. Therefore, (188)Re-Dox micelles may enable combined radiotherapy and chemotherapy to maximize the effectiveness of treatment for hepatocellular carcinoma. PMID:26719687

  5. Therapeutic and scintigraphic applications of polymeric micelles: combination of chemotherapy and radiotherapy in hepatocellular carcinoma

    PubMed Central

    Shih, Ying-Hsia; Peng, Cheng-Liang; Chiang, Ping-Fang; Lin, Wuu-Jyh; Luo, Tsai-Yueh; Shieh, Ming-Jium

    2015-01-01

    This study evaluated a multifunctional micelle simultaneously loaded with doxorubicin (Dox) and labeled with radionuclide rhenium-188 (188Re) as a combined radiotherapy and chemotherapy treatment for hepatocellular carcinoma. We investigated the single photon emission computed tomography, biodistribution, antitumor efficacy, and pathology of 188Re-Dox micelles in a murine orthotopic luciferase-transfected BNL tumor cells hepatocellular carcinoma model. The single photon emission computed tomography and computed tomography images showed high radioactivity in the liver and tumor, which was in agreement with the biodistribution measured by γ-counting. In vivo bioluminescence images showed the smallest size tumor (P<0.05) in mice treated with the combined micelles throughout the experimental period. In addition, the combined 188Re-Dox micelles group had significantly longer survival compared with the control, 188ReO4 alone (P<0.005), and Dox micelles alone (P<0.01) groups. Pathohistological analysis revealed that tumors treated with 188Re-Dox micelles had more necrotic features and decreased cell proliferation. Therefore, 188Re-Dox micelles may enable combined radiotherapy and chemotherapy to maximize the effectiveness of treatment for hepatocellular carcinoma. PMID:26719687

  6. Combined modality treatment for stage I-II non-Hodgkin's lymphomas: CVP versus BACOP chemotherapy

    SciTech Connect

    Bajetta, E.; Valagussa, P.; Bonadonna, G.; Lattuada, A.; Buzzoni, R.; Rilke, F.; Banfi, A.

    1988-07-01

    This paper reports the 5-year results of a prospective randomized study beginning in 1976 on 177 evaluable patients with pathologic Stage I-IE and II-IIE non-Hodgkin's lymphomas with diffuse histology according to the Rappaport classification. Treatment consisted of either CVP or BACOP chemotherapy (3 cycles) followed by regional radiotherapy (40 to 50 Gy) and further cycles of either combination. In both arms, complete remission at the end of combined treatment was high (CVP 93%, BACOP 98%) regardless of age, stage or bulky disease. At 5 years, the comparative freedom from first progression was 62% for CVP vs 78% for BACOP (p = 0.02), respectively. Clinically relevant differences favoring BACOP chemotherapy were essentially documented in patients with large cell lymphomas (International Working Formulation), those with Stage II having more than three involved anatomical sites, bulky disease and age over 60 years. Recurrence within radiation fields was documented in only 5% of complete responders. Combined treatment was, in general, well tolerated particularly when BACOP was used. In only 2 patients given CVP post radiation cutaneous fibrosis was documented. Second solid tumors were detected in 4 patients. One patient started on CVP died because of brain stem necrosis after 45 Gy. We conclude that in Stage I-II patients with nodal and extranodal diffuse non-Hodgkin's lymphomas, particularly large cell lymphomas, combined modalit