Science.gov

Sample records for 5-fluorouracil combination chemotherapy

  1. 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.

  2. Preserved learning and memory in mice following chemotherapy: 5-Fluorouracil and doxorubicin single agent treatment, doxorubicin-cyclophosphamide combination treatment.

    PubMed

    Fremouw, Thane; Fessler, Christy L; Ferguson, Robert J; Burguete, Yamil

    2012-01-01

    Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. A number of underlying mechanisms have been proposed, however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. As part of a multifaceted approach, animal models of chemotherapy induced cognitive impairment are being developed. Thus far, the majority of animal studies have utilized rats, however, mice may prove particularly beneficial in studying genetic risk factors for developing chemotherapy induced cognitive impairment. Thus, C57BL/6J mice were treated once a week for three weeks with saline, doxorubicin and cyclophosphamide (D&C), doxorubicin (Dox), or 5-fluorouracil (5-FU). Recent and remote contextual fear conditioning and novel object recognition (NOR) was assessed. Despite significant toxic effects as assessed by weight loss, the chemotherapy treated mice performed as well as control mice on all task. As are some humans, C57BL/6J mice may be resistant to at least some aspects of chemotherapy induced cognitive decline.

  3. Onset of Manic Episode during Chemotherapy with 5-Fluorouracil

    PubMed Central

    Ha, Jee Hyun; Hwang, Dae-Yong; Park, Doo-Heum; Ryu, Seung-Ho

    2011-01-01

    The authors report a case of 5-Fluorouracil (5-FU) induced manic episode in an elderly female without any previous psychiatric history. The patient presented manic symptoms after 4th cycle of 5-FU chemotherapy after surgery of rectal cancer. After cessation of chemotherapy and administration of olanzapine and divalproex sodium, symptoms were subsided within 10 days. PMID:21519541

  4. [The effect of combination chemotherapy to adapted to chronotherapy with 5-fluorouracil, leucovorin, mitomycin C and cisplatin in patients with gastric or colorectal cancer].

    PubMed

    Kamoshita, N; Yokomori, T; Iesato, H; Ohya, T; Nagaoka, H; Okabe, T; Kato, Y; Takeyoshi, I; Ohwada, S; Morishita, Y

    2000-05-01

    We performed combination chemotherapy adapted to chronotherapy with 5-fluorouracil, leucovorin, mitomycin C and cisplatin in 11 patients with gastric cancer and 7 with colorectal cancer. Treatment consisted of a 5-day course of continuous arterial or intravenous infusion of 5-FU (500 mg/body/day), arterial or intravenous infusion of leucovorin (20 mg/body/day) at 6:00 p.m. on days 1-5, arterial or intravenous infusion of mitomycin C (2 mg/body) at 9:00 a. m. on day 5, and arterial or intravenous infusion of cisplatin (20-80 mg/body) at 6:00 p.m. on day 5. The effective rate against gastric cancer was 73%; however, the effective rate against colorectal cancer was 29%. During and after this therapy, there was only a little appetite loss, nausea and stomatitis.

  5. 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.

  6. Antitumor effects of anti-CD40/CpG immunotherapy combined with gemcitabine or 5-fluorouracil chemotherapy in the B16 melanoma model.

    PubMed

    Qu, Xiaoyi; Felder, Mildred A R; Perez Horta, Zulmarie; Sondel, Paul M; Rakhmilevich, Alexander L

    2013-12-01

    Our previous studies demonstrated that anti-CD40 mAb (anti-CD40) can synergize with CpG oligodeoxynucleotides (CpG) to mediate antitumor effects by activating myeloid cells, such as macrophages in tumor-bearing mice. Separate teams have shown that chemotherapy with gemcitabine (GEM) or 5-fluorouracil (5-FU) can reduce tumor-induced myeloid-derived suppressor cells (MDSC) in mice. In this study we asked if the same chemotherapy regimens with GEM or 5-FU will enhance the antitumor effect of anti-CD40 and CpG. Using the model of B16 melanoma growing intraperitoneally in syngeneic C57BL/6 mice, we show that these GEM or 5-FU treatment regimens reduced MDSC in the peritoneal cavity of tumor-bearing mice. Treatment of mice with GEM or 5-FU did not significantly affect the antitumor function of macrophages as assessed in vitro. In vivo, treatment with these GEM or 5-FU regimens followed by anti-CD40/CpG resulted in antitumor effects similar to those of anti-CD40/CpG in the absence of GEM or 5-FU. Likewise, reduction of MDSC by in vivo anti-Gr-1 mAb treatment did not significantly affect anti-CD40/CpG antitumor responses. Together, the results show that the GEM or 5-FU chemotherapy regimens did not substantially affect the antitumor effects induced by anti-CD40/CpG immunotherapy.

  7. 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

  8. Induction Chemotherapy with Cisplatin and 5-Fluorouracil in Advanced Head and Neck Cancers: A Short Term Response Evaluation

    PubMed Central

    Rao, Raghavendra; Shenoy, Vijendra; Hegde, Mahesh Chandra; Prasad, Vishnu; Prasad, Krishna

    2015-01-01

    Background Considering the uprising number of Head and neck cancer in the state with limited options of medical and surgical treatment, the focus of this study involved on chemotherapy in advanced Head and neck cancers. The aim of this study was to evaluate the efficacy and toxicity of combination of Cisplatin and 5-Fluorouracil (PF) as induction chemotherapy in patients in locally advanced squamous cell cancer of head and neck. Materials and Methods Forty four patients with previously untreated stage III -IV advanced and inoperable cases were included in this prospective study. Induction chemotherapy consisted of 3 cycles of Cisplatin 100mg/mt2 as infusion on day 1, 5-Fluorouracil of 750mg/mt2 on day 2, 5-Fluorouracil of 1000mg/mt2 as infusion on day 3 in an inpatient basis. Cycles were repeated with an interval of 21 days. Patients were evaluated within a period of 3 weeks at the end of completion of third cycle of chemotherapy. Post chemotherapy local therapy was individualized based on the response, site and stage of the tumour. Results Out of 44 eligible and evaluable patients, major dominance was noted in male group constituting 68%. After induction chemotherapy 58.8% of stage III experienced stable response, & 44% had partial response. In stage IV, 44% showed a stable response and 33.3% had partial response. But in comparison to primary tumour response and nodal response, which had a significant clinical response, the overall response of malignancy with respect to stage and site specificity was clinically insignificant. Moderate adverse reaction was noted in 47.6% and 42.1% had mild reactions. Majority of patients experienced grade 3 adverse events, of which anaemia in females and leucopenia in males pre-dominated. Conclusion With the use of cisplatin and 5-FU as induction chemotherapy agents in advanced and inoperable squamous cell carcinoma of head and neck, a distinct benefit was seen in stabilizing the tumour from progression. But achieving a significant

  9. [The efficacy of the combined use of 5-fluorouracil electrophoresis and magnetotherapy in experimental pancreatitis].

    PubMed

    Kents, V V; Tsympilova, T A; Mavrodiĭ, V M; Godlevskiĭ, L S

    1994-01-01

    As shown on the experimental model of rat acute pancreatitis, an intensive 5-fluorouracil electrophoresis course in combination with magnetotherapy significantly reduces the activity of blood trypsin, amylase, lipase and corticosterone. The treatment is thought effective in experimental pancreatitis.

  10. Bactericidal and cytotoxic effect of combination of norfloxacin and 5-fluorouracil.

    PubMed

    Castelli, M; Bertolini, A; Baggio, G; Aresca, P; Bossa, R; Galatulas, I

    1989-01-01

    Using the agar dilution technique, we examined the in vitro antibacterial activity of 5-fluorouracil and norfloxacin alone and in association against several bacterial strains. When administered in association, the two drugs did not antagonize each other in tests carried out on strains both sensitive and resistant to penicillins, cephalosporins, aminoglycosides, tetracyclines; furthermore their respective antibacterial properties remained largely unimpaired. The cytotoxic activity and the antitumoral effect of a combination of 5-fluorouracil and norfloxacin was determined in cultured tumor cells, and in mice bearing Ehrlich ascites carcinoma. No significant interference with the cytotoxic activity and antitumoral activity of 5-fluorouracil was observed.

  11. 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.

  12. Hepatocellular carcinoma stem cell-like cells are enriched following low-dose 5-fluorouracil chemotherapy.

    PubMed

    Zhan, Yongqiang; Mou, Lisha; Cheng, Kangwen; Wang, Chengyou; Deng, Xuesong; Chen, Junren; Fan, Zhibing; Ni, Yong

    2016-10-01

    It has been proposed that cancer stem cells (CSCs) are involved in tumor resistance to chemotherapy and tumor relapse. The goal of the present study was to determine the effect of low-dose 5-fluorouracil (5-Fu) on enriched hepatocellular CSC-like cells. Increased cell motility and epithelial-mesenchymal transition were observed by migration assay in human hepatoblastoma PLC/RAF/5 cells following 5-Fu treatment, as well as a significant enhancement in their sphere-forming abilities. CSC-like cells were identified by side population cell analysis. The percentage of CSC-like cells in the surviving cells was greatly increased in response to 5-Fu. These findings indicate that low-dose 5-Fu treatment may efficiently enrich the CSC-like cell population in PLC/RAF/5 cells.

  13. Suppressive effect of sinomenine combined with 5-fluorouracil on colon carcinoma cell growth.

    PubMed

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

    2014-01-01

    It is reported that sinomenine (SIN) and 5-fluorouracil (5-FU) both are effective for colon cancer, but their cooperative suppressive effects and toxicity remain to be clarified in detail. This study aimed to determine suppressive effects and toxicity of sinomenine (SIN) plus 5-fluorouracil (5-FU) on LoVo colon carcinoma cells in vitro and in vivo. CCK-8, Hoechst 33258 staining and an annexin V-FITC/PI apoptosis kit were used to detect suppressive effects. Western blotting was applied to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis. SIN or 5-FU or both were injected into nude mice, and then suppressive effects and side effects were observed. SIN plus 5-FU apparently inhibited the proliferation of LoVo cells and induced apoptosis. Moreover the united effects were stronger than individually (p<0.05). The results of annexin V-FITC /PI staining and Hoechst 33258 staining showed that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone was significantly higher than the control group (p<0.05). Expression of Bax and Bcl-2 was up-regulated and down-regulated respectively. SIN or 5-FU significantly inhibited effects on the volume of tumour xenografts and their combined suppressive effects were stronger (p<0.05). No obvious side effects were observed. It was apparent that the united effects of SIN and 5-FU on the growth of colorectal carcinoma LoVo cells in vitro and in vivo were superior to those using them individually, and it did not markedly increase the side effects of chemotherapy.

  14. [Adjuvant chemotherapy with mitoxantrone, cyclophosphamide and 5-fluorouracil in breast neoplasms: therapeutic life].

    PubMed

    Genre, D; Macquart-Moulin, G; Bouscary, M L; Viens, P; Cowen, D; Packer y Comyn, I; Moatti, J P; Maraninchi, D

    1997-03-01

    The chemotherapy side-effects are insufficiently documented while they strongly condition patients' quality of life. The aim of the study was to assess by means of a self-administered questionnaire the somatic symptoms experienced by breast cancer patients during their NCF (mitoxantrone + cyclophosphamide + 5-fluorouracil) chemotherapy and to demonstrate the interest of this self-report by comparing the frequency of side-effects assessed by the patients to that noted by the physicians in medical records. The study was carried out among 44 patients receiving their chemotherapy + radiotherapy at the Paoli-Calmettes Institute (marseille) between July 1994 and May 1995. The questionnaire comprized of 17 symptoms evaluated in terms of frequency, duration/severity and distress. The most frequent symptoms are: hair loss and nausea (75%), hot flush (57%), lack of appetite and headache (46%) associated with distress in 67 to 100% of cases. Their frequency was underestimated by the physicians in medical records. This study showed a large discordance patient-physician in the assessment of chemotherapy side-effects. The type of tool presented in this study could complement the usual scales of toxicity that do not provide an estimation of true patients' experience.

  15. Adjuvant chemotherapy with 5-fluorouracil in a patient with colorectal cancer and Familial Mediterranean Fever.

    PubMed

    Purim, Ofer; Sulkes, Aaron; Brenner, Baruch

    2007-07-01

    Colorectal cancer is a common malignancy often requiring adjuvant chemotherapy. Familial Mediterranean Fever is a chronic hereditary disease which is relatively prevalent in the Middle East and is associated with recurrent episodes of serosal, synovial or cutaneous inflammations. The aim of this paper was to describe a patient with Familial Mediterranean Fever who received fluorouracil-based adjuvant chemotherapy for colorectal cancer. A 56-year-old man with Familial Mediterranean Fever and amyloidosis was referred for evaluation and treatment following surgery for colorectal cancer. In light of his relatively young age, good general state of health and apparently well-controlled Familial Mediterranean Fever, he was treated with chemotherapy consisting of four cycles of 5-fluorouracil and leucovorin. The patient's clinical course during chemotherapy was unremarkable except for one minor attack of Familial Mediterranean Fever. The patient's follow-up was notable for periodic fluctuations in serum carcinoembryonic antigen levels, up to 4-fold of normal. The Familial Mediterranean Fever remained stable. Although our patient showed a good tolerability of treatment, the administration of chemotherapy to patients with Familial Mediterranean Fever raises several concerns. These include a potential deterioration in the Familial Mediterranean Fever status owing to chemotherapy-induced stress, the potential effect of Familial Mediterranean Fever or its treatment on the tolerability of chemotherapy and an overlapping toxicity of the drugs used to treat the two diseases. An increase in serum carcinoembryonic antigen in this setting may be related to the underlying pathophysiologic mechanism of Familial Mediterranean Fever but does not necessarily indicate disease recurrence. Clinicians should be aware of these issues considering the recent worldwide increase in colorectal cancer.

  16. 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

  17. 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.

  18. Effects of 5-fluorouracil chemotherapy on fatigue: role of MCP-1.

    PubMed

    Mahoney, S E; Davis, J M; Murphy, E A; McClellan, J L; Gordon, B; Pena, M M

    2013-01-01

    Chemotherapy has been known to cause severe side effects, including fatigue. While the mechanisms for chemotherapy induced fatigue (CIF) are likely to be multi-factorial in origin, it is thought that inflammation and anemia may play a role. The purpose of this study was to examine the effect of chemotherapy on fatigue in mice, and further, to begin to determine if inflammation and anemia may contribute to this response. For experiment 1, C57BL/6 mice were assigned to: vehicle (PBS), low (20 mg/kg), medium (40 mg/kg), or high (60 mg/kg) doses of 5-fluorouracil (5-FU). Voluntary physical activity (PA) was measured throughout the treatment period (day 1-5) as well as during the recovery period (day 6-14). In experiment 2, we examined the effects of 5-FU (60 mg/kg) on the inflammatory mediator MCP-1 and on markers of anemia (RBC, Hct and Hb). Finally, using MCP-1(-/-) mice we examined the role of MCP-1 on CIF (experiment 3). 5-FU reduced voluntary PA in a dose response manner (p<0.05). Plasma MCP-1 was increased following 5-FU treatment on both days 5 (p=0.10) and 14 (p<0.05). In addition, RBCs, Hct and Hb were reduced with 5-FU on days 5 and 14 (p<0.05). Both C57BL/6 and MCP-1(-/-) mice saw similar decrements in PA through the duration of the treatment period (days 1-5), however the MCP-1(-/-) mice recovered much earlier than wildtype mice. This study provides evidence of the dose response effect of a standard chemotherapy agent on fatigue and demonstrates a potential role of MCP-1 and presumably inflammation, and anemia.

  19. Pharmacokinetic characteristics of 5-fluorouracil and mitomycin C in intraperitoneal chemotherapy.

    PubMed

    Kuzuya, T; Yamauchi, M; Ito, A; Hasegawa, M; Hasegawa, T; Nabeshima, T

    1994-08-01

    Eight patients with malignancies confined to the peritoneal space participated in this study. Five hundred milligrams 5-fluorouracil or 10 mg mitomycin C was diluted in 1 L saline. The mixed solution was injected intraperitoneally through the semi-permanent peritoneal catheter. Blood and peritoneal fluid were collected after injection. 5-Fluorouracil concentrations in the peritoneal fluid were 1000 times those in serum, while mitomycin C concentrations were 100 times those in serum. Areas under the concentration vs time curve (AUC) were calculated by the trapezoidal method with extrapolation to infinity. The ratio of peritoneal fluid AUC to serum AUC was about 1400 for 5-fluorouracil and 80 for mitomycin C. Patterns for the absorption and elimination from systemic circulation were similar for both compounds. Drug concentrations in the peritoneal fluid and serum were analysed according to the compartment model. The half-life in the peritoneal fluid (t1/2p) and the rate constant from the peritoneal fluid to the systemic circulation (ka) were nearly equal for both 5-fluorouracil and mitomycin C (t1/2p, 1.0 h for 5-fluorouracil and 1.3 h for mitomycin C; ka 0.71 h-1 for 5-fluorouracil and 0.68 h-1 for mitomycin C), although the apparent volume of distribution (Vds/F) and clearance in the peritoneal cavity (CLp) for mitomycin C (78 L m-2 and 1.8 L h-1 m-2) were about twice the values for 5-fluorouracil (149 L m-2 and 0.8 L h-1 m-2).

  20. Impact of 5-fluorouracil metabolizing enzymes on chemotherapy in patients with resectable colorectal cancer.

    PubMed

    Ochiai, Takumi; Umeki, Masahiko; Miyake, Hiroshi; Iida, Tatsumi; Okumura, Minoru; Ohno, Kazuhide; Sakamoto, Masashi; Miyoshi, Nobukazu; Takahashi, Masahiko; Tsumura, Hidenori; Tokunaga, Yukihiko; Naitou, Haruhiko; Fukui, Takuji

    2014-09-01

    Although 5-fluorouracil (5-FU) is an important drug for colorectal cancer (CRC) treatment, no useful biomarker is currently available to predict treatment response. Since 5-FU is converted into active or inactive forms by orotate phosphoribosyltransferase (OPRT) or dihydropyrimidine dehydrogenase (DPD), a correlation between these enzymes and response to 5-FU has been suggested. However, such a correlation has not been investigated prospectively. Therefore, in the present study, we aimed to prospectively evaluate whether OPRT and DPD were predictive factors of the response to 5-FU treatment in patients with resectable CRC. The present investigation was designed as a multicenter prospective cohort study. OPRT and DPD activities were assessed in biopsy samples, obtained surgically from patients with resectable CRC. The OPRT/DPD ratio was calculated and the cut-off values for this ratio were determined for 5-year disease-free survival (DFS) and overall survival (OS). Patients were treated with 5-FU/leucovorin (LV) regimens and oral 5-FU. The endpoint of this study was the correlation between the OPRT/DPD ratio and 5-year DFS and OS. The cut-off value for the OPRT/DPD ratio was determined by using the maximum χ2 statistic method against 5-year DFS and OS. Sixty-eight patients were enrolled from July 2003 to May 2005. The median follow-up period was 1925 days. The OPRT/DPD ratio cut-off values for 5-year DFS and OS were 0.015 and 0.013, respectively. During the 5-year DFS and OS periods, patients with higher cut-off values had a better prognosis than those with lower ratios (P=0.03 and 0.02, respectively). In conclusion, our results suggest that the OPRT/DPD ratio could be a predictive factor for response to 5-FU/LV adjuvant chemotherapy.

  1. 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.

  2. Single and combined supplementation of glutamine and n-3 polyunsaturated fatty acids on host tolerance and tumour response to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11)/5-fluorouracil chemotherapy in rats bearing Ward colon tumour.

    PubMed

    Xue, Hongyu; Le Roy, Séverine; Sawyer, Michael B; Field, Catherine J; Dieleman, Levinus A; Baracos, Vickie E

    2009-08-01

    Prior reports suggest that during irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin; CPT-11) chemotherapy in laboratory rats, the anti-tumour efficacy and diarrhoea toxicity could be modulated by n-3 PUFA and glutamine, respectively. We further examined how these two dietary elements, when provided individually and in combination, would affect the efficacy of a cyclical regimen of CPT-11/5-fluorouracil (5-FU), an accepted combination regimen for colorectal cancer. Prior to initiating chemotherapy, diets enriched either with glutamine (2 %, w/w total diet) or n-3 PUFA (0.88 %, w/w total diet) alone, inhibited Ward colon tumour growth (P < 0.05). These diets also completely or partially normalized the changes in peripheral leucocyte counts associated with the tumour-bearing state (e.g. neutrophil proportion/concentration and lymphocyte proportion). During chemotherapy, either glutamine- or n-3 PUFA-enriched diet enhanced tumour chemo-sensitivity, and reduced body weight loss, anorexia and muscle wasting (v. animals fed control diet, P < 0.05). Surprisingly, providing both glutamine and n-3 PUFA together did not confer a greater benefit on tumour inhibition either in the presence or absence of chemotherapy; individual benefits associated with single treatments, particularly in respect to host nutritional status (i.e. body weight, food intake and muscle weight) and immune (peripheral leucocyte counts) features were instead partially or completely lost when these two nutrients were combined. These results draw into question the common assumption that there are additive or synergistic benefits of combinations of nutrients, which are beneficial on an individual basis, and suggest that co-supplementation with glutamine and n-3 PUFA is not indicated during chemotherapy with CPT-11 and 5-FU.

  3. The combination of docetaxel, cisplatin, and 5-fluorouracil in advanced gastric cancer: a single-institution experience.

    PubMed

    Ben Aharon, Irit; Purim, Ofer; Kundel, Yulia; Brenner, Ronen; Gordon, Noa; Sulkes, Aaron; Brenner, Baruch

    2012-03-01

    The addition of docetaxel to cisplatin and 5-fluorouracil was shown to confer a survival benefit in patients with advanced gastric cancer (one; AGC), although with increased toxicity. We hereby report our experience with the use of docetaxel, cisplatin, and 5-fluorouracil (DCF). Data on all consecutive patients who received first-line treatment with DCF at our institute were analyzed retrospectively. Twenty-three patients were included. The median age was 63 years. Patients received an average of 10 cycles (range, 1-24). All experienced grade ≥3 toxicity, requiring hospitalization in 35%. There was one toxic death. The median progression-free and overall survival rates were 10.0 and 12.8 months, respectively; the 2-year and 3-year survival rates were 22 and 17%, respectively. The DCF regimen is indeed associated with substantial toxicity, although manageable. Nevertheless, the observed benefit was remarkable compared with any previous report on chemotherapy in AGC, and should therefore represent a valid treatment option in AGC and a platform for future combinations.

  4. 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).

  5. 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

  6. Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group

    SciTech Connect

    Not Available

    1985-12-01

    One hundred fifty-seven patients with locally unresectable pancreatic carcinoma were randomly allocated to therapy with radiation and 5-fluorouracil or radiation and Adriamycin (doxorubicin). A total of 138 of 143 analyzable patients have died, and no differences in the relative survival impact of the treatments have been observed. Toxicity on the Adriamycin arm was more substantial and primarily attributable to Adriamycin chemotherapy after the completion of radiotherapy.

  7. Induction chemotherapy with cis-platinum and 5-fluorouracil for squamous cell carcinoma of the head and neck.

    PubMed Central

    Thyss, A.; Schneider, M.; Santini, J.; Caldani, C.; Vallicioni, J.; Chauvel, P.; Demard, F.

    1986-01-01

    One hundred and eight patients with squamous cell carcinoma of the upper aerodigestive tract (UADT) (T3, T4, NO-N3; 17% stage II, 54% stage III, 27% stage IV) were given three courses of chemotherapy before any local treatment. The regimen consisted of cis-platinum 100 mg m-2 on day 1 and 5-fluorouracil 1000 mg m-2 on days 2-6; drugs were administered by continuous infusion. The toxicity of this protocol was acceptable, as 82% of the patients were able to receive the initially scheduled drug dose. The overall response rate of 86.5% included a 35% rate of complete lesion regression. The effect of this regimen on primary tumours was especially remarkable--87.5% responses, including 47.5% complete responses. Results for lymph node metastases were not as good--66% responses, including 33% complete responses. The best results were obtained for tumours of the oropharynx and hypopharynx; oral cavity lesions were the most refractory. For those patients who were subsequently operated on, histological examination of the surgical specimen either confirmed sterilization or demonstrated the persistence of small disease foci. After local treatment, which consisted of radiotherapy alone for 69% of patients, the lesion control rate was 80%. At 18 months follow-up, the survival rate for patients who achieved a complete response with chemotherapy was significantly better than that for patients with a response of less than 50%. PMID:3801272

  8. Multifunctional nanovehicles for combined 5-fluorouracil and gold nanoparticles based on the nanoprecipitation method.

    PubMed

    Karmi, Abeer; Husseini, Ghaleb A; Faroun, Maryam; Sowwan, Mukhles

    2011-06-01

    To facilitate the administration of combined 5-Fluorouracil (5-FU) and gold nanoparticles (for photothermal treatment purposes), we developed 5-FU-gold-poly(lactide-co-glycolic acid) (5-FU-Au-PLGA) nanovehicles, via the nanoprecipitation method. The gold nanoparticles were incorporated inside the 5-FU-PLGA carriers using a roller mixer. Morphological analysis using atomic force microscopy (AFM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), indicated uniform, singly separated spherical nanoparticles (NPs). Drug content, recovery and entrapment in the NPs were approximated using UV-spectrophotometer data. Approximately 26% of nanoparticles were recovered after drying. The percentage of total drug content was about 30%, and the percentage of drug entrapment reached 57%. Electrostatic Force Microscopy images confirmed the presence of gold inside the drug-loaded nanoparticles. We speculate that the 20-nm gold particles were able to diffuse, after 12 hours of mixing (using the roller mixer), into the PLGA matrix through the 100-nm pores (observed by SEM) without affecting the integrity of the drug delivery vehicle. These synthesized nanoparticles show promise as multimodal vehicles in the delivery of chemotherapeutic agents.

  9. 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.

  10. Genetic polymorphisms and response to 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

    PubMed Central

    Tecza, Karolina; Pamula-Pilat, Jolanta; Lanuszewska, Joanna; Grzybowska, Ewa

    2016-01-01

    Clinical resistance to chemotherapy is one of the major problems in breast cancer treatment. In this study we analyzed possible impact of 22 polymorphic variants on the treatment response in 324 breast cancer patients. Selected genes were involved in FAC chemotherapy drugs transport (ABCB1, ABCC2, ABCG2, SLC22A16), metabolism (CYP1B1, CYP2C19, GSTT1, GSTM1, GSTP1, TYMS, MTHFR, DPYD), drug-induced damage repair (ERCC1, ERCC2, XRCC1) and involved in regulation of DNA damage response and cell cycle control (ATM, TP53). Apart from preexisting metastases three polymorphic variants were independent prognostic high risk factors of lack of response to FAC chemotherapy. Our results showed that the response to treatment depended of the variability in genes engaged in drugs’ transport (ABCC2 c.-24C>T, ABCB1 p.Ser893Ala/Thr) and in DNA repair machinery (ERCC2 p.Lys751Gln). Furthermore, the growing number of high-risk genotypes was reflected in gradual increase in risk of the non-responsiveness to treatment- from OR 2.68 for presence of two genotypes to OR 9.93 for carriers of all three negative genotypes in the group of all patients. Similar gene-dosage effect was observed in the subgroup of TNBCs. Also, TFFS significantly shortened with the increasing number of high-risk genotypes, with median of 54.4 months for carriers of one variant, to 51.5 and 34.9 months for the carriers of two and three genotypes, respectively. Our results demonstrate that results of cancer treatment are the effect of many clinical and genetic factors. It seems that multifactorial polymorphic models could be a potentially useful tool in personalization of cancer therapies. The novelty in our model is the over representation of triple negative breast cancer (TNBC) patients among the carriers of all unfavorable polymorphic variants. This finding contributes to the elucidation of the mechanisms of drug resistance in this subgroup of breast cancer patients. PMID:27527855

  11. 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

  12. A phase II study of 5-fluorouracil/leucovorin in combination with paclitaxel and oxaliplatin as first-line treatment for patients with advanced gastric cancer.

    PubMed

    Lin, Rong-Bo; Fan, Nan-Feng; Guo, Zeng-Qing; Wang, Xiao-Jie; Liu, Jie; Chen, Ling

    2008-12-01

    The objective of this study was to evaluate the efficacy and safety of the POF regimen (biweekly 5-fluorouracil/leucovorin combined with paclitaxel and oxaliplatin) as first-line treatment for advanced gastric cancer (AGC). Twenty-seven previously untreated patients with advanced adenocarcinoma of the gastric or gastroesophageal junction were eligible for this study. The chemotherapy regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m(2)) followed by oxaliplatin (85 mg/m(2)) and leucovorin (400 mg/m(2)), administered simultaneously over a 2-hour infusion period, followed by an infusion of 5-fluorouracil (2400 mg/m(2)) over a 46-hour period. Twenty-one patients had measurable lesions: four complete responses, eight partial responses and seven stable diseases. At a median follow-up of 610 days, median survival was 348 days. Frequent grade 3 to 4 toxicities were: neutropenia (29.6%), stomatitis (7.4%), nausea (7.4%), vomiting (7.4%), hepatic dysfunction (3.7%), and fatigue (18.5%). No treatment-related deaths occurred. The POF regimen appears to be efficacious and is well tolerated in patients with AGC.

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

    PubMed Central

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

    2016-01-01

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

  14. Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer.

    PubMed

    Ikeda, Hirokuni; Taira, Naruto; Nogami, Tomohiro; Shien, Kazuhiko; Okada, Masanori; Shien, Tadahiko; Doihara, Hiroyoshi; Miyoshi, Shinichiro

    2011-11-01

    Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo.

  15. [Two cases of Wernicke´s encephalopathy that developed during total parenteral nutrition in colon cancer patients treated with 5-fluorouracil-based chemotherapy].

    PubMed

    Cho, Kyung Pyo; Lee, Jae Sung; Seong, Ji Seok; Woo, Yong Moon; Cho, Young Jun; Jeong, Beom Jin; Sohn, Jee Hoon; Kim, Su-Jung

    2014-09-25

    Wernicke's encephalopathy (WE) caused by thiamine deficiency is an acute neurological disorder. Clinically, the classic triad of WE consists of ophthalmoplegia, ataxia, and mental status changes. Thiamine deficiency is known to occur commonly in chronic alcoholic patients. Sometimes, it can occur in patients after gastrointestinal surgery and in those with malabsorption. In addition, patients undergoing renal dialysis, suffering from hyperemesis gravidarum, receiving total parenteral nutrition (TPN), and being treated with chemotherapeutic agents are also prone to develop thiamine deficiency. Herein, we report two cases of WE that developed following simultaneous 5-fluorouracil (5-FU) chemotherapy and TPN in colon cancer patients which was successfully treated with thiamine administration.

  16. 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

  17. 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.

  18. Synergistic effects of puerarin combined with 5-fluorouracil on esophageal cancer.

    PubMed

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

    2014-11-01

    Puerarin is an isoflavone derived from kudzu roots with a wide range of biological and medicinal properties. The aim of the present study was to investigate the inhibitive effects of puerarin combined with 5‑fluorouracil (5‑FU) on Eca‑109 esophageal cancer cells in vitro and in vivo. Inhibitive effects of the treatments on Eca‑109 cells were detected by cell counting kit‑8, Hoechst 33258 staining and flow cytometry. A tumor xenograft model was established in nude mice. Puerarin and 5‑FU, administered either in combination or individually, were injected into mice and the inhibitive effects along with any side effects were observed. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Puerarin and 5‑FU, administered as combined treatment or individual drugs, significantly inhibited proliferation and induced marked apoptosis. The mean growth inhibition rate (± standard deviation) reached 87.27±5.37% and the apoptotic rate at 48 h reached 36.18±1.24% in the combined treatment group. The percentages of apoptotic cells induced by puerarin and 5‑FU (combined or alone) were significantly higher than those of the control group (P<0.05). Puerarin or 5‑FU alone significantly inhibited the growth of xenograft tumors in comparison to the control group (P<0.05), with inhibition rates of 76.93 and 72.21%, respectively. The drugs combined exhibited a significantly greater effect than either drug alone (P<0.05), with the tumor inhibition rate reaching 89.06%. During the course of chemotherapy, no evident side effects were observed. The results suggested that the combined inhibitive effects of puerarin and 5‑FU were greater than the effects of the agents used individually. In addition, puerarin combined with 5‑FU exhibited synergistic effects at lower concentrations and promoted apoptosis, but did not increase the side effects of chemotherapy, which indicated that puerarin may be a safe and effective

  19. Synergistic antitumor effect of puerarin combined with 5-fluorouracil on gastric carcinoma.

    PubMed

    Guo, Xu-Feng; Yang, Zi-Rong; Wang, Jun; Lei, Xiao-Fei; Lv, Xiao-Guang; Dong, Wei-Guo

    2015-04-01

    Combination chemotherapy is a crucial method in the treatment of gastric cancer. The aim of the present study was to investigate the inhibitory effects of puerarin and 5‑fluorouracil (5‑FU) on BGC‑823 gastric cancer cells in vitro and in vivo. The in vitro growth inhibition of puerarin or 5‑FU alone or combined on BGC‑823 cells was determined using a cell counting kit 8 (CCK‑8) on living cells. Apoptotic morphological features and proteins expression levels were detected by Hoechst 33258 staining, an Annexin V/propidium iodide apoptosis kit and western blot analysis, respectively. Tumor xenografts were established in nude mice and the inhibitory effects and side effects were detected. Results of the CCK‑8, Hoechst 33258 staining and flow cytometry revealed that the combined treatment was more effective than the separate treatments. The tumor volume was 90.65% of that of the controls and the mean tumor weight was only 0.125 g at the end of the experiment in the combination group compared with the control group (0.822 g). In addition, it was determined that liver and renal toxicity did not increase in combined treatment. These findings showed that puerarin and 5‑FU produced a significant synergic effect on gastric cancer cells, while there was no increase in side effects.

  20. Effect of 5-fluorouracil combination therapy on RNA processing in human colonic carcinoma cells.

    PubMed Central

    Greenhalgh, D. A.; Parish, J. H.

    1990-01-01

    We have evaluated the RNA-directed cytotoxicity of 5-fluorouracil (5-FU) in human colonic carcinoma cells. The mode of action of 5-FU and its effects on human pre-rRNA processing were then examined. From these data, possible reasons why the disruption of pre-rRNA maturation could induce cytotoxic effects are considered. The results imply that inhibition of thymidylate synthase is not the sole primary cytotoxic lesion in this cell line. First, exogenous thymidine (dTHd) enchanced cytotoxicity. Second, addition of dThd to the cells was found to enhance incorporation of 5-FU into total cellular RNA. Third, 5-FU disrupted rRNA processing by a different mechanism from actinomycin D and methotrexate (MTX), suggesting that the inhibition was not just a consequence of cell death. Finally, the addition of dThd was found to enhance the disruption of rRNA processing consistent with an increase in concentration of 5-FU. These data are discussed in the light of literature reports and their potential for optimising 5-FU protocols. Images Figure 3 Figure 4 Figure 5 PMID:2328208

  1. Predictive markers for the response to 5-fluorouracil therapy in cancer cells: Constant-field gel electrophoresis as a tool for prediction of response to 5-fluorouracil-based chemotherapy.

    PubMed

    Saleh, E M; El-Awady, R A; Anis, N

    2013-01-01

    The prediction of response or severe toxicity and therapy individualisation are extremely important in cancer chemotherapy. There are few tools to predict chemoresponse or toxicity in cancer patients. We investigated the correlation between the induction and repair of DNA double-strand breaks (DSBs) using constant-field gel electrophoresis (CFGE) and evaluating cell cycle progression and the sensitivity of four cancer cell lines to 5-fluorouracil (5FU). Using a sulphorhodamine-B assay, colon carcinoma cells (HCT116) were found to be the most sensitive to 5FU, followed by liver carcinoma cells (HepG2) and breast carcinoma cells (MCF-7). Cervical carcinoma cells (HeLa) were the most resistant. As measured by CFGE, DSB induction, but not residual DSBs, exhibited a significant correlation with the sensitivity of the cell lines to 5FU. Flow cytometric cell cycle analysis revealed that 14% of HCT116 or HepG2 cells and 2% of MCF-7 cells shifted to sub-G1 phase after a 96-h incubation with 5FU. Another 5FU-induced cell cycle change in HCT116, HepG2 and MCF-7 cells was the mild arrest of cells in G1 and/or G2/M phases of the cell cycle. In addition, 5FU treatment resulted in the accumulation of HeLa cells in the S and G2/M phases. Determination of Fas ligand (Fas-L) and caspase 9 as representative markers for the extrinsic and intrinsic pathways of apoptosis, respectively, revealed that 5FU-induced apoptosis in HCT116 and HepG2 results from the expression of Fas-L (extrinsic pathway). Therefore, the induction of DNA DSBs by 5FU, detected using CFGE, and the induction of apoptosis are candidate predictive markers that may distinguish cancer cells which are likely to benefit from 5FU treatment and the measurement of DSBs using CFGE may aid the prediction of clinical outcome.

  2. Combined environmental risk assessment for 5-fluorouracil and capecitabine in Europe.

    PubMed

    Straub, Jürg Oliver

    2010-07-01

    An environmental risk assessment (ERA) was made for the old cytostatic active pharmaceutical ingredient 5-fluorouracil (5-FU) and for capecitabine (CAP), which is a prodrug of 5-FU. This ERA is based on published and company internal data as well as new test results for physicochemical, human metabolism, biodegradability, environmental partitioning and fate, and acute and chronic ecotoxicity properties of the active substance 5-FU as well as on use sales data for 5-FU and CAP in Europe. Predicted environmental concentrations (PECs) were extrapolated following the EMEA 2006 Guideline on ERA for human pharmaceuticals and the European Union 2003 Technical Guidance Document (TGD) for risk assessment as well as the TGD-based application EUSES v2.0. Actual amounts sold were taken from IMS Health Databases, in order to refine the default use and EMEA penetration factor as well as the PECs. Moreover, available measured environmental concentrations (MECs) were used to supplement PECs. A predicted no-effect concentration (PNEC) for 5-FU was derived from chronic ecotoxicity data. Except for the simplistic EMEA Phase I default PEC, the risk characterization by PEC:PNEC and MEC:PNEC ratios for various environmental compartments resulted in no significant risk. As the EMEA Phase I PEC does not integrate documented human metabolism and environmental degradation, in contrast to refined PEC derivations, it is inferred that the current use of CAP and 5-FU does not present any evident risk to the environment. An additional evaluation of persistence, bioaccumulation, and toxicity (PBT) properties supports the conclusion of no significant environmental risk for 5-FU and CAP.

  3. 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

  4. Predictive markers for the response to 5-fluorouracil therapy in cancer cells: Constant-field gel electrophoresis as a tool for prediction of response to 5-fluorouracil-based chemotherapy

    PubMed Central

    SALEH, E. M.; EL-AWADY, R. A.; ANIS, N.

    2013-01-01

    The prediction of response or severe toxicity and therapy individualisation are extremely important in cancer chemotherapy. There are few tools to predict chemoresponse or toxicity in cancer patients. We investigated the correlation between the induction and repair of DNA double-strand breaks (DSBs) using constant-field gel electrophoresis (CFGE) and evaluating cell cycle progression and the sensitivity of four cancer cell lines to 5-fluorouracil (5FU). Using a sulphorhodamine-B assay, colon carcinoma cells (HCT116) were found to be the most sensitive to 5FU, followed by liver carcinoma cells (HepG2) and breast carcinoma cells (MCF-7). Cervical carcinoma cells (HeLa) were the most resistant. As measured by CFGE, DSB induction, but not residual DSBs, exhibited a significant correlation with the sensitivity of the cell lines to 5FU. Flow cytometric cell cycle analysis revealed that 14% of HCT116 or HepG2 cells and 2% of MCF-7 cells shifted to sub-G1 phase after a 96-h incubation with 5FU. Another 5FU-induced cell cycle change in HCT116, HepG2 and MCF-7 cells was the mild arrest of cells in G1 and/or G2/M phases of the cell cycle. In addition, 5FU treatment resulted in the accumulation of HeLa cells in the S and G2/M phases. Determination of Fas ligand (Fas-L) and caspase 9 as representative markers for the extrinsic and intrinsic pathways of apoptosis, respectively, revealed that 5FU-induced apoptosis in HCT116 and HepG2 results from the expression of Fas-L (extrinsic pathway). Therefore, the induction of DNA DSBs by 5FU, detected using CFGE, and the induction of apoptosis are candidate predictive markers that may distinguish cancer cells which are likely to benefit from 5FU treatment and the measurement of DSBs using CFGE may aid the prediction of clinical outcome. PMID:23255942

  5. A Phase I Trial of Oblimersen Sodium in Combination With Cisplatin and 5-Fluorouracil in Patients with Advanced Esophageal, Gastroesophageal Junction and Gastric Carcinoma

    PubMed Central

    Raab, Rachel; Sparano, Joseph A.; Ocean, Allyson J.; Christos, Paul; Ramirez, Mark; Vinciguerra, Vincent; Kaubisch, Andreas

    2012-01-01

    Purpose To determine the maximum tolerated dose of oblimersen, an antisense oligonucleotide directed to the Bcl-2 mRNA, in combination with cisplatin and 5-flourouracil in patients with advanced gastric and esophageal carcinoma. Methods Patients were treated with escalating doses of oblimersen administered by continuous intravenous infusion (CIVI) days 1 to7, CIVI 5-fluorouracil (5-FU) days 4 to 7, and cisplatin on day 4 every three weeks. Results Fifteen patients received a total of 49 courses of oblimersen at doses of 3, 5, or 7 mg/kg/d given as a seven day CIVI in combination with 4 or 5 day CIVI of 5-FU (1000 or 750 mg/m2/d) plus intravenous cisplatin (100 or 75 mg/m2 over 2 hours). The recommended phase II dose of oblimersen was 5 mg/kg/day in combination with 5-FU (750 mg/m2/day for 4 days) and cisplatin (75 mg/m2). The most common grade 3 to 4 adverse events that occurred in at least 10% of patients at all dose levels included neutropenia (33%), hypokalemia (27%), infection (20%), and mucositis, fatigue, dizziness, thrombosis, and dehydration (in 13% for each category). Conclusion The combination of oblimersen with 5-FU and cisplatin chemotherapy is feasible in patients with advanced upper gastrointestinal cancer, with antitumor activity observed in gastric carcinoma. PMID:19738454

  6. Prognostic significance of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in biliary tract cancer patients receiving adjuvant 5-fluorouracil-based chemotherapy

    PubMed Central

    KIM, KWAN WOO; KWON, HYUK-CHAN; KIM, SUNG-HYUN; OH, SUNG YONG; LEE, SUEE; LEE, JI HYUN; ROH, MYUNG HWAN; KIM, MIN CHAN; KIM, KI HAN; KIM, YOUNG HOON; ROH, YOUNG HOON; JEONG, JIN SOOK; KIM, HYO-JIN

    2013-01-01

    Biliary tract cancer (BTC) is a relatively uncommon type of cancer, accounting for ∼4% of the malignant neoplasms of the gastrointestinal tract. The aim of this study was to determine whether the expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) predict clinical outcome in BTC patients treated with adjuvant 5-fluorouracil (5-FU)-based chemotherapy. TS and TP expression were found to be significantly correlated with cancer location (P=0.044 and 0.031, respectively). The multivariate analysis revealed that age [hazard ratio (HR)=2.157, P=0.008], stage (HR=2.234, P<0.001), resection margin status (HR=2.748, P=0.004) and TP expression (HR=2.014, P=0.039) were independently associated with overall survival (OS). PMID:24649282

  7. Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study

    PubMed Central

    De Placido, S; Lopez, M; Carlomagno, C; Paoletti, G; Palazzo, S; Manzione, L; Iannace, C; Ianniello, G P; De Vita, F; Ficorella, C; Farris, A; Pistillucci, G; Gemini, M; Cortesi, E; Adamo, V; Gebbia, N; Palmeri, S; Gallo, C; Perrone, F; Persico, G; Bianco, A R

    2005-01-01

    The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2 × 2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73–1.09) for patients receiving FA and 0.99 (95% CI 0.80–1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95% CI: 0.80–1.30) and 0.94 (95% CI 0.73–1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients. PMID:16222322

  8. Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer.

    PubMed

    Ye, Yan-Wei; Hu, Shuang; Shi, Ying-Qiang; Zhang, Xie-Fu; Zhou, Ye; Zhao, Chun-Lin; Wang, Guo-Jun; Wen, Jian-Guo; Zong, Hong

    2013-12-01

    Our previous findings revealed that FGFR4 may be a novel therapeutic target for gastric cancer. The aim of the present study was to explore the effects of a combination of PD173074 (PD) and 5-fluorouracil (5-Fu) on the biological behavior of gastric cancer cell lines and the relevant mechanisms involved. MKN45, a gastric cancer cell line, was treated with each single agent alone or a combination of FGF19, PD and 5-Fu. Then, a series of functional assays were performed using CCK-8 assay and flow cytometry. Western blot analysis was used to determine the expression of signaling pathway and downstream-related molecules in the MKN45 cells following the different treatments. As the concentration of PD and 5-Fu increased, the cell viability gradually decreased; the viability of the combination group was less than the viability following single administration. Western blot analysis showed that FGFR4 expression was weak in the 5-Fu-treated groups when compared with the control. PD markedly increased the apoptosis rate of MKN45 cells when compared to the control; the apoptosis rate in the cells treated with the combination of PD and 5-Fu was higher than that in the cells following single treatment. Furthermore, PD reduced the expression of p-ERK and Bcl-xl and increased caspase-3 expression. Inhibition of the activity of FGFR4 may be the main mechanisms of PD effect while 5-Fu reduced FGFR4 expression. Furthermore, the effects of the combination of 5-Fu and PD in inhibiting proliferation, increasing apoptosis and arresting cell cycle were superior to these effects following the single agent treatments, suggesting that the two drugs applied in combination may contribute to the effective treatment of gastric cancer.

  9. 5-Fluorouracil Adjuvant Chemotherapy Does Not Increase Survival in Patients with CpG Island Methylator Phenotype Colorectal Cancer

    PubMed Central

    Jover, Rodrigo; Nguyen, Thuy-Phuong; Pérez-Carbonell, Lucía; Zapater, Pedro; Payá, Artemio; Alenda, Cristina; Rojas, Estefanía; Cubiella, Joaquín; Balaguer, Francesc; Morillas, Juan D.; Clofent, Juan; Bujanda, Luis; Reñé, Josep M; Bessa, Xavier; Xicola, Rosa M.; Nicolás-Pérez, David; Castells, Antoni; Andreu, Montserrat; Llor, Xavier; Boland, C. Richard; Goel, Ajay

    2011-01-01

    Background & Aims 5-FU-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy. Methods We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP-positive (CIMP+) if at least 3 promoters were methylated. Results Tumors from 29.5% (89/302) of patients were CIMP+; this did not influence disease-free survival (log rank=.26). Of tumors of TNM stages II–III (n=196), 32.7% were CIMP+. Among patients with CRC stages II–III who did not receive adjuvant 5-FU chemotherapy, those with CIMP+ tumors had longest times of disease-free survival (log rank=.04); patients with CIMP+ tumors who received chemotherapy had shorter times of disease-free survival (log rank=0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of disease-free survival (log-rank=.00001). However, in patients with CIMP+ tumors, adjuvant 5-FU chemotherapy did not affect time of disease-free survival (log rank=.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR]=0.6; 95% confidence interval [CI], .5–.8). Among patients with CIMP+ tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR=0.8; 95% CI, 0.3–2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR=2.0; 95% CI, 1.1–3.8) Conclusion Patients with CIMP+ colorectal tumors do not benefit from 5-FU–based adjuvant chemotherapy. PMID:21185836

  10. Combined radiotherapy, 5-fluorouracil continuous infusion and weekly oxaliplatin in advanced rectal cancer: a phase I study.

    PubMed

    François, Eric; Ychou, Marc; Ducreux, Michel; Bertheault-Cvitkovic, Frédérique; Giovannini, Marc; Conroy, Thierry; Lemanski, Claire; Thomas, Olivier; Magnin, Valérie

    2005-12-01

    The aim of this study was to determine the maximum-tolerated dose (MTD) of weekly oxaliplatin combined with 5-fluorouracil (5FU) continuous infusion administered concomitantly with fractionated radiotherapy in patients presenting advanced rectal cancer. Forty-three patients with rectal cancer (stage T3/T4 (n = 24), metastatic (n = 17) and 2 with local recurrence), were included. The radiotherapy dose delivered was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 days per week). The initial weekly oxaliplatin dosage was 30 mg/m2 and the 5FU dosage 150 mg/m2/d. The oxaliplatin and 5FU doses were escalated. Eight dose levels were tested. At dose level 8 (oxaliplatin 80 mg/m2, 5FU 225 mg/m2/d), 2 patients out of 4 presented dose-limiting toxicity (severe diarrhoea with dehydration and fatal shock, rectovesical fistula). At dose level 7, 2 further patients presented with grade 3 diarrhoea. The main toxicity of the combination was diarrhoea. The hematological and neurological toxicities were not severe and were not dose-limiting. Out of the 30 patients undergoing surgery, 4 (13.3%) presented with pathological complete response and 4 (13.3%) only presented with microscopic residual disease. The results from this study enabled determination of the recommended weekly oxaliplatin dose (60 mg/m2) combined with 5FU continuous infusion (225 mg/m2) and fractionated radiotherapy (45 Gy) in the pre-operative treatment of advanced rectal cancer. The good safety profile of the regimen, associated with promising results in terms of histological response, suggest that the regimen could be developed in future phase II/III studies.

  11. Combination of thymidine phosphorylase gene transfer and deoxyinosine treatment greatly enhances 5-fluorouracil antitumor activity in vitro and in vivo.

    PubMed

    Ciccolini, J; Cuq, P; Evrard, A; Giacometti, S; Pelegrin, A; Aubert, C; Cano, J P; Iliadis, A

    2001-12-01

    We reported previously that 5-fluorouracil (FUra) efficacy could be enhanced by increasing tumoral thymidine phosphorylase (TP) activity. Potentiated TP yield was achieved by either transfecting cells with human TP gene (A. Evrard et al., Br. J. Cancer, 80: 1726-1733, 1999) or associating FUra with 2'-deoxyinosine (d-Ino), a modulator providing the tumors with TP cofactor deoxyribose 1-phosphate (J. Ciccolini et al., Clin. Cancer Res., 6: 1529-1535, 2000). The purpose of the present work was to study the effects of a combined modulation (TP gene transfer + use of d-Ino) on the sensitivity to FUra of the LS174T human colorectal cell line. Results showed a near 4000 times increase of cell sensitivity in vitro after double (genetic + biochemical) modulation. This potentiation of tumor response was accompanied by a total change in the FUra anabolic pathway with a 5000% increase of cytosolic fluorodeoxyuridine monophosphate, a stronger and longer inhibition of thymidylate synthase, and 300% augmentation of DNA damage. Besides, whereas thymidine failed to inhibit FUra cytotoxicity in LS174T wild-type cells, the potentiation of the antitumor activity observed in the modulating regimen was partly reversed by thymidine, indicative of thymidylate synthase as the main drug target. The impact of this double modulation was next investigated in xenograft-bearing nude mice. Results showed that whereas FUra alone was completely ineffective on wild-type tumor growth, the size of TP-transfected tumors in animals treated with the FUra/d-Ino combination was reduced by 80% (P < 0.05). Our results suggest that FUra exhibits stronger antiproliferative activity when activated via TP through the DNA pathway and that high tumoral TP activity therefore leads to enhanced sensitivity to fluoropyrimidines.

  12. Paclitaxel or 5-fluorouracil/esophageal stent combinations as a novel approach for the treatment of esophageal cancer.

    PubMed

    Liu, Jieying; Wang, Zhongmin; Wu, Keqin; Li, Jing; Chen, Weiluan; Shen, Yuanyuan; Guo, Shengrong

    2015-01-01

    Currently, esophageal cancer is rarely curable, and herein, a paclitaxel or 5-fluorouracil/esophageal stent combination (PTX or 5-FU/stent) was used to provide a new approach to treat this cancer. The PTX or 5-FU/stent was prepared by covering a nitinol stent with a bilayered polymer film that consisted of a layer of 50% PTX or 5-FU and a layer of drug-free backing. These treatment modalities were evaluated in vivo after implantation into the porcine esophagus. The percentages of the drugs that permeated from the backing layer over a period of 95 days were very small (0.61% for 5-FU), and an overwhelming majority of the PTX and the 5-FU was released from the other side of the film. During the follow-up period (120 days), the drug/stent was always maintained in the porcine esophagus, and did not show any obvious systemic or local toxicities. In contrast, this treatment had an effect on the inhibition of tissue proliferation and ulceration. In addition, the drug concentrations were highest in the esophagus compared with in the heart, liver, spleen, lung, kidney and blood (81500.0 ± 9475.2 ng/g vs. 3.9 ± 0.3 ng/mL of PTX in the plasma at 13 days). The PTX/stent and the 5-FU/stent have a dual function as both a stent and a local drug delivery device, which provides a potential treatment modality with high efficacy and non systematic toxicity for esophageal cancer.

  13. 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

  14. Preexposure of MCF-7 breast cancer cell line to dexamethasone alters the cytotoxic effect of paclitaxel but not 5-fluorouracil or epirubicin chemotherapy

    PubMed Central

    Buxant, Frederic; Kindt, Nadège; Noël, Jean-Christophe; Laurent, Guy; Saussez, Sven

    2017-01-01

    Purpose Glucocorticoids (GCs) are often administered prior to any chemotherapeutics to prevent the secondary effects of anticancer agents. Glucocorticoid receptors (GRs) are expressed in several types of cancer cells, particularly in several histological types of breast cancer. Activation of GRs is not associated with any specific cellular response. Both proapoptotic and antiapoptotic responses have been observed, depending on the study or the type of breast cancer cells. Therefore, it is of relevance to investigate the possible modulation of apoptotic effect of chemotherapeutic agents when cancerous cells have previously been exposed to GCs. Methods In vitro cell growth was assayed by counting MCF-7 cells upon exposure to epirubicin (25 nM), 5-fluorouracil (5-FU) (15 µM), and paclitaxel (15 nM), either with or without prior exposure to the GC dexamethasone (Dex) (100 nM). Results Following preexposure to Dex, the antiapoptotic activity of paclitaxel was significantly reduced by 8.5% (p<0.05), but the activities of epirubicin and 5-FU remained unaltered. Conclusion In light of the finding that the response of MCF-7 cells pretreated with Dex was significantly reduced, we recommend that the function of GCs should be defined more precisely if they are to be used in conjunction with chemotherapy. PMID:28352202

  15. The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells.

    PubMed

    González-Sarrías, Antonio; Tomé-Carneiro, Joao; Bellesia, Andrea; Tomás-Barberán, Francisco A; Espín, Juan Carlos

    2015-05-01

    Chemotherapy increases the overall survival in colorectal cancer (CRC) patients. 5-Fluorouracil (5-FU) remains as a drug of first choice in CRC therapy over the last four decades. However, only 10-15% of patients with advanced CRC respond positively to 5-FU monotherapy. Therefore, new strategies to enhance the 5-FU effectiveness, overcome the tumor cell resistance and decrease the unspecific toxicity are critically needed. Urolithin A (Uro-A) is the main metabolite produced by the human gut microbiota from the dietary polyphenol ellagic acid. Uro-A targets the colonic mucosa of CRC patients, and preclinical studies have shown the anti-inflammatory and cancer chemopreventive activities of this metabolite. We evaluated here whether Uro-A, at concentrations achievable in the human colorectum, could sensitize colon cancer cells to 5-FU and 5'DFUR (a pro-drug intermediate of 5-FU). We found that both 5-FU and 5'DFUR arrested the cell cycle at the S phase by regulating cyclins A and B1 in the human colon cancer cells Caco-2, SW-480 and HT-29, and also triggered apoptosis through the activation of caspases 8 and 9. Co-treatments with Uro-A decreased IC50 values for both 5-FU and 5'DFUR and additionally arrested the cell cycle at the G2/M phase together with a slight increase in caspases 8 and 9 activation. Overall, we show that Uro-A potentiated the effects of both 5-FU and 5'DFUR on colon cancer cells. This suggests the need for lower 5-FU doses to achieve similar effects, which could reduce possible adverse effects. Further in vivo investigations are warranted to explore the possible role of Uro-A as a chemotherapy adjuvant.

  16. Docetaxel, cisplatin and 5-fluorouracil adjuvant chemotherapy following three-field lymph node dissection for stage II/III N1, 2 esophageal cancer.

    PubMed

    Hashiguchi, Tadasuke; Nasu, Motomi; Hashimoto, Takashi; Kuniyasu, Tetsuji; Inoue, Hirohumi; Sakai, Noritaka; Ouchi, Kazutomo; Amano, Takayuki; Isayama, Fuyumi; Tomita, Natsumi; Iwanuma, Yoshimi; Tsurumaru, Masahiko; Kajiyama, Yoshiaki

    2014-09-01

    To determine the efficacy of postoperative adjuvant chemotherapy with docetaxel + cisplatin + 5-fluorouracil (DCF) in lymph node metastasis-positive esophageal cancer, we retrospectively analyzed 139 patients with stage II/III (non-T4) esophageal cancer with lymph node metastasis (1-6 nodes), who did not receive preoperative treatment and underwent three-field lymph node dissection in the Juntendo University Hospital between December, 2004 and December, 2009. The tumors were histologically diagnossed as squamous cell carcinoma. The patients were divided into two groups, a surgery alone group (S group, 88 patients) and a group that received postoperative DCF therapy (DCF group, 51 patients). The disease-free and overall survival were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as N1 and N2, according to the TNM classification. There were no significant differences between the S and DCF groups regarding clinicopathological factors other than intramural metastasis and main tumor location. The presence of intramural metastasis, blood vessel invasion and the number of lymph nodes were identified as prognostic factors. The 5-year disease-free and overall survival were 55.8 and 57.3%, respectively, in the S group and 52.8 and 63.0%, respectively, in the DCF group. These differences were not considered to be statistically significant (P=0.789 and 0.479 for disease-free and overall survival, respectively). Although there were no significant differences in disease-free and overall survival between the S and DCF groups in N1 cases, both disease-free and overall survival were found to be better in the DCF group (54.2 and 61.4%, respectively) compared to the S group (29.6 and 28.8%, respectively) in N2 cases (P=0.029 and 0.020 for disease-free and overall survival, respectively). Therefore, postoperative adjuvant chemotherapy with DCF was shown to improve disease-free and

  17. 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.

  18. Pharmacokinetic study and clinical evaluation of a slow-release 5-fluorouracil implant in pancreatic cancer patients.

    PubMed

    Li, Jing Quan; Yang, Jing Chun; Liang, Jie Xiong; Wang, Shi Liang

    2016-01-01

    The aim of this research was to study the pharmacokinetic characteristics of a slow-release 5-fluorouracil implant as well as to evaluate the clinical drug activity of this preparation in pancreatic cancer patients. Pharmacokinetic characteristics of the slow-release 5-fluorouracil implant were evaluated by examining the half-life time (T1/2) and apparent volume of distribution (Vd) in pancreatic cancer patients; the slow-release 5-fluorouracil implant was administered through interstitial chemotherapy (tumor interstitium implantation). In the drug activity study, 36 locally advanced unresectable pancreatic cancer patients were divided randomly into an experimental treatment group (n=18) and a standard treatment group (n=18). The experimental treatment group was treated with interstitial chemotherapy of a slow-release 5-fluorouracil implant combined with systemic chemotherapy of gemcitabine; the standard treatment group was treated with systemic chemotherapy of gemcitabine. An internal drainage procedure was used when biliary and/or gastrointestinal tract obstruction occurred in the two groups. Clinical benefit response, including pain (visual analogue scale), analgesic drug use, general conditions (Karnofsky performance score), weight changes, and survival status, was observed. T1/2 of the slow-release 5-fluorouracil implant was 5475.8±136.4 min, whereas Vd was 45275.0±1028.6 l. Clinical benefit response in the experimental treatment group was better than that in the standard treatment group. The experimental treatment group had longer median survival time compared with the standard treatment group. The slow-release 5-fluorouracil implant could deliver drugs mainly in the regional area of the tumor and prolong the drug action time; interstitial chemotherapy of a 5-fluorouracil implant combined with systemic chemotherapy of gemcitabine could improve the quality of life and survival status of pancreatic cancer patients. The method was promising and worthy of

  19. 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

    Martino-Echarri, Estefania; Henderson, Beric R; Brocardo, Mariana G

    2014-10-30

    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.

  20. 5-fluorouracil induced pericarditis.

    PubMed

    Killu, Ammar; Madhavan, Malini; Prasad, Kavita; Prasad, Abhiram

    2011-04-15

    Cardiac toxicity is an infrequent, but potentially serious side effect of 5-fluorouracil (5-FU). The reported incidence of 5-FU-induced cardiotoxicity is approximately 3%, although estimates vary from 1.2% to 18%. Cardiac death occurs in less than 1%. The prompt recognition of cardiac toxicity demands a thorough understanding of the myriad of potential cardiac manifestations and a high index of suspicion. The most common presentation is angina pectoris while other manifestations, namely myocardial infarction, left ventricular dysfunction, arrhythmias and sudden death have been recognised. The authors report an unusual case of myopericarditis masquerading as myocardial infarction.

  1. 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

  2. Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance)

    PubMed Central

    Lee, Adam M.; Shi, Qian; Alberts, Steven R.; Sargent, Daniel J.; Sinicrope, Frank A.; Berenberg, Jeffrey L.; Grothey, Axel; Polite, Blase; Chan, Emily; Gill, Sharlene; Kahlenberg, Morton S.; Nair, Suresh G.; Shields, Anthony F.; Goldberg, Richard M.; Diasio, Robert B.

    2015-01-01

    Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G) and four variants within a haplotype (hapB3), in 1953 stage III colon cancer patients who received adjuvant FOLFOX +/- cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C displayed at least one grade≥3 5FU-AE, resulting in no statistically significant association (ORadj.=1.47, 95%CI=0.90-2.43, p=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy. PMID:26658227

  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. The effectiveness of intravenous 5-fluorouracil-containing chemotherapy after curative resection for gastric carcinoma: A systematic review of published randomized controlled trials.

    PubMed

    Hu, Jian-Kun; Li, Chun-Mei; Chen, Xin-Zu; Chen, Zhi-Xin; Zhou, Zong-Guang; Zhang, Bo; Chen, Jia-Ping

    2007-08-01

    This is a review of randomized controlled trials of intravenous 5-flurorouracil (5-FU)-containing chemotherapy after curative resection versus surgery alone in patients with gastric carcinoma to determine the impact on survival rate, safety and economics. Data sources were the Cochrane Library (2006, Issue 2), Pub-Medline and Chinese Biomedical Database. We included 22 randomized controlled trials comparing 4501 patients. Intravenous 5-FU-containing chemotherapy after curative resection had a slightly significant improvement in 3-, 5- and 7-year overall survival rate (OR 1.49, 1.41 and 1.32). No benefit of postoperative disease-free survival rate was induced by 5-FU-containing chemotherapy. Sensitivity analysis was restricted to trials with the highest methodological quality, and the result was similar when the studies with Jadad score less than 3' were excluded. Subgroup analyses found borderline improved overall survival rate in both Western and Eastern countries but the statistical significance was stronger in the Eastern subset. The combinations of 5-FU plus mitomycin C, 5-FU plus cytosine arabinoside and 5-FU plus adriamycin or epidoxorubicin induced potentially more improvement of 3- and 5-year overall survival rates. Severe toxicities were reported in 1629 patients from 15 included trials, and hematological and gastrointestinal toxicities were the most remarkable side effects, around 5%-15% respectively. The chemotherapy-related overall mortality was 1.1%. No trials mentioned cost-effectiveness analysis. Although the results provide some evidence of a beneficial effect of adjuvant chemotherapy with 5-FU-containing regimens, they are inconclusive due to the limitations of methodological quality of including randomized controlled trials. Large scale randomized controlled trials with a positive result are still mandatory before postoperative chemotherapy are recommended.

  5. Enhanced Efficacy of 5-Fluorouracil in Combination with a Dual Histone Deacetylase and Phosphatidylinositide 3-Kinase Inhibitor (CUDC-907) in Colorectal Cancer Cells

    PubMed Central

    Hamam, Rimi; Ali, Dalia; Vishnubalaji, Radhakrishnan; Alsaaran, Zaid F.; Chalisserry, Elna Paul; Alfayez, Musaad; Aldahmash, Abdullah; Alajez, Nehad M.

    2017-01-01

    Background/Aims: 5-Fluorouracil (5-FU) is widely used in the treatment of patients with colorectal cancer (CRC). However, the efficacy of 5-FU as a single agent is limited, with multiple undesired side effects. Therefore, the aim of the current study was to assess the efficacy of CUDC-907 (a dual inhibitor of histone deacetylase and phosphatidylinositide 3-kinase) in combination with 5-FU against CRC cells. Materials and Methods: Cell viability was determined using AlamarBlue and colony formation assays. Acridine orange/ethidium bromide staining and flow cytometry were used to measure apoptotic and necrotic events, as well as cell cycle progression. Immunoblotting was used to assess acetylation of histone H3 and phosphorylation of AKT. Results: Our data revealed enhanced toxicity of CUDC-907 against HCT116, RKO, COLO-205, and HT-29 CRC cells when combined with 5-FU. Similarly, the colony formation capability of HCT116 cells was suppressed by the combination treatment. Cells treated with CUDC-907 and 5-FU underwent apoptosis and necrosis, and exhibited increased polyploidy. Furthermore, CRC cells treated with CUDC-907 exhibited a higher degree of histone H3 lysine 9 acetylation (H3K9ac) and reduced AKT phosphorylation (Ser473). Conclusion: Our data revealed, for the first time, the enhanced inhibitory effect of CUDC-907 against CRC cells when combined with 5-FU, supporting the application of this combination as a potential therapeutic strategy in CRC treatment. PMID:28139498

  6. Modified 5-fluorouracil: Uridine phosphorylase inhibitor

    NASA Astrophysics Data System (ADS)

    Lashkov, A. A.; Shchekotikhin, A. A.; Shtil, A. A.; Sotnichenko, S. E.; Mikhailov, A. M.

    2016-09-01

    5-Fluorouracil (5-FU) is a medication widely used in chemotherapy to treat various types of cancer. Being a substrate for the reverse reaction catalyzed by uridine phosphorylase (UPase), 5-FU serves as a promising prototype molecule (molecular scaffold) for the design of a selective UPase inhibitor that enhances the antitumor activity of 5-FU and exhibits intrinsic cytostatic effects on cancer cells. The chemical formula of the new compound, which binds to the uracil-binding site and, in the presence of a phosphate anion, to the phosphate-binding site of UPase, is proposed and investigated by molecular simulation methods.

  7. 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

  8. 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

  9. Efficacy and Safety of Bolus 5-Fluorouracil and L-Leucovorin as Salvage Chemotherapy for Oral Fluoropyrimidine-Resistant Unresectable or Recurrent Gastric Cancer: A Single Center Experience

    PubMed Central

    Muranaka, Tetsuhito; Yuki, Satoshi; Sawada, Kentaro; Harada, Kazuaki; Kawamoto, Yasuyuki; Nakatsumi, Hiroshi; Sakamoto, Naoya

    2016-01-01

    Purpose The International Organization for Standardization-5fluorouracil (FU) 10 trial found that bolus 5-FU and l-leucovorin was not inferior to S-1 in the treatment of gastric cancer (GC). Continuous 5-FU and the rapid injection of 5-FU have different anti-cancer effects. Thus, bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. Materials and Methods We retrospectively analyzed the medical records of all patients with S-1 or capecitabine-resistant, unresectable, or recurrent GC treated with bolus 5-FU and l-leucovorin between January 2010 and December 2015 at Hokkaido University Hospital. The bolus 5-FU and l-leucovorin regimen consisted of intravenous l-leucovorin (250 mg/m2/2 h) and bolus 5-FU (600 mg/m2) administered once weekly followed by a 2-week rest period; each cycle was repeated every 8 weeks. Results A total of 14 patients were identified. The disease control rate was 35.7%. The median progression-free survival was 1.6 months (95% confidence interval [CI], 1.3~2.0 months), and the median overall survival was 6.3 months (95% CI, 4.7~7.9 months). No patient died from treatment-related causes. The most common severe adverse event associated with bolus 5-FU and l-leucovorin was neutropenia, which occurred in 21.4% of patients. Conclusions Bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. We are planning a multi-center prospective phase II trial to evaluate the efficacy and safety of bolus 5-FU and l-leucovorin treatment for pre-treated unresectable or recurrent GC to confirm the results of this limited, retrospective study. PMID:27752395

  10. 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.

  11. 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

  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 5-fluorouracil and 2-morphilino-8-phenyl-4H-chromen-4-one may inhibit liver cancer stem cell activity.

    PubMed

    Peng, Yu-Chong; Lu, Shi-Dong; Zhong, Jian-Hong; Xie, Zhi-Bo; You, Xue-Mei; Peng, Ning-Fu; Li, Le-Qun

    2016-08-01

    This work aims to evaluate the impact of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) combined 5-fluorouracil (5-FU) for the activity of CD90+ liver cancer cells derived from the human liver cancer cell line MHCC97H. MHCC97H sphere-forming cells (MSFCs) were amplified in serum-free medium and CD90+ cells were isolated from bulk MSFCs using flow cytometry. The phenotype of these CD90+ cells which show liver cancer stem cells (LCSCs) behavior was validated in vitro and in a xenograft model in nude mice. MSFCs, CD90+ liver cancer cells (CD90+ LCCs), and parental MHCC97H cells were treated with no drug, LY294002 alone, 5-FU alone, or both drugs together and then compared in terms of stem cell-related gene expression, proliferation, and invasion. Stem cell phenotype increased with increasing proportion of CD90+ cells, in ascending order: parental MHCC97H cells, MSFCs, and CD90+ liver cancer cells. LY294002 reduced the expression of CD90, Nanog, SALL4, and SHP2 in a concentration-dependent manner in CD90+ LCCs and MSFCs, but not in parental cells. LY294002 blocked AKT phosphorylation via the PI3K/AKT signaling pathway and inhibited CD90+ LCCs proliferation and tumorigenicity in vitro and in vivo. CD90+ liver cancer cells can express liver cancer stem cell phenotype. LY294002 inhibits the proliferation and invasion of MHCC97H-derived CD90+ LCCs and sensitized CD90+ LCCs-derived tumors to 5-FU in the current study which may provide insight into the association between the LY294002 combined 5-FU and liver cancer stem cell (LCSCs).

  14. [Cardiac toxicity of 5-fluorouracil].

    PubMed

    Fournier, C; Benahmed, M; Blondeau, M

    1989-02-01

    A 67 year-old patient receives 5-fluorouracil for vocal chord cancer. During the perfusion, atypical angina pain occurs, accompanied with offset of ST above the baseline in standard leads and in V4 through V6. The pain subsides spontaneously in 45 minutes. These ECG alterations are followed 48 hours later by diffuse inverted T waves with lengthened QT. Cardiac ultrasonography and isotopic angiography do not show any abnormality of the left ventricular function, but myocardial tomoscintigraphy with labelled thallium show a lower hypofixation on exertion. The cardiac toxicity of 5-fluorouracil is in frequent. It is usually believed that it involves a coronary spasm, as suggested by the ECG tracing in the reported cases. The incident, which may be painful or painless, may result in a myocardial infarction or even sudden death during the perfusion. Therefore, it is advisable to discontinue the treatment as soon as an angina-type pain occurs.

  15. 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

  16. Anti-tumor activity of Sann-Joong-Kuey-Jian-Tang alone and in combination with 5-fluorouracil in a human colon cancer colo 205 cell xenograft model.

    PubMed

    Cheng, Chun-Yuan; Lin, Yi-Hsiang; Su, Chin-Cheng

    2010-01-01

    Malignant tumors are the leading cause of death in Taiwan; among these, colon cancer ranks third as a cause of cancer-related death. Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicinal prescription, has been used to treat lymph node diseases and infectious lesions, and exhibits cytotoxic activity in many cancer cell lines. Our previous studies demonstrated that SJKJT inhibits the proliferation of human colon cancer colo 205 cells in vitro. The aim of this study was to evaluate the anti-tumor activity of SJKJT alone and in combination with 5-fluorouracil (5-FU) in vivo. SCID mice bearing human colon cancer colo 205 cell xenografts were administered SJKJT alone (30 mg/kg daily, p.o.), SJKJT (30 mg/kg daily, p.o.) in combination with 5-FU (30 mg/kg weekly, i.p.), or vehicle alone. At the end of the 4-week dosing schedule, the tumor and animal body weights were individually measured. The SCID mice were sacrificed with CO2 inhalation, the xenograft tumors were dissected, and the protein expression of microtubule-associated protein light chain 3 (MAP-LC3-II) in colo 205 xenograft tumors was measured by Western blotting. In the control, SJKJT-, and SJKJT plus 5-FU-treated mice, the tumor weights were 6.37±2.57, 0.43±0.35 and 1.63±0.46 g, and the mice body weights were 29±0.55, 29±2.71 and 27±0.77 g, respectively. Treatment with SJKJT resulted in a reduction in tumor weight compared with the control group, indicating that SJKJT inhibits tumor growth in a colo 205 xenograft model. SJKJT also increased LC3-II protein expression as compared to the controls. The present study shows that SJKJT alone or in combination with 5-FU has a positive effect on the treatment of SCID mice bearing human colon cancer colo 205 cell xenografts. This suggests that SJKJT has therapeutic potential in the treatment of human colon cancer.

  17. Experiments on the efficacy and toxicity of locoregional chemotherapy of liver tumors with 5-fluoro-2'-deoxyuridine (FUDR) and 5-fluorouracil (5-FU) in an animal model.

    PubMed

    Bartkowski, R; Berger, M R; Aguiar, J L; Henne, T H; Dörsam, J; Geelhaar, G H; Schlag, P; Herfarth, C

    1986-01-01

    For the investigation of locoregional chemotherapy of liver neoplasms we developed a standardized animal model in the rat. Continuous infusion therapy or repeated bolus injections of FUDR or 5-FU were given via the hepatic artery, the portal vein or the vena cava in tumor-bearing animals. The efficacy of the treatment was determined by measuring the tumor volume 3 weeks after tumor cell implantation. For the evaluation of the local and systemic toxicity serum GOT, GPT, and total bilirubin were determined. DNA single strand breaks were assessed in isolated liver and bone marrow cells. Inhibition of colony formation of bone marrow stem cells was determined by CFU-C and CFU-S bioassay. A significant reduction of tumor growth was observed only after continuous infusion of FUDR via the hepatic artery. Systemic toxicity was lowest in this group for both compounds while the local liver toxicity was only slightly elevated.

  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. Combination treatment of human umbilical cord matrix stem cell-based interferon-beta gene therapy and 5-fluorouracil significantly reduces growth of metastatic human breast cancer in SCID mouse lungs.

    PubMed

    Rachakatla, Raja Shekar; Pyle, Marla M; Ayuzawa, Rie; Edwards, Sarah M; Marini, Frank C; Weiss, Mark L; Tamura, Masaaki; Troyer, Deryl

    2008-08-01

    Umbilical cord matrix stem (UCMS) cells that were engineered to express interferon-beta (IFN-beta) were transplanted weekly for three weeks into MDA 231 breast cancer xenografts bearing SCID mice in combination with 5-fluorouracil (5-FU). The UCMS cells were found within lung tumors but not in other tissues. Although both treatments significantly reduced MDA 231 tumor area in the SCID mouse lungs, the combined treatment resulted in a greater reduction in tumor area than by either treatment used alone. These results indicate that a combination treatment of UCMS-IFN-beta cells and 5-FU is a potentially effective therapeutic procedure for breast cancer.

  20. 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.

  1. 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

  2. Pneumocystis Carinii Pneumonia Following 5-Fluorouracil Administration

    PubMed Central

    Hardy, Robert; Cummings, Clinton; Faulkner, Marquetta; Obianyo, Ifeanyi

    1987-01-01

    A 54-year-old man who had been treated with monthly courses of 5-fluorouracil for one year developed Pneumocystis carinii pneumonia. No evidence of significant, permanent, immunologic impairment was evident one year after the patient became infected. An infection associated with 5-fluorouracil treatment is implicated. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:3501015

  3. 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.

  4. 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.

  5. 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.

  6. Factors predicting efficacy of oxaliplatin in combination with 5-fluorouracil (5-FU) ± folinic acid in a compassionate-use cohort of 481 5-FU-resistant advanced colorectal cancer patients

    PubMed Central

    Bensmaïne, M A; Marty, M; Gramont, A de; Brienza, S; Lévi, F; Ducreux, M; François, E; Gamelin, E; Bleiberg, H; Cvitkovic, E

    2001-01-01

    A statistical analysis was performed on the patient data collected from two compassionate-use programmes using oxaliplatin (Eloxatin®) + 5-fluorouracil (5-FU) ± folinic acid (FA), to identify predictive factors for oxaliplatin-based salvage treatment in patients with 5-FU-resistant advanced colorectal cancer (ACRC). 481 5-FU-resistant ACRC patients, most with performance status ≤ 2, ≥ 3 involved sites, and ≥ 2 prior lines of chemotherapy, received oxaliplatin + 5-FU ± FA. Prognostic factors associated with overall response rate (ORR), time to progression (TTP) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The ORR was 16% (95% CI: 13–20), the median TTP was 4.2 months (95% CI: 3.4–4.6), and the median OS was 9.6 months (95% CI: 8.6–10.6). The multivariate analysis indicated poor (≥ 2 WHO) performance status (PS), a large number of prior chemotherapy regimens (≥ 3), a low baseline haemoglobin level (< 10 g/dl), and a triweekly (vs biweekly) treatment administration schedule as significantly associated (P< 0.05) with a lower ORR. Sex (male), number of organs involved (≥3) and alkaline phosphatase (AP) level (≥ 2 × the upper limit of normal) were associated (P< 0.05) with shorter TTP. Poor PS, a large number of organs involved, and elevated AP were independently and significantly correlated with shorter OS. Our analysis identified a relationship between efficacy results of oxaliplatin + 5-FU ± FA treatment in 5-FU-resistant ACRC patients and baseline prognostic factors related to PS, extent of disease and number of prior regimens. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11506488

  7. Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid.

    PubMed

    Vogt, Ulf; Bielawski, Krzysztof P; Bosse, Ulrich; Schlotter, Claus M

    2004-11-01

    Breast cancer has a significant capacity to metastasize to bone. Bisphosphonates are the standard treatment for hypocalcaemia of malignancy (HCM), which is a common complication of bone metastasis. The combination of bisphosphonates with standard anticancer drugs such as paclitaxel or tamoxifen results in a synergistic apoptotic effect greater than that produced by either single agent alone. Potential antitumour effects in vitro of the two bisphosphonates zoledronic acid (Zol) and ibandronate (Ib) (each at 30 microM) combined with different anticancer drug combinations: cyclophosphamide/metotrexate/5-fluorouracil (CMF), epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET), and epirubicin/docetaxel (EDoc) were investigated using ATP-cell viability assay (ATP-CVA). Twenty cases of female primary, invasive breast cancer were assessed. Ibandronate and zoledronic acid alone showed an inhibitory effect on breast cancer tumour cells in vitro. The breast tumour growth inhibition effect for those two drugs amounted to 22 and 25% respectively. Inhibitory effects were clearly visible for all four combinations of anticancer drugs together with both bisphosphonates. Combinations of anticancer drugs with zoledronic acid seem to be more effective with respect to tumour growth inhibition than combinations with ibandronate.

  8. Cisplatin and Short-Term 5-Fluorouracil Infusion for Paraneoplastic Microangiopathic Hemolytic Anemia in Gastric Cancer: A Case Report and Review of the Literature

    PubMed Central

    Sanatani, M. S.; Lazo-Langner, A.; Al-Rasheedy, I. M.

    2013-01-01

    Microangiopathic hemolytic anemia is a rare paraneoplastic syndrome accompanying adenocarcinoma of the stomach. We report on a patient presenting with anemia due to a combination of severe hemolysis and tumour bleeding, where the combination of cisplatin and 5-fluorouracil in a short course infusional regimen led to a complete response of the hematologic abnormalities in the first line setting. Relapse was successfully treated with second line docetaxel; however the response was relatively short-lived. Overall survival was 16 months from diagnosis, which compares favourably to the survival of other reported cases. The chemotherapy regimens used in previously reported similar cases are reviewed. We suggest that a regimen based on bolus 5-fluorouracil, possibly with a platinum, should be investigated as a possible regimen of choice. PMID:24490094

  9. Exogenous IL-1Ra attenuates intestinal mucositis induced by oxaliplatin and 5-fluorouracil through suppression of p53-dependent apoptosis.

    PubMed

    Wang, Xia; Gao, Jin; Qian, Lan; Gao, Jing; Zhu, Shunying; Wu, Mingyuan; Zhang, Yang; Guan, Wen; Ye, Hao; Yu, Yan; Han, Wei

    2015-01-01

    Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect of many chemoagents, resulting in weight loss, diarrhea, and even death. The current treatments for CIM are palliative and have limited benefit. Interleukin-1 receptor antagonist is a natural antagonist of interleukin-1. Our previous studies showed the protective effect of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on the intestine in mice after 5-fluorouracil chemotherapy. In this study, we further evaluated rhIL-1Ra in the treatment of CIM induced by different chemoagents and their combination. Normal as well as tumor-bearing mice were administered oxaliplatin (L-OHP), 5-fluorouracil, or their combination to induce intestinal mucositis and mortality. rhIL-1Ra administered after the chemotherapy, but not after the onset of diarrhea, significantly improved mouse survival, attenuated body weight loss, and reduced the incidence, severity, and duration of diarrhea. Histological examination showed that rhIL-1Ra-treated mice had a relatively intact mucosa structure, more proliferating crypt cells, and higher acid mucin content than the vehicle-treated mice. rhIL-1Ra suppressed crypt apoptosis by reducing the levels of proapoptotic proteins in wild-type, but not in IL-1RI or p53 mice. In addition, rhIL-1Ra was as effective as octreotide acetate in the treatment of chemotherapy-induced diarrhea, but with the advantage of reducing the epithelial apoptosis, the major cause of CIM. Importantly, the tumor sensitivity to chemotherapy was not affected by rhIL-1Ra. Thus, our data strongly suggest that rhIL-1Ra may be useful for the treatment of intestinal mucositis and improving the quality of life for cancer patients on chemotherapy.

  10. Porokeratosis (Mibelli): treatment with topical 5-fluorouracil.

    PubMed

    McDonald, S G; Peterka, E S

    1983-01-01

    The case history of a patient with a solitary classic porokeratosis (Mibelli) on the hand is described. The lesion cleared without scarring with the use of topical 5-fluorouracil until a strong dermatitis was elicited, thus avoiding surgery and attendant restriction of function. No sign of recurrence developed in the following 2 years. The potential for malignant change in porokeratosis (Mibelli) and its resistance to topical treatment as documented in the literature are also reviewed.

  11. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.

    PubMed

    Liu, Ying; Ren, Zhonghai; Yuan, Long; Xu, Shuning; Yao, Zhihua; Qiao, Lei; Li, Ke

    2016-01-01

    Paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin treatments are effective strategies for patients with advanced esophageal squamous cell carcinoma. This study was to evaluate the safety and efficacy of paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin as first-line chemotherapy for patients with advanced esophageal squamous cell carcinoma. A total of 398 patients with advanced esophageal squamous cell carcinoma who received chemotherapy were included and divided into 2 groups: paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group. 195 patients received paclitaxel plus cisplatin and 203 patients received 5-fluorouracil plus cisplatin. The objective response rates were 42.5% and 38.4% for paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group, respectively (P=0.948). The median progression-free survival was 7.85 months (95% CI, 6.77-8.94 months) for the paclitaxel plus cisplatin group and 6.53 months (95% CI, 5.63-7.43 months) for the 5-fluorouracil plus cisplatin group with significant difference (P=0.02). The median overall survival was 13.46 months (95% CI, 12.01-14.91 months) for the paclitaxel plus cisplatin group and 12.67 months (95% CI, 11.87-13.47 months) for the 5-fluorouracil plus cisplatin group (P=0.204). The first-line chemotherapy of paclitaxel plus cisplatin had better median progression-free survival than 5-fluorouracil plus cisplatin in patients with advanced esophageal squamous cell carcinoma with tolerable toxicities.

  12. Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in the initial treatment of metastatic colorectal cancer: a multicentre two-part phase I/II study

    PubMed Central

    2009-01-01

    Background This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR) inhibitor cetuximab combined with irinotecan, folinic acid (FA) and two different doses of infusional 5-fluorouracil (5-FU) in the first-line treatment of EGFR-detectable metastatic colorectal cancer. Methods The 5-FU dose was selected on the basis of dose-limiting toxicities (DLTs) during part I of the study. Patients received cetuximab (400 mg/m2 initial dose and 250 mg/m2/week thereafter) and every 2 weeks irinotecan (180 mg/m2), FA (400 mg/m2) and 5-FU (either low dose [LD], 300 mg/m2 bolus plus 2,000 mg/m2 46-hour infusion, n = 7; or, high-dose [HD], 400 mg/m2 bolus plus 2,400 mg/m2; n = 45). Results Only two DLTs occurred in the HD group, and HD 5-FU was selected for use in part II. Apart from rash, commonly observed grade 3/4 adverse events such as leucopenia, diarrhoea, vomiting and asthenia occurred within the expected range for FOLFIRI. Among 52 patients, the overall response rate was 48%. Median progression-free survival (PFS) was 8.6 months (counting all reported progressions) and the median overall survival was 22.4 months. Treatment facilitated the resection of initially unresectable metastases in fourteen patients (27%): of these, 10 patients (71%) had no residual tumour after surgery, and these resections hindered the estimation of PFS. Conclusion The combination of cetuximab and FOLFIRI was active and well tolerated in this setting. Initially unresectable metastases became resectable in one-quarter of patients, with a high number of complete resections, and these promising results formed the basis for the investigation of FOLFIRI with and without cetuximab in the phase III CRYSTAL trial. PMID:19366444

  13. Capillary electrophoresis with online stacking in combination with AgNPs@MCM-41 reinforced hollow fiber solid-liquid phase microextraction for quantitative analysis of Capecitabine and its main metabolite 5-Fluorouracil in plasma samples isolated from cancer patients.

    PubMed

    Forough, Mehrdad; Farhadi, Khalil; Molaei, Rahim; Khalili, Hedayat; Shakeri, Ramin; Zamani, Asghar; Matin, Amir Abbas

    2017-01-01

    The purpose of this study is the development and validation of a simple, novel, selective and fast off-line microextraction technique combining capillary electrophoresis with in-column field-amplified sample injection (FASI) for the simultaneous determination of capecitabine (CAP) and its active metabolite, 5-Fluorouracil (5-FU), in human plasma. At the moment, there is a lack of using cost-effective CE tool combined with novel miniaturized sample clean-up techniques for analysis of these important anti-cancer agents in plasma samples. This paper intends to fill this gap and describe a simple off-line sample pretreatment by means of AgNPs@MCM-41 reinforced hollow fiber Solid/Liquid phase microextraction (AgNPs@MCM41-HF-SLPME) with subsequent quantitation by FASI-CE. The separation of analytes was performed using a BGE containing 60mM phosphate-Tris buffer (pH 7) with 10% methanol as an organic modifier. Before sample loading, a short water plug (50mbar, 3s) was injected to permit FASI for stacking. Various parameters affecting the off-line microextraction efficiency as well as FASI were optimized. Migration time was found to be 6.6 (±0.1)min for 5-FU and 7.4 (±0.2)min for CAP. The linearity, precision, accuracy, recovery, selectivity, specificity, stability as well as the robustness of the method was evaluated from spiked plasma samples during the course of validation. The results revealed that the presented technique demonstrates acceptable accuracy and precision, miniaturized sample preparation and a reduced need for complicated equipment along with an acceptable analysis time. The validated method was successfully applied to determine CAP and 5-FU in patient's plasma samples.

  14. A comparison of a 5% potassium hydroxide solution with a 5-fluorouracil and salicylic acid combination in the treatment of patients with anogenital warts: a randomized, open-label clinical trial.

    PubMed

    Işik, Selda; Koca, Rafet; Sarici, Gülben; Altinyazar, Hilmi Cevdet

    2014-09-01

    Anogenital warts are caused by human papillomavirus (HPV), over 30 types of which are infectious for the anogenital tract. Without treatment, warts may regress spontaneously, remain unchanged, or increase in number and size. This study compared the efficacy of a topical 5% potassium hydroxide (KOH) solution with that of a topical 0.5% 5-fluorouracil (5-FU) and 10% salicylic acid (SA) combination in the treatment of anogenital warts. Sixty patients were randomly assigned to receive topical KOH or 5-FU + SA. Both groups demonstrated a significant decrease in numbers of lesions (P < 0.05), but this difference was not significant at week 12 (P > 0.05). The mean number of lesions decreased from baseline to week 12 from 17.03 ± 12.64 to 3.73 ± 7.30 and from 16.13 ± 12.97 to 3.10 ± 4.90 in the KOH and 5-FU + SA groups, respectively (P < 0.001). Excellent clearance was achieved by 70.0 and 76.7% of patients in the KOH and 5-FU + SA groups, respectively. Marked improvement was seen in 13.3 and 20.0% of patients in the KOH and 5-FU + SA groups, respectively. At week 16, relapse was observed in two patients in the KOH group and three in the 5-FU + SA group (P > 0.05). No serious adverse events were reported. Neither treatment was more efficacious. Safety and ease of application are important goals in treatments for anogenital warts. A 5% KOH solution is a promising alternative treatment because it is effective and inexpensive and causes minimal side effects.

  15. 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.

  16. 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.

  17. Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: Updated results of a randomized multicentric trial in advanced head-and-neck cancer

    SciTech Connect

    Semrau, Robert . E-mail: Robert.Semrau@uk-koeln.de; Mueller, Rolf-Peter; Stuetzer, Hartmut; Staar, Susanne; Schroeder, Ursula; Guntinas-Lichius, Orlando; Kocher, Martin; Eich, Hans Theodor; Dietz, Andreas; Flentje, Michael; Rudat, Volker; Volling, Peter; Schroeder, Michael; Eckel, Hans Edmund

    2006-04-01

    Purpose: To prove an expected benefit of concurrent radiochemotherapy (RCT), a two-arm randomized multicentric study was performed. In a subgroup analysis the influence of pretherapeutical hemoglobin level (p-Hb) on survival under locoregional control (SLC) was tested. Patients and Methods: The study included primarily untreated Stage III/IV (International Union Against Cancer [UICC]) oropharyngeal and hypopharyngeal carcinomas. Patients were randomized to receive either hyperfractionated (hf) and accelerated (acc) RCT with two cycles 5-fluorouracil (600 mg/m{sup 2}/day) and carboplatin (70 mg/m{sup 2}/day) on Days 1-5 and 29-33 or hf-acc radiotherapy (RT) alone. Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique. Results: After a median follow-up time of 57 months, SLC is significantly better in RCT than in RT (p = 0.01), with median SLC of 17 months and 11 months, respectively. Also overall survival (OS) shows a benefit for RCT (p 0.016), with a median survival of 23 months for RCT and 16 months for RT. However, the benefit in SLC and OS is not seen in hypopharyngeal carcinomas. In a multivariate analysis of oropharyngeal cancer patients, p-Hb levels lower than 12.7 g/dL resulted in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels >13.8 g/dL did not further improve SLC. Conclusions: Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas. P-Hb levels >13.8 g/dL do not further improve SLC.

  18. Combination of the histone deacetylase inhibitor depsipeptide and 5-fluorouracil upregulates major histocompatibility complex class II and p21 genes and activates caspase-3/7 in human colon cancer HCT-116 cells

    PubMed Central

    Okada, Kouji; Hakata, Shuko; Terashima, Jun; Gamou, Toshie; Habano, Wataru; Ozawa, Shogo

    2016-01-01

    Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 µM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7. Microarray and subsequent gene ontology analyses revealed that compared to 5-FU or depsipeptide alone, the combination treatment of 5-FU and depsipeptide upregulated genes related to cell death and the apoptotic process consistent with the inhibition of colony formation and caspase-3/7 activation. These analyses indicated marked upregulation of antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class (GO:0002504) and MHC protein complex (GO:0042611). Compared with vehicle controls, the cells treated with the combination of 5-FU and depsipeptide showed marked induction (3- to 8.5-fold) of expression of MHC class II genes, but not of MHC class I genes. Furthermore, our global analysis of gene expression, which was focused on genes involved in the molecular regulation of MHC class II genes, showed enhancement of pro-apoptotic PCAF and CIITA after the combination of 5-FU and depsipeptide. These results may indicate a closer relationship between elevation of MHC class II expression and cellular apoptosis induced by the combination of depsipeptide and 5-FU. To the best of our knowledge, this is the first study to report that the combination of 5-FU and depsipeptide induces human colon cancer cell apoptosis in a concerted manner with the induction of MHC class II gene

  19. Sinomenine sensitizes gastric cancer cells to 5-fluorouracil in vitro and in vivo

    PubMed Central

    LIAO, FEI; YANG, ZIRONG; LU, XIAOHONG; GUO, XUFENG; DONG, WEIGUO

    2013-01-01

    Sinomenine (SIN) has been reported to exert antitumor effects in various types of human cancer. The present study aimed to investigate the effects of SIN on gastric cancer and to briefly address its mechanism of action. In this study, the single and combined effects of SIN with 5-fluorouracil (5-FU) on human gastric cancer cells were assessed using an MTT assay, a combination index method and an MKN-28 xenograft mice model. Levels of apoptosis were determined using Hoechst 33258 staining and flow cytometry. Expression levels of certain apoptosis-related proteins were examined by western blotting. mRNA levels of the 5-FU-associated gene, thymidylate synthase (TS), were measured by RT-PCR. The results showed that SIN enhances 5-FU-mediated cellular growth inhibition and apoptosis in gastric cancer cells, reduces TS mRNA accumulation and activates the mitochondrial apoptotic pathway. The same chemotherapy sensitizer effect of SIN was confirmed in vivo. SIN is a promising chemotherapy sensitizer for 5-FU. Our results indicate that this may be a potential combination chemotherapeutic strategy for gastric cancer. PMID:24260052

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

    PubMed

    Patel, Pinaki B; Thakkar, Vasudev R

    2015-03-01

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

  1. Synergy of interleukin 1 and granulocyte colony-stimulating factor: in vivo stimulation of stem-cell recovery and hematopoietic regeneration following 5-fluorouracil treatment of mice

    SciTech Connect

    Moore, M.A.S.; Warren, D.J.

    1987-10-01

    The human bladder carcinoma cell line 5637 produces hematopoietic growth factors (granulocyte and granulocyte/macrophage colony-stimulating factors (G-CSF and GM-CSF)) and hemopoietin 1, which synergizes with CSFs to stimulate colony formation by primitive hematopoietic stem cells in 5-fluorouracil-treated mouse bone marrow. Molecular and functional properties of hemopoietin 1 identified it as identical to interleukin 1..cap alpha.. (IL-1..cap alpha..). When bone marrow cells from 5-fluorouracil-treated mice were cultured in suspension for 7 days with recombinant human IL-1..cap alpha.. and/or G-CSF, it was found that the two factors synergized to enhance recovery of myelopoietic cells and colony-forming cells of both high and low proliferative potential. G-CSF alone did not sustain these populations, but the combination had greater-than-additive stimulating capacity. In vivo, 5-fluorouracil (150 mg/kg) produced profound myelosuppression and delayed neutrophil regeneration for up to 2 weeks in C3H/HeJ mice. Daily administration of recombinant human G-CSF or human IL-1..cap alpha.. accelerated recovery of stem cells, progenitor cells, and blood neutrophils by up to 4 days in 5-fluorouracil-treated C3H/HeJ and B6D2F/sub 1/ mice. The combination of IL-1..cap alpha.. and G-CSF acted synergistically, reducing neutropenia and accelerating recovery of normal neutrophil numbers by up to 7 days. These results indicate the possible therapeutic potential of combination therapy with IL-1 and hematopoietic growth factors such as G-CSF in the treatment of chemotherapy- or radiation-induced myelosuppression.

  2. Anti-EpCAM monoclonal antibody (MAb17-1A) based treatment combined with alpha-interferon, 5-fluorouracil and granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma.

    PubMed

    Liljefors, Maria; Ragnhammar, Peter; Nilsson, Bo; Ullenhag, Gustav; Mellstedt, Håkan; Frödin, Jan-Erik

    2004-09-01

    Monoclonal antibodies (MAbs) have different modes of action and toxicity profile compared to chemotherapeutics, which makes it interesting to combine these drugs. Addition of cytokines to MAb therapy may also augment immune effector functions utilized by MAb. In an effort to improve the therapeutic effect of a MAb-based regimen in colorectal carcinoma (CRC) patients, the effects of a combination of alpha-interferon (alpha-IFN), 5-fluorouracil (5-FU), granulocyte-macrophage colony-stimulating factor (GM-CSF) and mouse MAb17-1A was evaluated in 27 patients with metastatic disease. alpha-IFN was given s.c. once daily for 5 consecutive days and at days 4 and 5, 5-FU was administered as a daily i.v. bolus injection. After 2 days rest, GM-CSF was given s.c. once daily, days 8-14 and on day 10, MAb17-1A was given i.v. The treatment cycle was repeated every 4th week. One patient achieved a partial remission and 13 patients showed a minor response or stable disease >3 months, inducing an overall response rate of 54%. Responding patients survived significantly longer than non-responding patients (p=0.021). Median overall survival time for all patients was 75 weeks and progression-free survival time 15 weeks. Adverse events related to alpha-IFN, GM-CSF and 5-FU were as expected. The frequency of patients with an immediate-type allergic reaction (ITAR) against MAb17-1A at the 1st, 2nd, 3rd and 4th treatment cycles was 11%, 52%, 62% and 64% respectively. The planned MAb17-1A dose had to be reduced by repeated infusions. No patient received full dose of MAb17-1A from the 3rd cycle and onward. Compared to historical control patients treated with MAb17-1A alone, the present combination regimen seemed to improve the response rate (54% vs 15%) as well as progression-free survival (15 vs 7 weeks; p<0.05).

  3. Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.

    PubMed

    Mani, Sridhar; Rudin, Charles M; Kunkel, Katie; Holmlund, Jon T; Geary, Richard S; Kindler, Hedy L; Dorr, F Andrew; Ratain, Mark J

    2002-04-01

    The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor

  4. 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.

  5. 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

  6. Antitoxic Activity of Extract from Salix Viminalis Leaves under Conditions of 5-Fluorouracil Treatment.

    PubMed

    Aksinenko, S G; Suslov, N I; Povet'eva, T N; Nesterova, Yu V; Kharina, T G; Kravtsova, S S

    2015-11-01

    Injection of 5-fluorouracil to animals caused a pronounced toxic effect. Therapeutic and preventive treatment with Salix viminalis leaf extract significantly reduced the negative effects of the antitumor drug: promoted recovery of the bone marrow, peripheral blood, and visceral parameters and prevented ulceration. Combined use of the cytostatic and Salix viminalis extract increased the efficiency of antitumor therapy.

  7. 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.

  8. Bioavailability and feasibility of subcutaneous 5-fluorouracil.

    PubMed

    Borner, M M; Kneer, J; Crevoisier, C; Brunner, K W; Cerny, T

    1993-09-01

    Continuous intravenous (i.v.) infusion of 5-fluorouracil (5-FU) has been shown to be superior to bolus regimens in terms of response rates and toxicity. However, a continuous infusion is more expensive and prone to complications such as thromboembolism and infections. A way to circumvent these problems would be to administer 5-FU subcutaneously (s.c.). To assess feasibility and bioavailability of s.c. 5-FU, eight patients with advanced cancer received 250 mg 5-FU as an infusion over 90 min either intravenously (i.v.) or s.c. into the abdominal wall. The mean +/- s.d. bioavailability of s.c. 5-FU was 0.89 +/- 0.23. The interpatient variability for the area under the plasma concentration-time curve was 48% for the s.c. and 36% for the i.v. infusion. No local side effects were observed. To test the local tolerance of a more prolonged administration three patients received 930-1,000 mg m-2 5-FU by 24-h continuous s.c. infusion. The steady-state plasma levels were comparable to i.v. infusion. One patient developed a painless skin pigmentation at the s.c. infusion site. However, the same reaction was observed at the forearm after i.v. infusion. We conclude that at the dose studied s.c. 5-FU has an almost complete bioavailability and is well tolerated. Further work will show, whether prolonged s.c. infusion can be used as a safe and economical alternative to i.v. infusion.

  9. Bioavailability and feasibility of subcutaneous 5-fluorouracil.

    PubMed Central

    Borner, M. M.; Kneer, J.; Crevoisier, C.; Brunner, K. W.; Cerny, T.

    1993-01-01

    Continuous intravenous (i.v.) infusion of 5-fluorouracil (5-FU) has been shown to be superior to bolus regimens in terms of response rates and toxicity. However, a continuous infusion is more expensive and prone to complications such as thromboembolism and infections. A way to circumvent these problems would be to administer 5-FU subcutaneously (s.c.). To assess feasibility and bioavailability of s.c. 5-FU, eight patients with advanced cancer received 250 mg 5-FU as an infusion over 90 min either intravenously (i.v.) or s.c. into the abdominal wall. The mean +/- s.d. bioavailability of s.c. 5-FU was 0.89 +/- 0.23. The interpatient variability for the area under the plasma concentration-time curve was 48% for the s.c. and 36% for the i.v. infusion. No local side effects were observed. To test the local tolerance of a more prolonged administration three patients received 930-1,000 mg m-2 5-FU by 24-h continuous s.c. infusion. The steady-state plasma levels were comparable to i.v. infusion. One patient developed a painless skin pigmentation at the s.c. infusion site. However, the same reaction was observed at the forearm after i.v. infusion. We conclude that at the dose studied s.c. 5-FU has an almost complete bioavailability and is well tolerated. Further work will show, whether prolonged s.c. infusion can be used as a safe and economical alternative to i.v. infusion. PMID:8353044

  10. Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma.

    PubMed

    Rani, Isha; Sharma, Bhoomika; Kumar, Sandeep; Kaur, Satinder; Agnihotri, Navneet

    2017-03-01

    5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell-associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.

  11. Spray Dried Formulation of 5-Fluorouracil Embedded with Probiotic Biomass: In Vitro and In Vivo Studies.

    PubMed

    Sharma, Anshul; Arora, Malika; Goyal, Amit K; Rath, Goutam

    2017-03-08

    The present study is utilizing the targeted therapeutic approach and antioxidant potential of selected probiotic biomass in mitigating toxic side effects of chemotherapeutic agents. Multicomponent carrier system consisting of 5-fluorouracil (5-FU) and selected probiotic strain with higher free radical scavenging activity was prepared using spray drying technique. Prepared spray dried microparticles were characterized for various physical, pharmaceutical, and biopharmaceutical properties including particle size, moisture content, entrapment efficiency, in vitro drug release, DSC, XRD, cell uptake, histopathology, and pharmacokinetic studies. In addition to the above, optimized formulation was subjected to in vivo targeting efficacy studies using radiographic technique. Optimized formulation meets the necessary physical requirement for pharmaceutical powder. X-ray studies revealed that the prepared spray dried formulations are able to target the colon. Pharmacokinetic endpoints with an extended t 1/2 and lower C max indicate lower systemic toxicity. Intact nature of colonic epithelium in experimental formulation clearly demonstrates the protective role of Lactobacillus rhamnosus in minimizing the harmful consequence induced by 5-FU. Existing outcomes provide the basis for a combination of targeted therapeutic approach with natural antioxidant capacity of potential probiotic strain which could help to mitigate the problems associated with traditional chemotherapy.

  12. [Dihydropirymidine dehydrogenase (DPD)--a toxicity marker for 5-fluorouracil?].

    PubMed

    Jedrzychowska, Adriana; Dołegowska, Barbara

    2013-01-01

    In proceedings relating to patients suffering from cancer, an important step is predicting response and toxicity to treatment. Depending on the type of cancer, physicians use the generally accepted schema of treatment, for example pharmacotherapy. 5-fluorouracil (5-FU) is the most widely used anticancer drug in chemotherapy for colon, breast, and head and neck cancer. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency, which is responsible for the metabolism of 5-FU, may experience severe side effects during treatment, and even death. In many publications the need for determining the activity of DPD is discussed, which would protect the patient from the numerous side effects of treatment. However, in practice these assays are not done routinely, despite the high demand. In most cases, a genetic test is used to detect changes in the gene encoding DPD (such as in the USA), but because of the large number of mutations the genetic test cannot be used as a screening test. Dihydropyrimidine dehydrogenase activity has been shown to have high variability among the general population, with an estimated proportion of at least 3-5% of individuals showing low or deficient DPD activity. In this publication we presents data about average dihydropirymidine dehydrogenase activity in various populations of the world (e.g. Japan, Ghana, Great Britain) including gender differences and collected information about the possibility of determination of DPD activity in different countries. Detection of reduced DPD activity in patients with planned chemotherapy will allow a lower dosage of 5-FU or alternative treatment without exposing them to adverse reactions.

  13. Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity.

    PubMed

    Peters, Eric J; Kraja, Aldi T; Lin, Shiow J; Yen-Revollo, Jane L; Marsh, Sharon; Province, Michael A; McLeod, Howard L

    2009-05-01

    Identifying relevant cytotoxicity genes using an ex-vivo lymphoblastoid cell line (LCLs) model has distinct advantages for pharmacogenomic discovery studies of cancer chemotherapy, including standardized treatment conditions, availability of large numbers of samples, and publicly available genotypic data. However, there is little proof of principal data to confirm the promise of this approach. One of the known targets of 5-fluorouracil (5-FU) treatment is thymidylate synthase (TYMS). We hypothesized that genetic variants in TYMS would alter cytotoxicity because of 5-FU treatment using a LCL model system. LCLs from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees (N=427) were treated with eight concentrations of 5-FU for 72 h, and cytotoxicity was determined using an Alamar Blue assay. For a subset of the 30 International Haplotype Mapping project (HapMap) trios, genotype data for 46 single-nucleotide polymorphism (SNP) variants encompassing the TYMS gene were downloaded from the HapMap website. Using a mixed models approach, each SNP was tested for association to 5-FU cytotoxicity in the subset of HapMap trios. Putatively associated SNPs (P<0.01), were then genotyped in the remaining LCLs in the CEPH pedigrees and tested for association. Two intronic SNPs in TYMS (rs2847153 and rs2853533) were significantly associated (P<0.01) with 5-FU cytotoxicity in the HapMap subset using the mixed models approach. After genotyping these SNPs in the full CEPH pedigrees, the associations with cytotoxicity showed a more reliable significance (P<0.0005), as a result of the increase in sample size. These results highlight the importance of the TYMS gene variants in response to 5-FU treatment. Furthermore, they provide additional biological validation of the relevance of LCLs as a model for pharmacogenomic gene discovery in cancer chemotherapy.

  14. Rationale for combining immunotherapy with chemotherapy.

    PubMed

    Dalgleish, Angus G

    2015-01-01

    Immunotherapy has usually been considered as an alternative to more traditional modalities. Moreover, it has previously been felt that chemotherapy is inherently immunosuppressive and not suitable for combining with immunotherapy. In this review, the concept of combining different modalities that result in cell death, such as radiotherapy and chemotherapy, with immunotherapy is explored. Tumors actively cause immune suppression which can be reversed by their removal but when this is not possible, enhancing the immune response with nonspecific immune stimulation can enhance the response to other modalities, such as radiotherapy and chemotherapy. Additionally, several chemotherapy agents at low doses selectively inhibit regulatory and suppressor cells.

  15. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer

    PubMed Central

    Liu, Ying; Ren, Zhonghai; Yuan, Long; Xu, Shuning; Yao, Zhihua; Qiao, Lei; Li, Ke

    2016-01-01

    Paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin treatments are effective strategies for patients with advanced esophageal squamous cell carcinoma. This study was to evaluate the safety and efficacy of paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin as first-line chemotherapy for patients with advanced esophageal squamous cell carcinoma. A total of 398 patients with advanced esophageal squamous cell carcinoma who received chemotherapy were included and divided into 2 groups: paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group. 195 patients received paclitaxel plus cisplatin and 203 patients received 5-fluorouracil plus cisplatin. The objective response rates were 42.5% and 38.4% for paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group, respectively (P=0.948). The median progression-free survival was 7.85 months (95% CI, 6.77-8.94 months) for the paclitaxel plus cisplatin group and 6.53 months (95% CI, 5.63-7.43 months) for the 5-fluorouracil plus cisplatin group with significant difference (P=0.02). The median overall survival was 13.46 months (95% CI, 12.01-14.91 months) for the paclitaxel plus cisplatin group and 12.67 months (95% CI, 11.87-13.47 months) for the 5-fluorouracil plus cisplatin group (P=0.204). The first-line chemotherapy of paclitaxel plus cisplatin had better median progression-free survival than 5-fluorouracil plus cisplatin in patients with advanced esophageal squamous cell carcinoma with tolerable toxicities. PMID:27822423

  16. Treatment of corneal squamous cell carcinoma using topical 1% 5-fluorouracil as monotherapy.

    PubMed

    Dorbandt, Daniel M; Driskell, Elizabeth A; Hamor, Ralph E

    2016-05-01

    The purpose of this report is to discuss the use of topical 1% 5-fluorouracil as a sole therapy for canine corneal squamous cell carcinoma (SCC). A 12-year-old castrated male pug was evaluated for a well-demarcated, central, 3 mm in diameter, pale pink, raised, right corneal mass. An incisional biopsy was obtained using a #64 beaver blade after topical anesthesia and without sedation. A definitive diagnosis of corneal SCC was obtained after histopathologic evaluation of the biopsy. Topical 1% 5-fluorouracil ointment was applied to the right eye four times daily for 2 weeks followed by no treatment for 2 weeks, then treatment again twice daily for 2 weeks. The cornea remained free of recurrence 10 months after cessation of treatment. In dogs affected with corneal SCC, topical 1% 5-fluorouracil monotherapy may be a viable and cost-effective treatment option with minimal side effects. This chemotherapy agent may also have an effect on corneal pigmentation. Chronic cyclosporine therapy did not contribute to the pathogenesis of corneal SCC in the case described.

  17. Synthesis of PEGylated fullerene-5-fluorouracil conjugates to enhance the antitumor effect of 5-fluorouracil

    NASA Astrophysics Data System (ADS)

    Dou, Zengpei; Xu, Yingying; Sun, Hongfang; Liu, Yuanfang

    2012-07-01

    Many drugs have been delivered by different types of nanoscale vehicles to enhance their therapeutic efficacy. 5-Fluorouracil (5FU) is a widely used antitumor drug, however its bioavailability still needs to be improved. Herein we synthesized a polyethylene glycol monomethylether-C60-5FU conjugate (mPEG-C60-5FU) and evaluated its antitumor efficacy in vitro. The results show that the inhibition abilities of mPEG-C60-5FU to the human breast cancer cell line MCF-7 and the human gastric carcinoma cell line BGC-823 are significantly higher than that of 5FU. The conjugate has good stability in murine serum for at least 24 h. Moreover, the PEGylated fullerene (mPEG-C60) vehicle is non-toxic to MCF-7 cells. These results demonstrate that mPEG-C60 is an efficient vehicle for the delivery of 5FU.

  18. 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.

  19. 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

  20. Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats.

    PubMed

    Friberg, L E; Freijs, A; Sandström, M; Karlsson, M O

    2000-11-01

    Models of leukopenia after chemotherapy are mainly empirical. To increase the derived models' potential of mechanistic understanding and extrapolation, more physiologically based models are being developed. To date, presented models cannot characterize the often-observed rebound of leukocytes. Therefore, a model able to describe the transient decrease and rebound in leukocytes was developed. Three different dosing regimens of 5-fluorouracil were given to rats. One group received a single dose of 127 mg/kg. The other two groups received two and three injections of 63 mg/kg and 49 mg/kg, respectively, with a 2-day interval. Leukocyte counts were followed for 23 to 25 days after the first dose. Plasma concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic and pharmacodynamic models were developed using NONMEM. 5-Fluorouracil showed one-compartment disposition with capacity-limited elimination. The 49-mg/kg dose injected on three occasions produced the lowest leukocyte count (28% of baseline) and the most prominent rebound of the schedules, despite the fact that the fractionated regimens produced only 52 to 56% of the area under the concentration-time curve from time 0 to infinity in the single-dose group. The final semiphysiological model included two 5-fluorouracil-sensitive and two -insensitive transit compartments as well as a compartment of circulating leukocytes. Second order rate constants from the transit compartments and a negative feedback from the circulating leukocytes to the input of the first sensitive compartment characterized the pronounced changes in leukocyte counts. A posterior predictive check as well as predictions into a new data set showed that our model could well predict the schedule-dependent leukopenic effects of 5-fluorouracil.

  1. 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.

  2. The synergistic effect of organic silicone quaternary ammonium salt and 5-fluorouracil on hepatocellular carcinoma in vitro and in vivo.

    PubMed

    Wang, Juan-Xia; Zhang, Ling-Yi; Zhang, Jun; Ding, Hui; Wang, Dong-Min; Wang, Zhi-Ping

    2014-09-01

    Hepatocellular carcinoma (HCC) is the third most common type of cancer worldwide, causing over 370,000 deaths per year, with approximately half of them in China. Chemotherapy is the optimal treatment for patients with advanced HCC, although chemoresistance has become a significant obstacle to successful liver cancer surgery. In this paper, we have assessed the characteristics of drugs to explore the effects of individual and combined action of organic silicone quaternary ammonium salt (Jieyoushen) and 5-fluorouracil (5-FU). The results of MTT assays showed that single and combined action of Jieyoushen and 5-FU can inhibit the proliferation of liver carcinoma cell lines in a dose-dependent and time-dependent manner, respectively. Electron microscopy and Hoechst 33342 staining showed characteristic apoptotic bodies in apoptotic cells treated with Jieyoushen and 5-FU. Flow cytometry results indicated that the percentage of cells at G0/G1 phase gradually increased, whereas it gradually decreased during the S phase after treatment. Taken together, these results suggest that the combination of Jieyoushen with 5-FU exerts a synergistic anticancer effect on HCC growth and that targeted therapeutic strategies may improve HCC sensitivity to chemotherapy.

  3. 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

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

    PubMed

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

    2015-01-22

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

  5. Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin: nonclinical safety and pharmacokinetics.

    PubMed

    Gaudreault, Jacques; Shiu, Vanessa; Bricarello, Ann; Christian, Brian J; Zuch, Christina L; Mounho, Barbara

    2005-01-01

    Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor approved for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic colorectal cancer. The Saltz regimen (irinotecan/5-FU/leucovorin [LV]) is a first-line treatment for this indication. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with the Saltz regimen to cynomolgus monkeys, and to determine if the pharmacokinetics of bevacizumab, irinotecan, SN38 (the active metabolite of irinotecan), or 5-FU were affected by combined administration. Male cynomolgus monkeys were intravenously administered the Saltz regimen (125 mg/m2 irinotecan, 500 mg/m2 5-FU, 20 mg/m2 LV) alone (n = 4) or concomitantly with 10 mg/kg bevacizumab (n = 5) on days 1 and 8. All animals survived to euthanasia on day 15. Adverse effects associated with the Saltz regimen included diarrhea and neutropenia. Macroscopically, two animals from each group had small thymus glands that correlated microscopically with lymphoid depletion. Myeloid hypoplasia and/or erythroid hyperplasia was observed in the sternal bone marrow of most animals. These effects were considered to be associated with the Saltz regimen; concomitant bevacizumab administration did not alter the severity of these findings. Irinotecan and 5-FU were observed to be rapidly eliminated (t1/2 = 1 h and 0.5 h, respectively). Although the number of animals in each group was small and no statistical comparison between groups was performed, bevacizumab did not affect the disposition of either agent. These results indicate that bevacizumab can be safely administered in combination with the Saltz regimen without pharmacokinetic interaction.

  6. Successful Treatment of Calcium Hydroxylapatite Nodules With Intralesional 5-Fluorouracil, Dexamethasone, and Triamcinolone.

    PubMed

    Aguilera, Shino Bay; Aristizabal, Miguel; Reed, Ann

    2016-09-01

    Although infrequent, non-inflammatory nodules are potential complications associated with dermal filler injections. There is a lack of consensus in the literature regarding potential treatments to help resolve nodules associated with calcium hydroxylapatite (CaHA) filler injections. This case report describes the successful treatment of a non-inflammatory nodule related to CaHA injection using a combination of 5-fluorouracil, dexamethasone, and triamcinolone.

    J Drugs Dermatol. 2016;15(9):1142-1143.

  7. 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.

  8. 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.

  9. Phase II clinical trial of cisplatin, 5-fluorouracil, and ifosfamide as treatment for advanced locoregional head and neck carcinoma.

    PubMed

    Sánchez Parra, M; Churruca, C; Paredes, A; Lacasta, A; López de Argumedo, G; Alvárez, I; Abad, T; Egana, L; Guimón, E; Piera, J M

    1999-02-01

    The association of ifosfamide with cisplatin and 5-fluorouracil for the management of advanced squamous cell carcinoma of the head and neck was assessed in this trial. Ifosfamide was given initially to 12 patients in combination with standard fixed doses of cisplatin and 5-fluorouracil, at 1,000 mg/m2 daily on days 2, 3, and 4. Two patients died of neutropenia and severe infection, and the authors recruited seven more patients who were treated with a lower dose of ifosfamide, 800 mg/m2 daily on days 2, 3, and 4. One of the seven patients died of neutropenia and severe infection. Three complete remission were observed in 18 patients evaluable for efficacy. The study was closed early because of the severe toxicity profile demonstrated by this scheme and because of no clear advantage in efficacy versus cisplatin plus 5-fluorouracil combinations.

  10. Combination chemotherapy in vitro exploiting glutamine metabolism of human glioma and medulloblastoma.

    PubMed

    Dranoff, G; Elion, G B; Friedman, H S; Bigner, D D

    1985-09-01

    The human glioma-derived cell line D-54 MG and the human medulloblastoma-derived cell line TE-671 have been shown to be sensitive in culture to the pharmacological interference with glutamine metabolism by acivicin, 6-diazo-5-oxo-L-norleucine, and methionine sulfoximine. Using as a guide the multiple contributions of glutamine to the biosynthesis of proteins, purines, and pyrimidines, we now have identified six additional antimetabolites active against these lines in vitro at clinically relevant concentrations. The 50% growth-inhibitory levels of the drugs against D-54 MG in 6-day continuous exposure experiments were: L-asparaginase, 0.057 IU/ml; 5-fluorouracil, 0.5 micrograms/ml; 6-mercaptopurine, 0.8 micrograms/ml; actinomycin D, 0.0007 micrograms/ml; N-phosphonacetyl-L-aspartic acid, 2.3 micrograms/ml; and 5-azacytidine, 0.2 micrograms/ml (3-day exposure. The corresponding 50% growth-inhibitory values in TE-671 were: L-asparaginase, 0.54 IU/ml; 5-fluorouracil, 1.5 micrograms/ml; 6-mercaptopurine, 4.7 micrograms/ml; actinomycin D, 0.00044 micrograms/ml; N-phosphonacetyl-L-aspartic acid, 4.5 micrograms/ml; and 5-azacytidine, 0.49 micrograms/ml. Dipyridamole up to 10 micrograms/ml was inactive against both lines. The isobologram method was used to evaluate the effectiveness of several two-drug combinations which were biochemically designed. The sums of the optimal fractional inhibitory concentrations for the pairs were: acivicin plus L-asparaginase, 0.14; acivicin plus methionine sulfoximine, 0.40; 6-diazo-5-oxo-L-norleucine plus methionine sulfoximine, 0.60; acivicin plus 6-mercaptopurine, 1.0, all in TE-671; and acivicin plus 5-fluorouracil, 0.79, in D-54 MG. Our findings suggest that an antimetabolite regimen exploiting glutamine sensitivity might improve the chemotherapy of some human gliomas and medulloblastomas.

  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. Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis

    PubMed Central

    Guo, Jian-Hai; Zhang, Hang-Yu; Gao, Song; Zhang, Peng-Jun; Li, Xiao-Ting; Chen, Hui; Wang, Xiao-Dong; Zhu, Xu

    2017-01-01

    AIM To evaluate the efficiency and safety of hepatic artery infusion chemotherapy (HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer (CRC) liver metastasis (CRCLM). METHODS A retrospective analysis of patients with unresectable CRCLM who failed systemic chemotherapy and were subsequently treated with HAIC at our institute from May 2013 to April 2015 was performed. A total of 24 patients were treated with 5-fluorouracil, and 18 patients were treated with raltitrexed. RESULTS The median survival time (MST) from diagnosis of CRC was 40.8 mo in the oxaliplatin plus raltitrexed (TOMOX) arm and 33.5 mo in the oxaliplatin plus 5-fluorouracil (FOLFOX) arm (P = 0.802). MST from first HAIC was 20.6 mo in the TOMOX arm and 15.4 mo in the FOLFOX arm (P = 0.734). Median progression-free survival (PFS) from first HAIC was 4.9 mo and 6.6 mo, respectively, in the TOMOX arm and FOLFOX arm (P = 0.215). Leukopenia (P = 0.026) was more common in the FOLFOX arm, and hepatic disorder (P = 0.039) was more common in the TOMOX arm. There were no treatment-related deaths in the TOMOX arm and one treatment-related death in the FOLFOX arm. Analysis of prognostic factors indicated that response to HAIC was a significant factor related to survival. CONCLUSION No significant difference in survival was observed between the TOMOX and FOLFOX arms. HAIC treatment with either TOMOX or FOLFOX was demonstrated as an efficient and safe alternative choice. PMID:28293087

  13. Downregulation of caveolin-1 increases the sensitivity of drug-resistant colorectal cancer HCT116 cells to 5-fluorouracil

    PubMed Central

    Li, Zhaoyang; Wang, Ning; Huang, Changxin; Bao, Yanhong; Jiang, Yiqian; Zhu, Guiting

    2017-01-01

    Colorectal cancer is the third most common type of cancer in men and women. Chemotherapy is an important treatment strategy for patients with terminal stage cancer. However, the development of drug resistance hampers the effectiveness of chemotherapy. Therefore, an effective therapeutic approach to target chemoresistance-associated cellular molecules is required. In the present study, drug-resistant human colorectal cancer HCT116 cells were developed by treating HCT116 cells with increasing concentrations of 5-fluorouracil (5-FU). The present study indicated that the drug-resistance cells (DRC) were resistant to 5-FU compared with parental HCT116 cells by detecting cell survival using an MTT assay. Additionally, the expression of the chemoresistance-associated protein caveolin-1 (Cav-1) was assessed by reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that the Cav-1 expression level was significantly higher in DRC compared with that in the parental HCT116 cells. Next, Cav-1 was silenced by small interfering RNA (siRNA) or was inhibited with its specific inhibitor methyl β-cyclodextrin (MCD). MTT assay demonstrated that Cav-1 siRNA and MCD resensitized DRC to 5-FU. These data reveal that Cav-1 was involved in the development of resistance, suggesting that Cav-1 is a potential target for the treatment of colorectal cancer chemoresistance. In addition, 5-FU combined with Cav-1 siRNA or its specific inhibitor may increase the effectiveness of the treatment strategy. PMID:28123586

  14. 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.

  15. Iontophoretic delivery of 5-fluorouracil through excised human stratum corneum.

    PubMed

    Singh, B N; Jayaswal, S B

    2008-04-01

    The objective of this study was to determine the effects of ionization, current density and penetration enhancers on the iontophoretic delivery of 5-fluorouracil (5-FU) through excised human stratum corneum (HSC). The iontophoretic (cathodal) transport of 5-FU was assessed in vitro at three physiologically relevant pH values of 5.0, 7.4 and 8.0, at various levels of current density ranging between 0.15 to 0.98 mA/cm2, and in the presence of suitable penetration enhancers, namely Azone(®) (AZ), lauryl alcohol (LA), and isopropyl myristate (IPM). The steady-state flux at constant current density (0.47 mA/cm(2)) was increased by approximately 19, 10 and 27 fold at pH 5, 7.4 and 8.0, respectively. The effect of current density at pH 7.4 exhibited a linear correlation between current density and steady-state flux (r = 0.98, p = 0.002), which indicates the potential of iontophoresis for controlled transdermal delivery of 5-FU. The combination of cathodal iontophoresis with IPM produced an additive enhancement which may be attributed to aggravated skin perturbation effect and increased skin conductivity. Other enhancers such as AZ and LA produced negative or no further enhancement respectively, when used in conjunction with cathodal iontophoresis. It may be therefore concluded that pH and current density play critical role during iontophoretic delivery of 5-FU, and combination of a chemical penetration enhancer and iontophoresis can not be always viewed as a synergistic strategy which should be evaluated on a case-by-case basis for each drug candidate/enhancer combination.

  16. Oral Administration of Surface-Deacetylated Chitin Nanofibers and Chitosan Inhibit 5-Fluorouracil-Induced Intestinal Mucositis in Mice

    PubMed Central

    Koizumi, Ryo; Azuma, Kazuo; Izawa, Hironori; Morimoto, Minoru; Ochi, Kosuke; Tsuka, Takeshi; Imagawa, Tomohiro; Osaki, Tomohiro; Ito, Norihiko; Okamoto, Yoshiharu; Saimoto, Hiroyuki; Ifuku, Shinsuke

    2017-01-01

    This study investigated the prophylactic effects of orally administered surface-deacetylated chitin nanofibers (SDACNFs) and chitosan against 5-fluorouracil (5-FU)-induced intestinal mucositis, which is a common side effect of 5-FU chemotherapy. SDACNFs and chitosan abolished histological abnormalities associated with intestinal mucositis and suppressed hypoproliferation and apoptosis of intestinal crypt cells. These results indicate that SDACNF and chitosan are useful agents for preventing mucositis induced by anti-cancer drugs. PMID:28134832

  17. Erythroplasia of Queyrat treated with topical 5-fluorouracil*

    PubMed Central

    Antônio, João Roberto; Antônio, Carlos Roberto; Trídico, Lívia Arroyo; Alves, Fernanda Tomé; Rollemberg, Ivan

    2016-01-01

    We report a 33-year-old male patient diagnosed with erythroplasia of Queyrat. The patient had an erythematous and eroded lesion affecting more than 50% of the glans associated with bleeding and local pain. Despite previous indication of penectomy, he was successfully treated with topical 5-fluorouracil.

  18. 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.

  19. 5-fluorouracil toxicity in the treatment of colon cancer associated with the genetic polymorphism 2846 A>G (rs67376798).

    PubMed

    González-Perera, Itamar; Gutiérrez-Nicolás, Fernando; Nazco-Casariego, Gloria J; Ramos-Díaz, Ruth; Hernández-San Gil, Raquel; Pérez-Pérez, José A; González García, Jonathan; González De La Fuente, Guillermo A

    2016-04-27

    Colorectal cancer is the second most common cancer in Europe. Most antineoplastic regimens in first-line treatment involve 5-fluorouracil or oral prodrug capecitabine, combined with other antineoplastic agents such as oxaliplatin or irinotecan. It is well known that 5-fluorouracil and capecitabine are agents that can be toxic in cases of decreased dihydropyrimidine dehydrogenase activity because this enzyme is the main limiting factor in the metabolism of both agents. In this paper, we describe the case of a patient who developed severe toxicity to 5-fluouracil and who had a mutation in the gene encoding the enzyme dihydropyrimidine dehydrogenase.

  20. Structural analysis of 5-fluorouracil and thymine solid solutions

    NASA Astrophysics Data System (ADS)

    Vogt, Frederick G.; Vena, Joseph A.; Chavda, Manisha; Clawson, Jacalyn S.; Strohmeier, Mark; Barnett, Maria E.

    2009-08-01

    Solid-state analysis with powder X-ray diffraction (PXRD), solid-state NMR (SSNMR), and other spectroscopic and physical methods can provide detailed structural information about organic and pharmaceutical cocrystals. In this study, a range of solid-state analysis methods are used to characterize co-crystallized solid solutions of 5-fluorouracil and thymine. 1H, 13C and 19F SSNMR and PXRD methods are used to study the structure and disorder present in a solid solution previously prepared by solution evaporation methods; here the solid solution is prepared over a wider stoichiometric range by solvent-drop grinding techniques. Long-range perturbations of key chemical shifts are detectable by SSNMR, indicating that the solid solution is not random. Cross-polarization and heteronuclear correlation SSNMR experiments between 1H, 13C, and 19F nuclei offer insight into the structure of this solid solution, and density functional theory (DFT) methods are applied to calculate lattice energies and NMR properties in order to understand the population of the two primary disordered sites in the crystal structure. In addition, a second solid solution of 5-fluorouracil and thymine is reported and analyzed. This solid solution, which was produced by solvent-drop grinding experiments and characterized by SSNMR and powder X-ray diffraction methods, is determined to be an isostructural phase to that of anhydrous thymine with the inclusion of 5-fluorouracil defects. A similar effect does not occur under excess 5-fluorouracil conditions; instead, phase-separated Form 1 of 5-fluorouracil and anhydrous thymine are obtained. DFT calculations are applied to offer a possible explanation for this disparity.

  1. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells

    PubMed Central

    2010-01-01

    Background Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells. Methods HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed. Results 5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21Cip1 and p27Kip1 and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti

  2. Synergistic effect of puerarin and 5-fluorouracil on hepatocellular carcinoma.

    PubMed

    Zeng, Yan-Ping; Yang, Zi-Rong; Guo, Xu-Feng; Jun, Wang; Dong, Wei-Guo

    2014-12-01

    Hepatocellular carcinoma (HCC) is one of the most common types of human malignancy worldwide, which is becoming increasingly resistant to traditional drug treatments. Puerarin combined with 5-fluorouracil (5-FU) may be a useful treatment for liver cancer. The primary aim of the present study was to determine whether combined treatment with 5-FU and puerarin is more effective against the hepatocellular carcinoma (HCC) cell line, SMMC7721, than treatment with 5-FU or puerarin alone. The growth inhibition of SMMC7721 cells by puerarin or 5-FU alone or in combination was determined by the Cell Counting Kit-8 assay, in vitro. Apoptotic morphological features and the percentage of apoptotic cells were detected using Hoechst 33258 staining and an Annexin V/PI apoptosis kit, respectively. In addition, a tumor xenograft model was established in nude mice using SMMC7721 cells. Puerarin and 5-FU alone or in combination were injected into the mice, and the inhibition of tumor growth was evaluated by monitoring tumor volume and weight. Treatment with 6,400 or 640 μM 5-FU resulted in growth inhibition of 95.56±0.81 and 75.91±3.54%, respectively. The combination index values were <1 when the fraction of affected cells was between 0.2555 and 0.7420. Furthermore, the percentage of apoptotic cells was markedly increased in the combined treatment group when compared with that of the individual treatment groups, in vitro and in vivo. Individual treatment with puerarin resulted in a tumor volume inhibition rate (IR) of 70.58% and a tumor weight IR of 46.20%. Treatment with 5-FU was found to decrease the tumor volume by 76.26% and tumor weight by 49.86%. In the combined treatment group, the tumor volume and weight IRs were 93.11 and 75.21%, respectively. A marked increase in the inhibition of tumor growth and the number of apoptotic cells in response to combined treatment with puerarin and 5-FU was identified with no observed liver or renal toxicity. These results suggest that

  3. [Combination chemotherapy of experimental leukemia].

    PubMed

    Emanuel', N M; Konovalova, N P; D'iachkovskaia, R F

    1977-01-01

    In the present work an attempt was made to gain greater therapeutic effect of diazane coupled with adriamycin and sarcolysin. Leucemias L-1210 and La served as a model. In leucosis La diazane was injected once in 5 days. Either an additional injection of adriamycin two days prior to diazane injection or sarcolysin injected simultaneously with diazane enabled the authors to obtain a distinct synergestic effect. In leucemia L-1210 a simultaneous administration of diazane and sarcolysin also contributes to considerably longer survival of leucemic animals. Such combinations are likely to be promising in their clinical use.

  4. Vibrational spectra, tautomerism and thermodynamics of anticarcinogenic drug: 5-Fluorouracil

    NASA Astrophysics Data System (ADS)

    Rastogi, V. K.; Palafox, M. Alcolea

    2011-09-01

    The FT-IR and FT-Raman spectra of 5-Fluorouracil were recorded in the solid phase in the regions 400-4000 cm -1 and 50-4000 cm -1, respectively. The vibrational spectra were analysed and the observed fundamentals were assigned to different normal modes of vibration. The experimental wavenumbers were compared with the scaled vibrational values using DFT methods: the Ar matrix data were related to gas phase calculations, while the values of the solid state spectra were compared to those with dimer simulations. The study indicates that some features that are characteristic of vibrational spectra of uracil and its derivatives are retained in the spectrum of 5-fluorouracil and it exists in ketonic form in the solid phase. The tautomerism was also studied and the spectra of the two most stable forms were simulated. The calculated wavenumbers have been employed to yield thermodynamic properties.

  5. 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

  6. A new magnetic nanocapsule containing 5-fluorouracil: in vivo drug release, anti-tumor, and pro-apoptotic effects on CT26 cells allograft model.

    PubMed

    Shakeri-Zadeh, Ali; Shiran, Mohammad-Bagher; Khoee, Sepideh; Sharifi, Ali Mohammad; Ghaznavi, Habib; Khoei, Samideh

    2014-10-01

    The purpose of this study was to create an optimized method for preparation of 5-fluorouracil-loaded magnetic poly lactic-co-glycolic acid nanocapsules and to investigate its potential as multifunctional carriers to deliver therapeutic agents for tumor-targeted therapies. The in vitro release of the newly synthesized 5-fluorouracil-loaded poly lactic-co-glycolic acid magnetic nanocapsules was investigated in phosphate-buffered saline medium using the dialysis method. In vivo release studies of the magnetic nanocapsules were performed in rabbits. Finally, the targeting properties, anti-tumor, and pro-apoptotic effects of this new magnetic nanocapsule on CT26 cells allograft model were studied. The effective diameter of nanocapsules was 67.2 nm. In vivo release investigations showed that 5-fluorouracil has a sustained release profile, prolonged lifetime in the rabbit plasma, and increased tissue appetency when loaded into the magnetic nanocapsule. Magnetic resonance imaging confirmed that the magnetic nanocapsules were successfully targeted to the tumor. Additionally, the anti-tumor studies revealed that the targeted therapy with magnetic nanocapsules containing 5-fluorouracil effectively inhibits the growth of tumors compared with 5-fluorouracil alone (P < 0.01). The present study demonstrates that this new magnetic nanocapsule can be considered a new nanotechnology-based cancer chemotherapy agent in vivo.

  7. Gambogic acid potentiates the chemosensitivity of colorectal cancer cells to 5-fluorouracil by inhibiting proliferation and inducing apoptosis

    PubMed Central

    Wei, Jianchang; Yang, Ping; Li, Wanglin; He, Feng; Zeng, Shanqi; Zhang, Tong; Zhong, Junbin; Huang, Di; Chen, Zhuanpeng; Wang, Chengxing; Chen, Huacui; Hu, He; Cao, Jie

    2017-01-01

    Chemotherapy using 5-fluorouracil (5-FU) for colorectal cancer (CRC) has low specificity and response rates, leading to severe side effects. Gambogic acid (GA), a traditional Chinese medicine, has multi-targeted anticancer effects, including growth inhibition and apoptosis induction. However, it is unclear whether a combination of 5-FU and GA has synergistic anticancer effects in CRC cells. In this study, SW480 and HCT116 human CRC cells and human intestinal epithelial cells (IECs) were treated with different concentrations of 5-FU, GA or 5-FU+GA. A Cell Counting kit-8 assay was conducted to quantify cell proliferation. The combination index (CI) was calculated and the median-effect principle was applied to analyze the interaction between 5-FU and GA. Flow cytometry was used to determine the percentage of cells undergoing apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting were applied to measure P53, survivin and thymidylate synthase (TS) mRNA and protein levels. It was found that 5-FU+GA more pronouncedly inhibited cell growth and induced apoptosis, compared with either monotherapy. CI values <1 indicated the synergistic effects of the drugs. 5-FU+GA further decreased P53, survivin and TS mRNA and protein levels in the two CRC cell lines compared with single drugs, whereas increased P53 protein levels were observed in HCT116 cells. Moreover, 5-FU+GA did not increase cytotoxicity to IECs. These results demonstrate that GA enhances the anticancer effects of 5-FU on CRC cells. Combined treatment with 5-FU and GA is effective and safe for CRC cells, and may become a promising chemotherapy treatment. PMID:28352348

  8. Fermented wheat germ extract induced cell death and enhanced cytotoxicity of Cisplatin and 5-Fluorouracil on human hepatocellular carcinoma cells.

    PubMed

    Tai, Cheng-Jeng; Wang, Wen-Ching; Wang, Chien-Kai; Wu, Chih-Hsiung; Yang, Mei-Due; Chang, Yu-Jia; Jian, Jiun-Yu; Tai, Chen-Jei

    2013-01-01

    Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Due to the difficulties of early diagnosis, curative treatments are not available for most patients. Palliative treatments such as chemotherapy are often associated with low response rate, strong adverse effects and limited clinical benefits for patients. The alternative approaches such as fermented wheat germ extract (FWGE) with anti-tumor efficacy may provide improvements in the clinical outcome of current therapy for HCC. This study aimed to clarify antitumor efficacy of FWGE and the combination drug effect of FWGE with chemotherapeutic agents, cisplatin and 5-fluorouracil (5-Fu) in human HCC cells, HepG2, Hep3B, and HepJ5. The present study indicated that FWGE exhibited potential to suppress HepG2, Hep3B, and HepJ5 cells, with the half maximal inhibitory concentrations (IC50) of FWGE were 0.494, 0.371 and 1.524 mg/mL, respectively. FWGE also induced Poly (Adenosine diphosphate ribose) polymerase (PARP) associated cell death in Hep3B cells. Moreover, the FWGE treatment further enhanced the cytotoxicity of cisplatin in all tested HCC cells, and cytotoxicity of 5-Fu in a synergistic manner in HepJ5 cells. Collectively, the results identified the anti-tumor efficacy of FWGE in HCC cells and suggested that FWGE can be used as a supplement to effectively improve the tumor suppression efficiency of cisplatin and 5-Fu in HCC cells.

  9. Chemoembolization alone vs combined chemoembolization and hepatic arterial infusion chemotherapy in inoperable hepatocellular carcinoma patients

    PubMed Central

    Gao, Song; Zhang, Peng-Jun; Guo, Jian-Hai; Chen, Hui; Xu, Hai-Feng; Liu, Peng; Yang, Ren-Jie; Zhu, Xu

    2015-01-01

    AIM: To compare the efficacy and safety of chemoembolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy (HAIC), including oxaliplatin (OXA), 5-fluorouracil (5-FU) and folinic acid (CF), in inoperable hepatocellular carcinoma (HCC) without distant metastasis. METHODS: Eighty-four inoperable HCC patients were enrolled. Thirty-nine patients underwent chemoembolization alone, and the other 45 patients underwent chemoembolization + HAIC (OXA/5-FU/CF) treatment non-randomly. The progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse reactions were compared between the two groups. RESULTS: A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS (mPFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease, with or without vessel invasion, the chemoembolization + HAIC group showed better mPFS when compared to chemoembolization alone, but no significant difference was found in patients with BCLC stage C disease. The parameter of pain (grade III-IV) in the chemoembolization + HAIC group was increased statistically. CONCLUSION: Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis. PMID:26420971

  10. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2014-01-01

    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 _CCl^* shape resonance in 5-chlorouracil. Exploratory calculations performed at selected C-Cl bond lengths suggest that the σ _CCl^* 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.

  12. 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

  13. Hemostatic absorbable gelatin sponge loaded with 5-fluorouracil for treatment of tumors

    PubMed Central

    Sun, Wei; Chen, Yinghui; Yuan, Weien

    2013-01-01

    Background Surgical tumor resection is the main treatment for tumors however the treatment process often results in massive bleeding and tumor cell residue. The main aim of this research was to address problems such as bleeding, systemic chemotherapy side effects while enhancing quality of life, and increasing drug concentrations at the tumor site by developing a novel formulation with local long-term efficacy for treatment of tumors and to stop bleeding. Methods 5-Fluorouracil (5-FU) was suspended in an ethyl acetate solution of poly D,L-lactide-co-glycolic acid (PLGA) and a vacuum drying method was applied. The hemostatic gelatin sponge loaded with 5-FU was prepared by absorption of the suspension. The in vitro and in vivo characteristics of the hemostatic gelatin sponge loaded with 5-FU (5-FU-HAGS) were investigated. Results 5-FU-HAGS (hemostatic absorbable gelatin sponge loaded with 5-fluorouracil) was successfully produced with controlled release of the content and was reproducibly suitable for local tumor treatment as an implant to stop bleeding. The encapsulation efficiency of 5-FU-HAGS was above 98%. The in vitro 5-FU release kinetic profile matched a near zero-order equation for 20 days. The in vivo 5-FU plasma concentration was at a more stable level than when 5-FU solution was administered by subcutaneous injection. Bleeding can be stopped more effectively by coating a piece of blank gelatin sponge. The survival ratio of tumor-bearing mice using a 5-FU-HAGS subcutaneous implant was higher when compared to mice given a subcutaneous injection of 5-FU solution. Conclusion The 5-FU-HAGS system is a potential and effective way of enhancing the survival ratio and improving the quality of life of tumor-bearing mice. PMID:23626465

  14. 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.

  15. 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

  16. A case of acute myocardial infarction during 5-fluorouracil infusion.

    PubMed

    Canale, Maria Laura; Camerini, Andrea; Stroppa, Stefano; Porta, Romana Prosperi; Caravelli, Paolo; Mariani, Mario; Balbarini, Alberto; Ricci, Sergio

    2006-11-01

    Cardiac toxicity is an uncommon side-effect of 5-fluorouracil (5-FU) treatment, consisting mainly of chest pain episodes with or without electrocardiographic changes and dysrhythmias. Here, we describe the case of a 56-year-old male patient with a diagnosis of advanced colorectal cancer who developed an acute myocardial infarction during 5-FU infusion. The patient was not affected by prior heart disease and did not show any classic risk factors for coronary heart disease. Coronary angiography examination revealed no evidence of coronary stenosis, supporting the hypothesis of a coronary artery spasm related to 5-FU infusion. Given the great number of cancer patients receiving 5-FU containing chemotherapeutic regimens, this rare but severe cardiac side-effect may be observed in both cardiologic and oncologic clinical practice. We suggest a tight clinical monitoring of all patients receiving 5-FU infusions, even in those without a prior history of heart disease.

  17. Combination radiation and chemotherapy for the treatment of squamous cell carcinoma of the male and female urethra.

    PubMed

    Licht, M R; Klein, E A; Bukowski, R; Montie, J E; Saxton, J P

    1995-06-01

    We report on 2 men and 2 women with locally advanced squamous cell carcinoma of the urethra who were treated with combination chemotherapy and radiation. Treatment consisted of 1,000 mg./M.2 5-fluorouracil plus 15 mg./M.2 mitomycin-C followed by 30 to 50 Gy. external beam radiation. The 2 women achieved durable complete responses, and are alive with no evidence of disease 94 and 43 months later, respectively. The men also had regional lymph node metastases, and 1 achieved complete response and has no evidence of disease 98 months posttreatment, while the other experienced partial response in the primary tumor and complete response in the involved inguinal nodes. The latter patient died of an unrelated cause with residual disease at 7 months. Only mild toxicity occurred in 3 patients. This regimen of chemotherapy and radiation is well tolerated and should be considered as primary therapy for invasive squamous cell carcinoma of the male and female urethra.

  18. Early Extracorporeal Membrane Oxygenation Support for 5-Fluorouracil-induced Acute Heart Failure with Cardiogenic Shock.

    PubMed

    Höllriegel, Robert; Fischer, Julia; Schuler, Gerhard

    2014-01-01

    A 50-year-old man with no previous history of cardiovascular disease or risk factors was admitted for syncope and orthopnea. Importantly, he underwent recent chemotherapy with 5-fluorouracil (5-FU) until 1 day before his acute presentation. In the emergency room, patient developed asystole and was successfully resuscitated for 2 min. At coronary angiography, no signs of coronary artery disease were detectable, but transthoracic echocardiography showed a severely decreased left-ventricular systolic function. Due to the progressive cardiogenic shock, an extracorporeal membrane oxygenation (ECMO) support was used as bridge-to-recovery and to avoid the use of sympathomimetics with their known disadvantages. On ECMO support, hemodynamic stabilization was evident and medical heart failure treatment was commenced. Left-ventricular function recovered to normal values within a short period of time. Cardiac complications after chemotherapy with 5-FU are not rare and should be taken into consideration even in acute heart failure with cardiogenic shock. ECMO as the most potent form of acute cardiorespiratory support enables complete relief of cardiac workload and therefore recovery of cardiac function.

  19. Bifidobacterium infantis has a beneficial effect on 5-fluorouracil-induced intestinal mucositis in rats.

    PubMed

    Yuan, K-T; Yu, H-L; Feng, W-D; Chong, P; Yang, T; Xue, C-L; Yu, M; Shi, H-P

    2015-03-01

    Intestinal mucositis is a common toxic side effect in cancer patients receiving high-dose chemotherapy. This study aimed to evaluate the beneficial effects of Bifidobacterium infantis in a rat model of intestinal mucositis induced by 5-fluorouracil (5-FU). Thirty male Sprague-Dawley rats were divided into three groups: control, 5-FU, and 5-FU + B. infantis. A single intraperitoneal injection of 5-FU (150 mg/kg) was used to induce intestinal mucositis. B. infantis (1×109 cfu) was administered for 11 days, starting from 7 days before 5-FU injection. Intestinal mucositis was evaluated based on body weight, villus height, immunohistological expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa beta (NF-κB), levels of the pro-inflammatory factors interleukin 1 beta and tumour necrosis factor alpha, and myeloperoxidase (MPO) concentration. The results showed that the 5-FU + B. infantis group demonstrated a higher body weight and villus height, increased expression of PCNA, reduced expression of NF-κB and pro-inflammatory factors, and lower MPO concentration compared to the 5-FU group. These data suggest that probiotic B. infantis is effective in reducing chemotherapy-induced intestinal mucositis in rats.

  20. 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.

  1. Fourier transform infrared microspectroscopy monitoring of 5-fluorouracil-induced apoptosis in SW620 colon cancer cells

    PubMed Central

    GAO, YANFENG; HUO, XIONGWEI; DONG, LIU; SUN, XUEJUN; SAI, HE; WEI, GUANGBING; XU, YIZHUANG; ZHANG, YUANFU; WU, JINGUANG

    2015-01-01

    Colon cancer is associated with a high incidence and a poor prognosis. The aim of the present study was to determine whether Fourier transform infrared (FTIR) microspectroscopy can be used to monitor the chemotherapy drug-induced apoptosis of SW620 colon cancer cells. The 50% inhibitory concentration (IC50) of 5-fluorouracil (5-FU), the main chemotherapeutic agent used for the treatment of colorectal cancer, was determined as the inhibition of growth of the SW620 cells using an MTT assay. Cell starvation and 5-FU treatment synergized to arrest the cells in the G1 and S phases of the cell cycle. FTIR combined with fluorescence activated cell sorting (FACS) analysis were used to analyze the SW620 cells following treatment with 5-FU for 12, 24 and 48 h. The apoptotic cells had several spectral characteristics. The relative peak intensity ratio (I1740/I1460) was significantly increased (P<0.05), the I1740/I1460 ratio, associated with a band of amino acid residues at 1,410 cm−1 was significantly increased at the early and late phases of cell death (P<0.05), the peaks at 1,240 cm−1 increased in wave number, a band at 1,040 cm−1, associated with polysaccharides, appeared at 24 and 48 h and then moved to a higher wave number and the I1040/I1460 ratio increased at the late stage of apoptosis. These results demonstrated that FTIR can be used as a label-free technique to monitor cancer cell apoptosis and to understand the spectral fingerprints of apoptotic cells. This suggested that FTIR spectral features have potential as a powerful tool to monitor cancer cell apoptosis. PMID:25503826

  2. 5-Fluorouracil affects assembly of stress granules based on RNA incorporation.

    PubMed

    Kaehler, Christian; Isensee, Jörg; Hucho, Tim; Lehrach, Hans; Krobitsch, Sylvia

    2014-06-01

    The antimetabolite 5-fluorouracil is a widely used chemotherapeutic for the treatment of several solid cancers. However, resistance to 5-fluorouracil remains a major drawback in its clinical use. In this study we report that treatment of HeLa cells with 5-fluorouracil resulted in de novo assembly of stress granules. Moreover, we revealed that stress granule assembly under stress conditions as well as disassembly is altered in cells treated with 5-fluorouracil. Notably, we discovered that RACK1, a protein mediating cell survival and apoptosis, is a component of 5-fluorouracil-induced stress granules. To explore the mode of action of 5-fluorouracil accountable for de novo stress granule assembly, we analyzed 5-fluorouracil metabolites and noticed that stress granule assembly is caused by RNA, not DNA incorporating 5-fluorouracil metabolites. Interestingly, we observed that other RNA incorporating drugs also cause assembly of stress granules. Thus, our results suggest that incorporation of chemotherapeutics into RNA may result in stress granule assembly with potential significance in chemoresistance.

  3. Acyclonucleosides, modified seco-nucleosides, and salicyl- or catechol-derived acyclic 5-fluorouracil O,N-acetals: antiproliferative activities, cellular differentiation and apoptosis.

    PubMed

    Marchal, Juan A; Núñez, María C; Aránega, Antonia; Gallo, Miguel A; Espinosa, Antonio; Campos, Joaquín M

    2009-01-01

    The goal of cancer chemotherapy with classical drugs - the destruction of the tumor cells - is often complicated by significant toxicity. As an alternative, induced differentiation modulates the cell programme by transforming malignant cells into mature cells with no proliferative potential. Our data demonstrate that (+/-)-1-{[3-(2-hydroxyethoxy)-1-isopropoxy]propyl}-5-fluorouracil inhibits proliferation, induces myogenic differentiation, increases the expression of proteins specifically present in normally differentiated skeletal muscle cells, and modifies the adhesion capacity of these cells against the rhabdomyosarcoma cell line RD. From a designing point of view, a benzene ring was fused to the side chain in order to increase the lipophilicity and anticancer activity of our molecules. Herein we report the preparation and biological activity of three compounds having the general formula (+/-)-1-[2-(5-substituted-2-hydroxybenzyloxy)-1-methoxyethyl]-5-fluorouracils. A catechol-derived compound such as (+/-)-1-[3-(2-hydroxyphenoxy)-1-methoxypropyl]-5-fluorouracil and two salicyl-derived compounds such as (+/-)-(Z)-1-[4-(2-hydroxyphenyl)-1-methoxy-but-3-enyl]-5-fluorouracil [(Z)-43] and its dihydrogenated derivative (+/-)-1-[4-(2-hydroxyphenyl)-1-methoxybutyl]-5-fluorouracil were prepared to complete the set of six O,N-acetals. The most active compound against the MCF-7 breast cancer cell line was (+/-)-(Z)-43 with an IC(50) = 9.40 +/- 0.64 microM. Differentiated breast cancer cells generate fat deposits within the cytoplasm. The MCF-7 cells trea-ed with (+/-)-(Z)-43 caused an increase in the lipid content over control cells after 3 days of treatment. Our results suggest that there may be significant potential advantages in the use of this new differentiating agent for the treatment of breast cancer.

  4. Mismatch Repair Proficiency and In Vitro Response to 5-Fluorouracil

    PubMed Central

    CARETHERS, JOHN M.; CHAUHAN, DHARAM P.; FINK, DANIEL; NEBEL, SIBYLLE; BRESALIER, ROBERT S.; HOWELL, STEPHEN B.; BOLAND, C. RICHARD

    2015-01-01

    Background & Aims The DNA mismatch repair (MMR) system recognizes certain DNA adducts caused by alkylation damage in addition to its role in recognizing and directing repair of interstrand nucleotide mismatches and slippage mistakes at microsatellite sequences. Because defects in the MMR system can confer tolerance to acquired DNA damage and, by inference, the toxic effects of certain chemotherapeutic agents, we investigated the effect of 5-fluorouracil (5-FU) on colon cancer cell lines. Methods We determined growth selection by cell enrichment assay and cloning efficiency after treatment with 5 μmol/L 5-FU, assayed nucleic 3H–5-FU incorporation, and analyzed the cell cycle by flow cytometry. Results 5-FU treatment provided a growth advantage for MMR-deficient cell lines, indicating a relative degree of tolerance to 5-FU by the MMR-deficient cell lines. Enhanced survival was statistically significant after 5 days of growth, and a 28-fold reduction in survival was noted in the MMR-proficient cells by clonagenic assays after 10 days of growth. Differences in nucleotide uptake of 5-FU did not account for the observed growth differences, and specific cell cycle checkpoint arrest was not detected. Conclusions Intact DNA MMR seems to recognize 5-FU incorporated into DNA but may do so in a different manner than other types of alkylation damage. Defective DNA MMR might be one mechanism for tumor resistance to 5-FU. PMID:10381918

  5. 5-Fluorouracil-radiation interactions in human colon adenocarcinoma cells

    SciTech Connect

    Buchholz, D.J.; Lepek, K.J.; Rich, T.A.

    1995-07-15

    The purpose of this investigation was to determine the effect of cellular proliferation and cell cycle stage on the ability of postirradiation 5-fluorouracil (5-FU) to radiosensitize cultured human colon adenocarcinoma Clone A cells. Cell survival curves were generated for irradiated: (a) log- and plateau-phase Clone A cells; and (b) Clone A cells separated by centrifugal elutriation into the various phases of the cell cycle; with and without postirradiation treatment with 100 {mu}g/ml 5-FU. Postirradiation treatment with 5-FU sensitized proliferating cells to a greater degree than it sensitized cells growing in plateau phase. The {beta} component of cell kill in log-phase cells was increased by a factor of 1.5 with a sensitizer enhancement ratio of 1.21 at the 0.01 survival level. Plateau-phase cells showed less radiosensitization (sensitizer enhancement ratio of 1.13 at the 0.01 survival level); however, there was a mild increase in both {alpha} and {beta} kill in plateau-phase cells. Elutriated G{sub 1} cells were the most radiosensitive, independent of treatment with 5-FU. The phase of the cell cycle had little effect on the ability of fluorouracil to radiosensitize Clone A cells. Proliferating cells are more susceptible to radiosensitization with 5-FU than plateau-phase cells are, but this effect appears to be independent of the phase of the cell cycle. 18 refs., 4 figs., 3 tabs.

  6. Molecularly imprinted polymers for 5-fluorouracil release in biological fluids.

    PubMed

    Puoci, Francesco; Iemma, Francesca; Cirillo, Giuseppe; Picci, Nevio; Matricardi, Pietro; Alhaiqu, Franco

    2007-04-18

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

  7. A phase I study of combination S-1 plus cisplatin chemotherapy with concurrent thoracic radiation for locally advanced non-small cell lung cancer.

    PubMed

    Chikamori, Kenichi; Kishino, Daizo; Takigawa, Nagio; Hotta, Katsuyuki; Nogami, Naoyuki; Kamei, Haruhito; Kuyama, Shoichi; Gemba, Kenichi; Takemoto, Mitsuhiro; Kanazawa, Susumu; Ueoka, Hiroshi; Segawa, Yoshihiko; Takata, Saburo; Tabata, Masahiro; Kiura, Katsuyuki; Tanimoto, Mitsune

    2009-07-01

    A combination of S-1, a newly developed oral 5-fluorouracil derivative, and cisplatin is reported to show anti-tumour activity against advanced non-small cell lung cancer (NSCLC). Because S-1 shows synergistic effects with radiation, we conducted a phase I study to evaluate the maximum tolerated doses (MTDs), recommended doses (RDs), and dose-limiting toxicities (DLTs) of cisplatin and S-1 when combined with concurrent thoracic radiation (total dose of 60 Gy with 2 Gy per daily fraction) in patients with locally advanced NSCLC. Chemotherapy consisted of two 4-week cycles of cisplatin administered on days 1 and 8, and S-1 administered on days 1-14. S-1/cisplatin dosages (mg/m(2)/day) were escalated as follows: 60/30, 60/40, 70/40, 80/40 and 80/50. Twenty-two previously untreated patients were enrolled. The MTDs and RDs for S-1/cisplatin were 80/50 and 80/40, respectively. DLTs included febrile neutropaenia, thrombocytopaenia, bacterial pneumonia and delayed second cycle of chemotherapy. No patient experienced radiation pneumonitis>grade 2 and only one patient experienced grade 3 radiation oesophagitis. The overall response rate was 86.4% with a median survival time of 24.4 months. These results indicate that combination cisplatin-S-1 chemotherapy with concurrent thoracic radiation would be a feasible treatment option and a phase II study is currently under way.

  8. Design and synthesis of new cholesterol-conjugated 5-Fluorouracil: a novel potential delivery system for cancer treatment.

    PubMed

    Radwan, Awwad A; Alanazi, Fares K

    2014-08-26

    Cholesterol-conjugated 5-fluorouracil prodrugs were designed to be carried in vivo via low density lipoproteins (LDL) and subsequently undergo LDL-receptor-mediated internalisation into cancer cells. In vivo anti-cancer evaluation was performed using 5-fluorouracil-cholesterol conjugate in a mouse model. The obtained prodrugs were more potent than 5-fluorouracil control drug at the same 5-fluorouracil content (3 mg·kg-1).

  9. Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90).

    PubMed Central

    Pierga, J. Y.; Jouve, M.; Asselain, B.; Livartowski, A.; Beuzeboc, P.; Diéras, V.; Scholl, S.; Dorval, T.; Palangié, T.; Garcia-Giralt, E.; Pouillart, P.

    1998-01-01

    Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m(-2) intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m(-2) i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m(-2) i.v. bolus on days 1, 2 and 3 or 'FULON' consisting of 5-fluorouracil 250 mg m(-2) day(-1) continuously infused from day 1 to day 22, doxorubicin 15 mg m(-2) i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m(-2) i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < or = 0.01). We conclude that the two regimens appeared equally effective but have different toxicities. PMID:9652764

  10. Oral Nucleotides Only Minimally Improve 5-Fluorouracil-Induced Mucositis in Rats.

    PubMed

    Mashtoub, Suzanne; Feo, Benjamin; Whittaker, Alexandra L; Lymn, Kerry A; Martinez-Puig, Daniel; Howarth, Gordon S

    2015-01-01

    Chemotherapy-induced mucositis is characterized by inflammation and ulceration of the intestinal mucosa, compromising intestinal function. Exogenous nucleotides have been reported to repair the mucosa. The nucleotide preparation, Nucleoforce F0328 (Nucleoforce), was investigated for its potential to ameliorate intestinal mucositis in rats. Female Dark Agouti rats (n = 8/group) were gavaged once daily with Nucleoforce (175 mg/kg) or water from Days 0 to 8 and injected (i.p.) with 5-fluorouracil (5-FU; 150 mg/kg) or saline on Day 5. Histological parameters (disease severity, crypt depth, and villus height measurements) and myeloperoxidase activity were quantified. P < 0.05 was considered significant. Jejunal and ileal histological disease severity scores were significantly increased by 5-FU, compared to normal controls (P < 0.05). Nucleoforce treatment in 5-FU-injected rats significantly reduced jejunal and ileal disease severity compared to 5-FU controls (P < 0.05). In 5-FU-injected rats, jejunal and ileal villus heights and crypt depths were significantly decreased compared to 5-FU controls, with no additional Nucleoforce effect (P > 0.05). Intestinal myeloperoxidase activity was significantly elevated by 5-FU (8.8-fold), compared to normal controls (P < 0.05), which was not normalized by Nucleoforce treatment (P > 0.05). Nucleoforce only partially improved parameters associated with experimentally-induced mucositis. Future studies could investigate increased concentrations, more frequent administration, or protective microencapsulation delivery methods, to increase bioavailability.

  11. Biodegradable three-dimension micro-device delivering 5-fluorouracil in tumor bearing mice.

    PubMed

    Ren, Xiaojiao; Zheng, Na; Gao, Yang; Chen, Tianning; Lu, Wen

    2012-01-01

    A novel three-dimension micro-device was formulated to control delivery of 5-fluorouracil (5-FU) for the treatment of solid tumors. The poly-(lactic-co-glycolic) acid (PLGA), which is both biocompatible and biodegradable, was used as carrier material. The characteristics of drug release in vitro and in vivo and the performance of the micro-device after implantation in tumor bearing mice were evaluated. A constant release profile from in vitro test was obtained for a period of 7 days, and it correlated well with the in vivo release profile. In the distribution experiment of 5-FU micro-device, it was demonstrated that 5-FU remained in the tumor tissues for more than 7 days after implantation. Likewise, we found that the 5-FU concentration in tumor correlated well with the in vivo release. Tumors treated with 5-FU loaded micro-device of three different dosages showed significant tumor reduction (P < 0.05) compared with empty control micro-device 7 days after administration. Moreover, the implantation treatment showed enhanced efficacy compared with the intraperitoneal administration with the same dosage. These results suggested that the three-dimensional micro-device may provide a promising local and controlled release drug delivery system, which may enable delivery of multiple drugs for post-surgical chemotherapy against solid tumor.

  12. 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

    2008-10-22

    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.

  13. 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.

  14. Layered inorganic nanocomposites: a promising carrier for 5-fluorouracil (5-FU).

    PubMed

    Kevadiya, Bhavesh D; Patel, Tapan A; Jhala, Devendrasinh D; Thumbar, Rahul P; Brahmbhatt, Harshad; Pandya, Maharshi P; Rajkumar, Shalini; Jena, Prasant K; Joshi, Ghanshyam V; Gadhia, Pankaj K; Tripathi, C B; Bajaj, Hari C

    2012-05-01

    We report here the intercalation of 5-fluorouracil (5-FU), an anticancer drug in interlayer gallery of Na(+) clay (Montmorillonite, MMT), with the assistance of biopolymer (chitosan, CS). The X-ray diffraction patterns, thermal and spectroscopic analyses indicated the drug intercalation into the clay interlayer space in support of CS and stabilized in the longitudinal monolayer by electrostatic interaction. In vitro drug release showed controlled release pattern. The genotoxic effect of drug was in vitro evaluated in human lymphocyte cell culture by comet assay, and results indicated significant reduction in DNA damage when drug was intercalated with clay and formulated in composites. The results of in vitro cell viability assay in cancer cells pointed at decreased toxicity of drug when encapsulated in Na(+)-clay plates than the pristine drug. In vivo pharmacokinetics, biodistribution, hepatotoxicity markers, e.g., SGPT and SGOT, and liver/testicular histology in rats showed plasma/tissue drug levels were within therapeutic window as compared to pristine drug. Therefore, drug-clay hybrid and composites can be of considerable value in chemotherapy of cancer with reduced side effects.

  15. Cytoprotective effects of fucoidan, an algae-derived polysaccharide on 5-fluorouracil-treated dendritic cells.

    PubMed

    Jeong, Bo-Eun; Ko, Eun-Ju; Joo, Hong-Gu

    2012-05-01

    Although chemotherapeutic anticancer agents are effective, they also attack normal immune cells due to a lack of selectivity. 5-Fluorouracil (5-FU) is a representative anticancer agent that induces immunosuppression in cancer patients as a side effect. Fucoidan is an algae-derived sulfated polysaccharide that has recently been recognized as a hematopoietic mobilizer and immunomodulator. In this study, we investigated the cytoprotective effect of fucoidan on dendritic cells (DCs) against 5-FU-induced cellular damage. Several kinds of assays including flow cytometric analysis demonstrated the cytoprotective efficacy of fucoidan. In addition, fucoidan increased the expression of immune-related surface markers on and the alloproliferative capacity of DCs exposed to 5-FU. For investigating action mechanism, the expression levels of apoptosis-related molecules were measured. Taken together, the results of this study suggest that fucoidan, a marine-derived polysaccharide, has cytoprotective effects on DCs, the most potent antigen-presenting cell type, against 5-FU-induced cellular damage. These results provide valuable information to use fucoidan as an immunostimulatory agent for the chemotherapy of cancer patients.

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

    SciTech Connect

    Doong, S.L.

    1988-01-01

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

  17. 5-fluorouracil in lethal mutagenesis of foot-and-mouth disease virus.

    PubMed

    Agudo, Rubén; Arias, Armando; Domingo, Esteban

    2009-06-01

    5-fluorouracil (FU) is a pyrimidine analogue extensively used in cancer chemotherapy. FU can be metabolized into 5-fluorouridine-triphosphate, which can be used as substrate for viral RNA-dependent RNA polymerases. This results in the incorporation of mutations into viral RNA. Accumulation of mutations may lead to loss of virus infectivity, in a process known as lethal mutagenesis. RNA virus pathogens are particularly difficult to control because they are highly mutable, and mutants resistant to antiviral agents are readily selected. Here, we review the basic principles of lethal mutagenesis as an antiviral approach, and the participation of FU in its development. Recent studies with foot-and-mouth disease virus indicate that FU can act both as an inhibitor and as a mutagen during foot-and-mouth disease virus replication. This dual activity renders FU an adequate drug for lethal mutagenesis. We suggest that structural and biochemical studies can contribute to the lead to new design of base or nucleoside analogues targeted specifically to viral polymerases.

  18. 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

  19. 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.

  20. 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.

  1. Tautomeric equilibria of 5-fluorouracil anionic species in water.

    PubMed

    Markova, Nadezhda; Enchev, Venelin; Ivanova, Galya

    2010-12-23

    It has long been postulated that rare tautomeric or ionized forms of nucleic acid bases may play a role in mispair formation. Therefore, ab initio quantum chemical investigations on the tautomeric equilibrium in 5-fluorouracil (5FU) and its anions (deprotonated from N1, AN1, and from N3, AN3) and their tautomeric forms in water were performed. The effect of the water as solvent was introduced using solute-solvent clusters (four water molecules). The influence of the water molecules on the tautomeric reactions between different forms was considered by multiple proton transfer mechanisms. We show that when a water dimer is located in the reaction site between the two pairs of N-H and C═O groups, the assistive effect of the water molecules is strengthened. All calculations of the solute-water complexes were carried out at an MP2 level of theory and supplemented with correction for higher order correlation terms at CCSD(T) level, using the 6-31+G(d,p) basis set. The ab initio calculated frequencies and Raman intensities of 5FU and its anions AN1, AN3, and dianion are in good agreement with the experimental Raman frequencies in aqueous solution at different pH. In order to establish the pH-induced structural transformation in the molecule of 5FU, further (1)H, (19)F, and (13)C NMR spectra in water solution for pH = 6.9-13.8 were acquired and the chemical shift alterations were determined as a function of pH. On the basis of NMR spectroscopic data obtained for 5FU in aqueous solution at alkaline pH, we suggest the existence of a mixture of the anionic tautomeric forms predicted by our theoretical calculations.

  2. 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

  3. Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells.

    PubMed

    Yang, Lu; Wu, Dingfang; Luo, Kewang; Wu, Shihua; Wu, Ping

    2009-04-18

    Despite recent significant advances in the treatment of human carcinoma (HCC), the results of chemotherapy to date remain unsatisfactory. 5-Fluorouracil (5-FU) still represents the cornerstone of treatment of carcinoma, and resistance to the actions of 5-FU is a major obstacle to successful chemotherapy. More effective treatment strategies may involve combinations of agents with activity against HCC. Andrographolide (ANDRO), a natural bicyclic diterpenoid lactone isolated from Andrographis paniculata, has been shown to suppress the growth of HCC cells and trigger apoptosis in vitro. To assess the suitability of ANDRO as a chemotherapeutic agent in HCC, its cytotoxic effects have been evaluated both as a single agent and in combination with 5-FU. ANDRO potentiates the cytotoxic effect of 5-FU in HCC cell line SMMC-7721 through apoptosis. ANDRO alone induces SMMC-7721 apoptosis with p53 expression, Bax conformation and caspase-3,8,9 activation. Surprisingly, the addition of ANDRO to 5-FU induces synergistic apoptosis, which could be corroborated to the increased caspase-8, p53 activity and the significant changes of Bax conformation in these cells, resulting in increased losses of mitochondrial membrane potential, increased release of cytochrome c, and activation of caspase-9 and caspase-3. Suppression of caspase-8 with the specific inhibitor z-IETD-fmk abrogates largely ANDRO/5-FU biological activity by preventing mitochondrial membrane potential disappearance, caspase-3,9 activation and subsequent apoptosis. The results suggest that ANDRO may be effective in combination with 5-FU for the treatment of HCC cells SMMC-7721.

  4. In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

    PubMed Central

    Fanciullino, R; Giacometti, S; Mercier, C; Aubert, C; Blanquicett, C; Piccerelle, P; Ciccolini, J

    2007-01-01

    Drug resistance is a major cause of treatment failure in cancer chemotherapy, including that with the extensively prescribed antimetabolite, 5-fluorouracil (5-FU). In this study, we tried to reverse 5-FU resistance by using a double-punch strategy: combining 5-FU with a biochemical modulator to improve its tumoural activation and encapsulating both these agents in one same stealth liposome. Experiments carried out in the highly resistant, canonical SW620 human colorectal model showed a up to 80% sensitisation to 5-FU when these cells were treated with our liposomal formulation. Results with this formulation demonstrated 30% higher tumoural drug uptake, better activation with increased active metabolites including critical-5-fluoro-2-deoxyuridine-5-monophosphate, superior inhibition (98%) of tumour thymidylate synthase, and subsequently, higher induction of both early and late apoptosis. Drug monitoring showed that higher and sustained exposure was achieved in rats treated with liposomal formulation. When examined in a xenograft animal model, our dual-agent liposomal formulation caused a 74% reduction in tumour size with a mean doubling in survival time, whereas standard 5-FU failed to exhibit significant antiproliferative activity as well as to increase the lifespan of tumour-bearing mice. Taken collectively, our data suggest that resistance to 5-FU can be overcome through a better control of its intratumoural activation and the use of an encapsulated formulation. PMID:17848948

  5. Emu oil expedites small intestinal repair following 5-fluorouracil-induced mucositis in rats.

    PubMed

    Mashtoub, Suzanne; Tran, Cuong D; Howarth, Gordon S

    2013-11-01

    Mucositis resulting from cancer chemotherapy is characterized by intestinal inflammation and ulceration. Previously, emu oil (EO) improved intestinal architecture (Br J Nutr, 2010) in a rat model of chemotherapy-induced mucositis. We investigated EO for its further potential to promote intestinal repair in this mucositis model. Female Dark Agouti rats (n = 8/group) were gavaged with water, olive oil (OO) or EO once daily (1 mL), injected with 5-fluorouracil (5-FU) or saline on day 5 and euthanized on day 8, 9, 10 or 11. Intestinal villus height (VH) and crypt depth (CD), neutral mucin-secreting goblet cell (GC) count, myeloperoxidase (MPO) activity and selected cytokines were quantified; P < 0.05 was considered significant. In 5-FU-injected rats, only EO administration significantly increased VH in the ileum (day 8), jejunum and jejunum-ileum junction (days 8 and 9) compared to 5-FU controls (P < 0.05). GC count was significantly reduced by 5-FU (jejunum: days 8 and 9; ileum: day 8; P < 0.05) and EO increased ileal GC on days 10 and 11 compared to 5-FU controls. MPO activity was significantly increased in jejunum (days 8 and 9) and ileum (day 8) following 5-FU injection, compared to normal controls (P < 0.05). Both EO and OO significantly reduced jejunal MPO on days 8 and 9; however, only EO decreased ileal MPO on day 8. Cytokine levels were not significantly affected by either oil or 5-FU administration at the day 8 time point. Promotion of repair from injury could represent a new mechanism of action for EO, suggesting potential as an adjunct to conventional treatment approaches for cancer management.

  6. Effects of 5-fluorouracil on the thiamin status of adult female rats.

    PubMed

    Basu, T K; Aksoy, M; Dickerson, J W

    1979-01-01

    The effect of 5-fluorouracil on the thiamin status of normal female adult rats has been investigated. Pre-treatment of the animals with the cytotoxic drug daily for 3 successive days resulted in a significant decrease in hepatic concentrations of thiamin concomitant with a decrease in thiamin-dependent transketolase enzyme activity and an increase in thiamin-pyrophosphate-(TPP-)stimulating effect in whole blood when compared with those of pair-fed control animals. The TPP effect of transketolase enzyme activity was also increased by 5-fluorouracil in vitro. Furthermore, the treatment with 5-fluorouracil resulted in decreased liver and spleen concentrations without affecting the urinary excretory levels of thiamin in animals supplemented with large doses of the vitamin. Giving a dose comparable to a human therapeutic dose caused a similar increase in the TPP effect. These results indicate that treatment with 5-fluorouracil may be associated with thiamin deficiency by increasing either the utilization or the breakdown of thiamin.

  7. Pharmacokinetic application of a bio-analytical LC-MS method developed for 5-fluorouracil and methotrexate in mouse plasma, brain and urine.

    PubMed

    Ganti, Vaishnavi; Walker, Ellen A; Nagar, Swati

    2013-08-01

    In the past we have reported significant cognitive deficits in mice receiving 5-fluorouracil in combination with low-dose methotrexate. To explain such interactions, a pharmacokinetic study was designed. A sensitive bio-analytical method was therefore developed and validated for 5-fluorouracil and methotrexate in mouse plasma, brain and urine with liquid chromatography coupled to a single quadrupole mass spectrometer. Chromatographic separation was accomplished by Agilent® Zorbax® SB-C18 column, with isocratic elution (5 mM ammonium acetate and methanol, 70:30, %v/v) at a flow rate of 300 μL/min. The limit of quantitation for both drugs was 15.6 ng/mL (plasma and brain) and 78.1 ng/mL (urine), with interday and intraday precision and accuracy ≤15% and a total run time of 6 min. This bio-analytical method was used for the pharmacokinetic characterization of 5-fluorouracil and methotrexate in mouse plasma, brain and urine over a period of 24 h. This method allowed characterization of the brain concentrations of 5-fluorouracil over a period of 24 h.

  8. 5-Fluorouracil-induced bilateral persistent serpentine supravenous hyperpigmented eruption, bilateral mottling of palms and diffuse hyperpigmentation of soles.

    PubMed

    Suvirya, Swastika; Agrawal, Avinash; Parihar, Anit

    2014-10-21

    A 42-year-old woman being treated with 5-fluorouracil for carcinoma of the sigmoid colon developed persistent serpentine supravenous hyperpigmented eruption (PSSHE), bilateral mottling of the palms and diffuse hyperpigmentation of the soles. To the best of our knowledge, such a combination of findings has not been reported earlier. Recognition and knowledge of this side effect are important as the dose of the drug need not be altered nor is there a need to replace the drug on worries about a serious adverse effect. However, changing the peripheral venous route to the central line can be useful in management of PSSHE.

  9. 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.

  10. Chemotherapy for Gallbladder Cancer

    MedlinePlus

    ... often used for gallbladder cancer include: Gemcitabine (Gemzar ® ) Cisplatin (Platinol ® ) 5-fluorouracil (5-FU) Capecitabine (Xeloda ® ) Oxaliplatin ( ... them more effective. For example, combining gemcitabine and cisplatin may help people live longer than getting just ...

  11. [Evolving 5-Fluorouracil Therapy to Achieve Enhanced Efficacy-Past and Current Efforts of Researchers].

    PubMed

    Maehara, Yoshihiko; Oki, Eiji; Saeki, Hiroshi; Tokunaga, Eriko; Kitao, Hiroyuki; Iimori, Makoto; Niimi, Shinichiro; Kataoka, Yuki; Emi, Yasunori; Kakeji, Yoshihiro; Baba, Hideo; Shirasaka, Tetsuhiko

    2016-07-01

    5-fluorouracil(5-FU)therapy has advanced greatly over the past 50 years, achieving enhanced therapeutic effects and reduced adverse effects. By taking advantage of the metabolism of 5-FU, researchers have made efforts to develop prodrugs, combination drug products, and combination therapy regimens via biochemical modulation(BCM)with alteration of the drug metabolism. Examples include the advent of the prodrug tegafur(FT), followed by tegafur-uracil(UFT)and tegafurgimeracil- potassium oxonate(S-1)as combined products based on BCM. In the current standard treatment for gastrointestinal cancers, anticancer 5-FU derivatives serve as a platform for combination regimens with other cytotoxic agents or molecular- targeted drugs. To provide further improvements in anticancer therapy outcomes, novel molecular-targeted agents, immune checkpoint inhibitors, and other drugs are being developed, but 5-FU remains an attractive target that shows further potential for increased efficacy. In the future, the evolution of anticancer therapy with 5-FU derivatives is expected to continue via a variety of approaches.

  12. Chemotherapy

    MedlinePlus

    ... the cancer cells. This is called palliative chemotherapy. Chemotherapy for conditions other than cancer Some chemotherapy drugs ... you'll receive. Side effects that occur during chemotherapy treatment Common side effects of chemotherapy drugs include: ...

  13. The use of morphometric and fractal parameters to assess the effects of 5-fluorouracil, interferon and dexamethasone treatment on colonic anastomosis healing: an experimental study in rats.

    PubMed

    Lętowska-Andrzejewicz, Katarzyna; Torres, Anna; Torres, Kamil; Dobrowolski, Piotr; Piersiak, Tomasz; Maciejewski, Ryszard; Gawron, Antoni; Staśkiewicz, Grzegorz; Plewa, Zbigniew

    2011-01-01

    Adjuvant chemotherapy and steroid therapy have been demonstrated to interfere with the wound healing process. The aim of this study was to evaluate the effects of 5-fluorouracil, interferon, and dexamethasone, on the healing of colon anastomosis by assessing morphometric and fractal parameters of the colonic wall. An experimental anastomosis of the ascending colon was performed in 60 male Wistar rats, which were then randomly assigned to four groups. On the second to sixth post-operative days, the rats were administered 5-fluorouracil, interferon-α, dexamethasone, or 0.9% NaCl solution as a control. Macroscopic, histomorphometric and microbiological evaluation was performed in order to assess healing of the anastomosis. In three animals from the dexamethasone group, there was leakage of anastomosis; adhesion formation was highest in the interferon group, and significantly higher than in the control and 5-fluorouracil groups. Histomorphometric parameter alterations were most pronounced on the seventh and fourteenth post-operative days in all treatment groups, with submucosal thickness the most affected parameter. Connective tissue fractal dimension was significantly decreased in those animals treated with interferon and dexamethasone. All three pharmaceutical agents impaired healing of anastomosis, and promoted infection in the anastomosis and skin wound sites. As dexamethasone induced both morphometric and macroscopic alterations, it was considered the most detrimental in this study.

  14. [Adjuvant chemotherapy of the colonic and rectal carcinoma: concepts and uptodate results].

    PubMed

    Weber, W; Nagel, G A

    1977-06-18

    The aim of adjuvant chemotherapy is the destruction of micrometastases after surgical removal of a malignant tumor. This treatment modality is gaining in importance in the light of experimental data and lcinical success in pediatric tumors. Results of ongoing studies in colo-rectal cancer show a marginal effect of prophylactic treatment with 5-fluorouracil. The treatment benefits in trials with historical controls are much greater than in studies with simultaneous controls. Use of historical controls is therefore of doubtful value. Ongoing trials use the combination of 5-fluorouracil and methyl-CCNU, which has been shown to double the remission rate in advanced gastrointestinal cancer. Adjuvant chemotherapy of colo-rectal cancer is still experimental and justified only in the framework of clinical trials.

  15. 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

  16. 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

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

    PubMed

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

    2017-01-01

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

  18. Rebamipide attenuates 5-Fluorouracil-induced small intestinal mucositis in a mouse model.

    PubMed

    Kim, Hyun Jin; Kim, Jin Hyun; Moon, Won; Park, Jongha; Park, Seun Ja; Song, Geun Am; Han, Seung Hee; Lee, Jong Hun

    2015-01-01

    5-Fluorouracil (5-FU)-induced intestinal mucositis is one of the most common morbidities in chemotherapy and involves the reactive oxygen species (ROS) system, apoptosis, and inflammatory cytokines. Rebamipide exerts a mucosal-protective effect, mediated through several mechanisms. The aim of this study was to evaluate the effects of rebamipide in 5-FU-induced mouse small-intestinal mucositis. BALB/c mice were assigned randomly to four groups; (1) control group (n=10; receiving saline orally for 6 d), (2) rebamipide group (n=10; 150 mg/kg rebamipide for 6 d orally), (3) 5-FU group (n=10; 30 mg/kg 5-FU for 5 d, intraperitoneally (i.p.)), and (4) rebamipide +5-FU group (n=10; 150 mg/kg rebamipide for 6 d orally and 30 mg/kg 5-FU for 5 d, i.p.). Body weights and diarrhea scales were assessed. At day 5, the mice were sacrificed. Small intestinal tissue was used for: (1) hematoxylin and eosin (HE) staining for determination of small intestinal villi height, (2) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, (3) immunohistochemistry for inducible nitric oxide synthase (iNOS), F4/80, and transforming growth factor (TGF)-β1, (4) measurement of serum and tissue GSH levels, and (5) measurement of serum tumor necrosis factor (TNF)-α levels. Rebamipide attenuated the severity of mucosal injury reflected by body weight changes, degrees of diarrhea, and heights of villi. Rebamipide reduced the expression of iNOS and TGF-β1, apoptosis, macrophage accumulation, serum TNF-α levels, and prevented reductions in serum and tissue glutathione (GSH) levels by 5-FU administration. These results suggest that rebamipide promotes several mechanisms of mucosal protection and attenuated the 5-FU-induced mucosal injury. In conclusion, administration of rebamipide may have significant protective effects against 5-FU-induced intestinal mucositis.

  19. Carcinoembryonic antigen expression level as a predictive factor for response to 5-fluorouracil in colorectal cancer.

    PubMed

    Eftekhar, Ebrahim; Naghibalhossaini, Fakhraddin

    2014-01-01

    Carcinoembryonic antigen (CEA) expression has been shown to protect cancer cell lines from apoptosis and anoikis. The aim of this study was to further elucidate the role of CEA expression on resistance to anticancer drugs in human colorectal cancer (CRC). We transfected CEA negative CRC cell line SW742 as well as CHO cells to overexpress CEA and their chemoresistance were assessed by MTT assay. In comparison to the parental cell lines, transfected cells had significantly increased resistance to 5-fluorouracil (5-FU). The results also showed a direct correlation between the amount of cellular CEA protein and 5-FU resistance in CEA expressing cells. We found no significant difference in sensitivity to cisplatin and methotrexate between CEA-transfected cells and their counter parental cells. We also compared the association between CEA expression and chemoresistance of 4 CRC cell lines which differed in the levels of CEA production. The CEA expression levels in monolayer cultures of these cell lines did not correlate with the 5-FU resistance. However, 5-FU treatment resulted in the selection of sub-populations of resistant cells that displayed increased CEA expression levels by increasing drug concentration. We analyzed the effect of 5-FU in a 3D multicellular culture generated from the two CRC cell lines, LS180 and HT29/219. Compared with monolayer culture, CEA production and 5-FU resistance in both cell lines were stimulated by 3D growth. In comparison to the 3D spheroids of parental CHO, we observed a significantly elevated 5-FU resistance in 3D culture of the CEA-expressing CHO transfectants. Our findings suggest that the CEA level may be a suitable biomarker for predicting tumor response to 5-FU-based chemotherapy in CRC.

  20. Combined preoperative neoadjuvant radiotherapy and chemotherapy for anal and rectal cancer

    SciTech Connect

    Smith, D.E.; Muff, N.S.; Shetabi, H.

    1986-05-01

    Neoadjuvant therapy combining 5-fluorouracil, mitomycin C, and moderate-dose radiotherapy was given preoperatively to 29 patients with adenocarcinoma of the rectum, 3 patients with squamous cell cancer, and 1 patient with basaloid carcinoma of the anus. Significant downstaging, and even eradication, of these lesions was realized in a high percentage of cases. Population-based data for the period of 1979 to 1984 which encompasses the time of our study indicate the survival of those treated by the neoadjuvant therapy was superior to that of patients treated by surgery alone or by surgery followed by radiotherapy. In general, patients with the poorest clinical presentation had been referred for this therapy.

  1. 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

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

    PubMed Central

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

    2011-01-01

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

  3. Chemotherapy

    MedlinePlus

    Cancer chemotherapy; Cancer drug therapy; Cytotoxic chemotherapy ... Philadelphia, PA: Elsevier Saunders; 2016:chap 179. National Cancer Institute. Chemotherapy and you: support for people who have cancer. ...

  4. Ultradeformable liposomes as multidrug carrier of resveratrol and 5-fluorouracil for their topical delivery.

    PubMed

    Cosco, Donato; Paolino, Donatella; Maiuolo, Jessica; Marzio, Luisa Di; Carafa, Maria; Ventura, Cinzia A; Fresta, Massimo

    2015-07-15

    Ultradeformable liposomes represent useful formulations able to increase the skin permeation of drug compounds. In this study, resveratrol- and 5-fluorouracil-loaded ultradeformable liposomes were investigated for the potential treatment of non-melanoma skin cancer. The in vitro anticancer activity of ultradeformable liposomes was tested on human skin cancer cells through viability-, cell cycle- and apoptosis-analysis. Furthermore, we tested the percutaneous permeation of ultradeformable liposomes using human stratum corneum and viable epidermis. The co-encapsulation of resveratrol and 5-fluorouracil (multi-drug carrier) in ultradeformable liposomes improved their anticancer activity on skin cancer cells as compared to both the free drug form and the single entrapped agents. These multi-drug ultradeformable liposomes arrest cell proliferation in G1/S, thus modifying the action of 5-fluorouracil and increasing the activity of resveratrol. This effect might depend on the ultradeformable liposomes, which may accumulate in deeper skin layers, thus generating a cutaneous depot from which resveratrol and 5-fluorouracil are gradually released. Resveratrol and 5-fluorouracil co-loaded ultradeformable liposomes could be a new nanomedicine for the treatment of squamous cell carcinoma, i.e., actinic keratosis, Bowen's disease, and keratoacanthoma.

  5. 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

  6. Sequential chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced head and neck cancer.

    PubMed

    Janinis, J; Papadakou, M; Panagos, G; Panousaki, A; Georgoulias, V; Hatzidaki, D; Lefantzis, D; Dokianakis, G

    2001-06-01

    The purpose of this phase II trial was to evaluate the toxicity of a sequential chemoradiotherapy approach using docetaxel, cisplatin, and 5-fluorouracil (5-FU) (DCF) with granulocyte colony-stimulating factor support in previously untreated patients with locally advanced head and neck cancer (HNC). Secondary endpoints included preliminary assessment of response. Patients with locally advanced HNC, a World Health Organization performance status 0 to 2, and no prior history of chemotherapy or radiotherapy were included. Treatment consisted of docetaxel 80 mg/m2 (1-hour infusion) on day 1, cisplatin 40 mg/m2 (1-hour infusion) on days 2 and 3, and 5-fluorouracil 1,000 mg/m2 (24-hour continuous infusion), on days 1 to 3, repeated every 28 days for a maximum of 4 cycles per patient. All patients received granulocyte colony stimulating factors subcutaneously between days 4 and 9. Radiation therapy (RT) to the primary tumor site and neck lymph nodes was planned within 5 weeks of the last cycle of chemotherapy. The primary tumor site received 60 to 70 Gy. Twenty patients (median age 56 years, range: 40-72 years) received a total of 60 cycles of DCF. The median number of cycles was 3 (range: 1-4 cycles). All patients were evaluable for toxicity and response. The most common acute nonhematologic toxicities from DCF induction chemotherapy included alopecia, mucositis, peripheral sensory neuropathy, onycholysis, and asthenia. Febrile neutropenia developed in two patients and grade IV diarrhea in one patient. There were no treatment-related deaths. The overall response rate (RR) after DCF induction chemotherapy was 90% (95% confidence interval [CI]: 76.8-103.1%). After the completion of RT, the overall RR was 95% with a complete response rate of 73% (95% CI: 49.9-90.1%). Organ preservation was achieved in eight patients with laryngeal cancer and one patient with base of tongue involvement. After a median follow-up of 36 months (range: 5-43 months) the median disease-free and

  7. 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.

  8. 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

  9. Effects of American ginseng on pharmacokinetics of 5-fluorouracil in rats.

    PubMed

    He, Yi-Sheng; Sun, Wei; Wang, Chong-Zhi; Qi, Lian-Wen; Yang, Jie; Li, Ping; Wen, Xiao-Dong; Yuan, Chun-Su

    2015-05-01

    The pharmacokinetics of 5-fluorouracil (5-FU) in combination with or without American ginseng (seven-consecutive days oral dose) in rats were evaluated using liquid chromatography-electrospray ionization-mass spectrometry (LC-MS). Chromatographic separation was performed on a reverse LC column within a total run time of 6.5 min, which allowed for a relatively quick analysis. The limit of quantification for 5-FU was 15 ng/mL and this method was linear over 15-50,000 ng/mL. This method supported stabilizing determination of the plasma concentration of 5-FU over a period of 24 h. Precision both interday and intraday (coefficient of variation) was within 14% and accuracy (relative error) ranged from -5 to 14%. In view of the observed pharmacokinetic parameters, including maximum concentration, time to maximum concentration, area under the concentration-time curve (AUC), mean residence time, elimination half-life and clearance, our results showed no significant differences in all of the pharmacokinetic parameters between the ginseng co-treated group and 5-FU alone group. Some increase in AUC was observed in 5-FU plus ginseng group; however, the difference did not reach statistical significance compared with 5-FU alone. It appeared that American ginseng administration did not significantly alter the kinetics of 5-FU. More studies are still needed to confirm our results.

  10. 5-Fluorouracil enteric-coated nanoparticles for improved apoptotic activity and therapeutic index in treating colorectal cancer.

    PubMed

    Tummala, Shashank; Kuppusamy, Gowthamarajan; Satish Kumar, M N; Praveen, T K; Wadhwani, Ashish

    2016-10-01

    5-Fluorouracil (5-FU) is one among the anti-cancer agents in FOLFORINOX treatment along with oxaliplatin and irinotecan for the treatment of colorectal cancer. Despite its potential activity on the tumor cells, it lacks site specificity partly attributed by its biodistribution to healthy cells resulting in toxic effects to healthy cells. Therefore, we have formulated 5-fluorouracil enteric-coated nanoparticles (5-FUEC) to localize the drug in the colon area that enables its prolonged presence in target area in a sustained manner. The current work emphasizes on enhanced anti-cancer activity of 5-FUEC sequencing its apoptotic activity on HCT 116 colorectal cancer cell lines in vitro. MTT assay exhibited 5.5-fold decrease in IC50 value of nanoparticles comparable to 5-FU. Nuclear fragmentation with irregular edges in nucleus of cells justified its improved activity. Furthermore, flow cytometric analysis confirms the majority of cells gated in early apoptotic (39.75%) and late apoptotic phase (36.25%). Acridine orange/ethidium bromide staining (AO/EB) exhibited cells with red fluorescence (indicating apoptosis) comparable to the control and 5-FU. γ-Scintigraphic studies determined the applicability and feasibility of the enteric coating with mean gastric emptying time, mean intestinal transit time and mean colon arrival time of 1.89 ± 0.03, 2.15 ± 0.05 and 4.03 ± 0.27 h, respectively. Moreover, nanoparticulate approach was found significant in reducing tumor size and volume in xenograft tumor models in vivo along with sustained release. These superior anti-cancer activities exhibited by 5-FUEC indicated that it could be a potential alternative to chemotherapy for colorectal cancer.

  11. Loss of miR-200 family in 5-fluorouracil resistant colon cancer drives lymphendothelial invasiveness in vitro.

    PubMed

    Senfter, Daniel; Holzner, Silvio; Kalipciyan, Maria; Staribacher, Anna; Walzl, Angelika; Huttary, Nicole; Krieger, Sigurd; Brenner, Stefan; Jäger, Walter; Krupitza, Georg; Dolznig, Helmut; Mader, Robert M

    2015-07-01

    Invasive colorectal cancer is associated with poor prognosis requiring treatment with systemic chemotherapies usually including 5-fluorouracil. A consequence of prolonged treatment is the acquisition of resistance eventually resulting in the recurrence of highly metastatic cancer cells. To address the relationship between drug resistance and increased lymphatic metastatic potential, we used a 3D co-culture model of colon tumour cell spheroids of parent CCL227 cells and subclones with gradually increasing resistance against 5-fluorouracil. From each investigated cell line, homogeneous tumour spheroids were generated in the presence of methylcellulose yielding emboli of ∼700 µm diameter. When invasive, tumour spheroids disrupt the continuous lymphendothelial cell (LEC) layer and generate a 'circular chemorepellent-induced defect' (CCID), reminiscent of the entry gates through which tumour emboli intravasate lymphatic vasculature. Here we provide evidence that increasingly chemoresistant colon cancer spheroids were strongly associated with enhanced intravasative properties. In naïve CCL227 spheroids, miR-200 family members were released into exosomes thereby repressing the epithelial to mesenchymal transition-regulating transcription factors ZEB1 and SLUG in LEC. As a consequence of attenuated plasticity and migration of LEC, CCID formation was impaired. Loss of exosomal transferred miR-200c in resistant colon cells rendered LEC more susceptible to pro-migratory signals that were generated and directly transmitted by colon cancer spheroids. This observation indicates a common molecular axis in colon cancer and LEC where miR-200 family members act as regulators of ZEB proteins. The data support the notion that horizontal miR-200 signalling prevents the permeation of cells into adjacent epithelia and contributes to organ integrity.

  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. Recent advances of cocktail chemotherapy by combination drug delivery systems.

    PubMed

    Hu, Quanyin; Sun, Wujin; Wang, Chao; Gu, Zhen

    2016-03-01

    Combination chemotherapy is widely exploited for enhanced cancer treatment in the clinic. However, the traditional cocktail administration of combination regimens often suffers from varying pharmacokinetics among different drugs. The emergence of nanotechnology offers an unparalleled opportunity for developing advanced combination drug delivery strategies with the ability to encapsulate various drugs simultaneously and unify the pharmacokinetics of each drug. This review surveys the most recent advances in combination delivery of multiple small molecule chemotherapeutics using nanocarriers. The mechanisms underlying combination chemotherapy, including the synergistic, additive and potentiation effects, are also discussed with typical examples. We further highlight the sequential and site-specific co-delivery strategies, which provide new guidelines for development of programmable combination drug delivery systems. Clinical outlook and challenges are also discussed in the end.

  14. Recent Advances of Cocktail Chemotherapy by Combination Drug Delivery Systems

    PubMed Central

    Hu, Quanyin; Sun, Wujin; Wang, Chao; Gu, Zhen

    2016-01-01

    Combination chemotherapy is widely exploited for enhanced cancer treatment in clinic. However, the traditional cocktail administration of combination regimens often suffers from varying pharmacokinetics among different drugs. The emergence of nanotechnology offers an unparalleled opportunity for developing advanced combination drug delivery strategies with the ability to encapsulate various drugs simultaneously and unify the pharmacokinetics of each drug. This review surveys the most recent advances in combination delivery of multiple small molecule chemotherapeutics using nanocarriers. The mechanisms underlying combination chemotherapy, including the synergistic, additive and potentiation effects, are also discussed with typical examples. We further highlight the sequential and site-specific co-delivery strategies, which provide new guidelines for development of programmable combination drug delivery systems. Clinical outlook and challenges are also discussed in the end. PMID:26546751

  15. 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.

  16. Takotsubo cardiomyopathy and 5-Fluorouracil: getting to the heart of the matter.

    PubMed

    Lim, Stephanie Hui-Su; Wilson, Sharon Mary; Hunter, Arnagretta; Hill, Jane; Beale, Philip

    2013-01-01

    Takotsubo cardiomyopathy is a rare but increasingly recognized phenomenon, which can occur as a side-effect of chemotherapeutic agents, in particular, the antimetabolite 5-fluorouracil. We describe a case of delayed Takotsubo cardiomyopathy after 3 weeks of adjuvant 5-fluorouracil for resected rectal adenocarcinoma in a 66-year-old female, supported by angiographic, electrocardiographic, and echocardiographic features. As a complication, she developed an apical mural thrombus with subsequent cerebral thromboembolic events and was successfully anticoagulated to make a full recovery. We present a review of the literature on Takotsubo cardiomyopathy secondary to 5-fluorouracil and the rare occurrence of thromboembolic complications. As this is a significant clinical phenomenon which involves a multispeciality approach to management, oncologists and cardiologists need to recognize it as a potential toxicity of a widely administered chemotherapeutic drug.

  17. [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.

  18. Oxo-hydroxy tautomerism of 5-fluorouracil: water-assisted proton transfer.

    PubMed

    Markova, Nadezhda; Enchev, Venelin; Timtcheva, Iliana

    2005-03-10

    Post-Hartree-Fock ab initio quantum chemical calculations were performed for 5-fluorouracil in the gas phase and in a three-water cluster. Full geometry optimizations of the 5-fluorouracil-water complexes were carried out at the MP2/6-31+G(d,p) level of theory. MP4/6-31+G(d,p)//MP2/6-31+G(d,p) and MP4/6-31++G(d,p)//MP2/6-31+G(d,p) single-point calculations were performed to obtain more accurate energies. In water solution, 5-fluorouracil exists mainly in the 2,4-dioxo form (A). We propose that the populations of the 2-hydroxy-4-oxo (B) and 4-hydroxy-2-oxo (D) tautomers are 1 x 10(-4)% and 3.9 x 10(-8)%, respectively, on the basis of the relative stabilities of the tautomers calculated at the MP4/6-31++G(d,p)//MP2/6-31+G(d,p) level of theory. A profound difference between isolated and hydrated 5-fluorouracil is noted for the height of the tautomerization barrier. In the absence of water, the process of proton transfer is very slow. The addition of water molecules decreases the barrier by 2.3 times, making the process much faster. The minimum energy path (MP2/6-31+G(d,p)) for water-assisted proton transfer in trihydrated 5-fluorouracil was followed. CNDO/S-CI calculations predict singlet pi-pi(*) electron transitions at 312 nm for B and at 318 nm for D. The fluorescence spectrum of 5-fluorouracil in water confirms the presence of the hydroxy tautomer.

  19. Surface Treatment with 5-Fluorouracil After Flexor Tendon Repair in a Canine in Vivo Model

    PubMed Central

    Zhao, Chunfeng; Zobitz, Mark E.; Sun, Yu-Long; Predmore, Kelly S.; Amadio, Peter C.; An, Kai-Nan; Moran, Steven L.

    2009-01-01

    Background: Topical 5-fluorouracil has been reported to reduce adhesions in animal models of tenolysis. The purpose of this study was to investigate the effects of topical 5-fluorouracil on adhesion formation after tendon repairs were subjected to immediate postoperative rehabilitation in a canine model in vivo. Methods: Sixty dogs were randomly assigned to either a 5-fluorouracil treatment (thirty dogs) or a control group (thirty dogs). Each treatment group was then divided into three survival time points: ten days, twenty-one days, and forty-two days. The second and fifth flexor digitorum profundus tendons from each dog were fully lacerated at the zone-II area and then were repaired. Passive motion therapy started at day 5 postoperatively and continued until the dogs were killed. The repaired tendons were evaluated for normalized work of flexion, gliding resistance, repair strength, gene expression for type-I and type-III collagen and transforming growth factor-β1, and histological appearance. Results: The normalized work of flexion of the repaired tendons treated with 5-fluorouracil was significantly lower than that of the repaired tendons without 5-fluorouracil treatment at ten days. However, there was no significant difference between treated and untreated tendons at twenty-one and forty-two days. There was also no significant difference in gliding resistance, repair failure strength, or stiffness between treated and untreated tendons at any time point, or in the gross or histological appearance of adhesions at the time of killing. The expression of types-I and III collagen and transforming growth factor-β1 of the repaired tendon with 5-fluorouracil treatment was significantly lower than that of the tendons without treatment at ten days postoperatively, but not at twenty-one or forty-two days. Conclusions: Although 5-fluorouracil treatment can reduce adhesions in in vivo models of tenolysis, this treatment had only a transient effect in an in vivo model of

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

    PubMed

    Lamberti, Monica; Porto, Stefania; Zappavigna, Silvia; Stiuso, Paola; Tirino, Virginia; Desiderio, Vincenzo; Mele, Luigi; Caraglia, Michele

    2015-05-01

    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.

  1. [Tumoral dihydropyrimidine dehydrogenase expression and efficacy of 5-fluorouracil plus leucovorin plus UFT therapy in patients with colorectal cancer].

    PubMed

    Ishida, Hideyuki; Ohsawa, Tomonori; Nakada, Hiroshi; Yokoyama, Masaru; Inokuma, Shigehisa; Shirakawa, Kazuo; Yamada, Hirofumi; Hashimoto, Daijo

    2004-06-01

    The purpose of this study was to examine the relation between tumoral expression of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme of the degradation pathway 5-fluorouracil (5-FU), and the efficacy of 5-FU based chemotherapy for colorectal cancer. Twenty-eight colorectal cancer patients who had underwent noncurative resection (n = 16) or had developed recurrence (n = 12) were enrolled. All patients were given 5-FU plus leucovorin intravenously and UFT (1 M Tegafur, 4 M Uracil) perorally. The expression levels of the DPD in the primary lesions were determined by the enzyme-linked immunosorbent assay. Group A (n = 10) consisted of one patient with complete response, 4 with partial response, and 5 with no change (time to disease progression (TTP) > = 90 days). Group B (n = 18) consisted of 14 patients with progressive disease and 4 with NC (time to progression, < 90 days). The tumoral DPD levels did not differ between the groups (p = 0.58). There were no effective cases (n = 6) whose tumoral DPD levels were equal to or more than 83.2 U/mg protein (high DPD expression). There were marked overlaps in the DPD levels between the two groups whose DPD levels were less than 83.0 U/mg protein (moderate or low expression). These results suggest that high expression of tumoral DPD would be predictive to failure of fluoropyrimidine-based treatment. However, it is unlikely to set the optimal cutoff value for predicting the efficacy of this type of chemotherapy.

  2. Wogonin potentiates the antitumor effects of low dose 5-fluorouracil against gastric cancer through induction of apoptosis by down-regulation of NF-kappaB and regulation of its metabolism.

    PubMed

    Zhao, Qing; Wang, Jia; Zou, Mei-Juan; Hu, Rong; Zhao, Li; Qiang, Lei; Rong, Jing-Jing; You, Qi-Dong; Guo, Qing-Long

    2010-09-01

    Traditional Chinese medicines have been recognized as a new source of anticancer drugs or chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects. Wogonin (WOG) has a potential for therapeutic use in the treatment of antitumor and chemoprophylaxis. 5-Fluorouracil (5-FU) is a key systemic chemotherapy drug and widely use in the treatment of solid tumors. In this study, we found that combination of WOG and 5-FU inhibited the viability of MGC-803 cells in a concentration-dependent manner and exhibited a synergistic anticancer effect (CI<1) when 5-FU was used at relatively low concentrations. The pro-apoptotic activity of two-drug combination was much stronger than single. Furthermore, WOG could decrease the mRNA levels of dihydropyrimidine dehydrogenase (DPD), the metabolic enzymes of 5-FU. WOG could inhibit the NF-kappaB nuclear translocation and I-kappaB phosphorylation. Moreover, combined treatment caused significantly growth inhibition of human tumor xenografts. In addition, WOG markedly enhanced the antitumor activity of low dose 5-FU (i.p. 10mg/kg/day), however there is no toxicity and influence on diet consumption in experimental animals. Taken together, our data's showed that WOG increased 5-FU retention for a prolonged catabolism by modulating 5-FU metabolic enzymes and sensitized the MGC-803 cells to 5-FU induced apoptosis by inhibiting the NF-kappaB nuclear translocation. The anti-gastric cancer effect of two-drug combination was much stronger than that of WOG or 5-FU alone. These results may be relevant to design new clinical therapeutic strategies against gastric cancer in future.

  3. 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

  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. Concurrent radiation, mitomycin C and 5-fluorouracil in poor prognosis carcinoma of cervix: preliminary results of a Phase I-II study

    SciTech Connect

    Thomas, G.; Dembo, A.; Beale, F.; Bean, H.; Bush, R.; Herman, J.; Pringle, J.; Rawlings, G.; Sturgeon, J.; Fine, S.

    1984-09-01

    Between July 1981 and June 1983, 27 patients with advanced primary squamous cell carcinoma (SCC) of cervix and 8 with recurrent disease were treated using a pilot regimen of combination chemotherapy (CT): Mitomycin C (MIT), 5 Fluorouracil (5 FU), and radiation therapy (RT). CT and RT doses on this Phase I-II Study were escalated to the current regimen. A split course of RT was used, either pelvic RT alone or the same pelvic RT plus para-aortic RT. CT was given by continuous IV infusion days 1 through 4 of each half-course of RT. This was followed by one application of intrauterine /sup 137/Cs when possible. Three of the 8 patients with recurrence in the pelvis or para-aortic nodes had a complete response (CR) to CT-RT and are alive without disease at 19, 19 and 22 months after treatment, respectively. Twenty of the 27 (74%) primary patients had a CR. With a median duration of follow-up of 6 months 4/20 have relapsed, 1 in RT field, 2 at distant sites, and 1 in both. The acute toxicity of this regimen was tolerable: 2/35 developed transient leukopenia with one febrile episode, 9/35 developed transient thrombocytopenia without bleeding. Symptomatic sigmoid strictures developed in two patients, one requiring surgical intervention. Typically, near complete regression of tumor is noted on completion of the external RT, reproducing the dramatic responses that have been observed in SCC of the anal canal, esophagus and head and neck, with this CT-RT regimen.

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

    NASA Astrophysics Data System (ADS)

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

    2010-09-01

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

  7. 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.

  8. A NONSTEADY STATE MODEL FOR THE TIGHT-BINDING INHIBITION OF THYMIDYLATE SYNTHETASE BY 5-FLUOROURACIL

    EPA Science Inventory

    5-Fluorouracil (5_FU) is a widely used chemotherapeutic drug and tratogen that was chosen as a prototypic toxicant to contruct a biologically based dose-resonse (BBDR) model (Setzer et. al., 2001). Part of the BBDR model simulates the inhibition of thymidylate synthetase (TS), a...

  9. Symmetrical drug-related intertriginous and flexural exanthema secondary to topical 5-fluorouracil.

    PubMed

    Powers, Roxann; Gordon, Rachel; Roberts, Kenrick; Kovach, Rodney

    2012-05-01

    We report the case of a 56-year-old man who developed a distinctive skin eruption after treating actinic keratoses on the dorsal aspects of his right and left hands with topical 5-fluorouracil (5-FU). The distribution of his rash was characteristic of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), also known as baboon syndrome.

  10. 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

  11. High Glucose Modulates Antiproliferative Effect and Cytotoxicity of 5-Fluorouracil in Human Colon Cancer Cells

    PubMed Central

    Ma, Yi-Shing; Yang, I-Ping; Tsai, Hsiang-Lin; Huang, Ching-Wen

    2014-01-01

    5-Fluorouracil (5-FU)-based chemotherapy is widely used for the treatment of colorectal cancer (CRC). While optimal doses of 5-FU are generally established based on a patient's estimated body surface area, the plasma concentrations of 5-FU vary among patients. In addition, hyperglycemia in patients with CRC has been reported as a risk factor in poor prognosis. The aim of the present study was to investigate whether hyperglycemia affects antiproliferative effect of 5-FU on the human colon cancer cells (SW480, SW620, LoVo, and HCT116). Growth inhibition of 5-FU was accessed by WST-8 assay. The effect of high glucose (HG, 15 mM) and 5-FU on the cellular proliferation was evaluated by flow cytometry analysis using 5-ethynyl-2′-deoxy-uridine (EdU) incorporation plus 7-AAD. Cell death was determined by flow cytometry using Annexin V-FITC and PI. The results showed that HG, compared to physiological normal glucose (NG) concentration (5 mM), leads to increased cell proliferation and increased GI50 of 5-FU in the four colon cancer cell lines. When the cells were pretreated with a low-dose 5-FU in NG condition, subsequent HG treatment eliminated inhibitory effect of 5-FU in cancer cell growth. In the presence of 5-FU (0.5 μg/mL for LoVo and HCT116; 1 μg/mL for SW480 and SW620), culture with HG for 72 h does not significantly altered cell cycle profile in the four cell lines but significantly increased DNA replication in SW620 (21%) and LoVo (17%). Flow cytometric analysis showed that HG protects cells against 5-FU-induced cell death in SW480. Finally, HG did not alter intracellular level of reactive oxygen species (ROS), although 5-FU indeed induced higher intracellular level of ROS. In conclusion, HG attenuates growth inhibition of 5-FU and our results indicate that decreased cell death and increased DNA replication may account for the attenuating effect of a HG environment on 5-FU-induced tumor growth inhibition. PMID:24283362

  12. STI571 SENSITIZES BREAST CANCER CELLS TO 5-FLUOROURACIL, CISPLATIN AND CAMPTOTHECIN IN A CELL TYPE-SPECIFIC MANNER

    PubMed Central

    Sims, Jonathan T.; Ganguly, Sourik; Fiore, Leann S.; Holler, Chris J.; Park, Eun-Sil; Plattner, Rina

    2009-01-01

    Previously, we demonstrated that Abl kinases are highly active in invasive breast cancer cell lines, and contribute to survival in response to nutrient deprivation, invasion and proliferation. To determine whether an Abl kinase inhibitor, STI571 (Gleevec; imatinib mesylate) sensitizes breast cancer cells to chemotherapeutic agents, we treated three breast cancer cell lines (BT-549, MDA-MB-231, and MDA-MB-468) that have active Abl kinases, with STI571 in combination with several conventional chemotherapeutic drugs frequently used to treat breast cancer, and assessed the effect on cell viability, proliferation, and apoptosis. We found that STI571 had synergistic effects with cisplatin in BT-549 and to some extent in MDA-MB-468 cells, STI571 synergized with camptothecin using an alternate dosing regimen in MDA-MB-231 cells, and STI571 synergistically sensitized MDA-MB-468 cells to paclitaxel and to high doses of 5-fluorouracil. Significantly, STI571 increased the ability of cisplatin to inhibit constitutive activation of PI3K/Akt, synergized with camptothecin to increase the stability of IκB in MDA-MB-231 cells, and in MDA-MB-468 cells, camptothecin and 5-fluorouracil inhibited STI571-dependent activation of STAT3. In other cell line/drug combinations, STI571 had additive or antagonistic effects, indicating that the ability of STI571 to sensitize breast cancer cells to chemotherapeutic agents is cell type-dependent. Significantly, unlike cisplatin, paclitaxel, and camptothecin, mechloroethamine was strongly antagonistic to STI571, and the effect was not cell line-dependent. Taken together, these data indicate that the cellular milieu governs the response of breast cancer cells to STI571/chemotherapeutic combination regimens, which suggests that treatment with these combinations requires individualization. PMID:19427998

  13. 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.

  14. 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.

  15. Hydrolytic pathway of 5-fluorouracil in aqueous solutions for clinical use.

    PubMed

    Legay, Rémi; Massou, Stéphane; Azéma, Joëlle; Martino, Robert; Malet-Martino, Myriam

    2014-09-01

    The purpose of the study was to investigate the degradation pathway of 5-fluorouracil (FU) in the situation of commercial formulations for clinical use, namely FU dissolved in sodium hydroxide (NaOH) solutions or Tris buffer at pH 8.5-9. Combination of data from (19)F, (1)H and (13)C NMR and in some cases MS led to the identification of 8 and 13 FU degradation products in NaOH and Tris solutions respectively. In FU NaOH solutions, the first stage of FU degradation is a stereoselective hydration of the C5-C6 double bond leading to 5,6-dihydro-5-fluoro-6-hydroxyuracil, the cis stereoisomer being predominant relative to the trans. The second stage involves either a defluorination step with formation of fluoride ion and 5-hydroxyuracil or the cleavage of the N3-C4 bond giving the two diastereoisomeric 2-fluoro-3-hydroxy-3-ureidopropanoic acids. The subsequent N1-C6 bond breakdown of these compounds releases urea and 2-fluoro-3-oxopropanoic acid (FOPA) which in turn losses easily carbon dioxide leading to the formation of fluoroacetaldehyde (Facet). The degradation pathway in FU-Tris solutions is identical, except that Tris reacts with the aldehydes FOPA and Facet to form oxazolidine adducts stable at pH 8.5 but in equilibrium with the aldehyde forms at physiological pH, whereas the high reactivity of free aldehydes leads to numerous unidentified degradation compounds all in very low amounts. The FOPA diastereoisomeric adducts react with Facet to form four diastereoisomeric fused bicyclic five-membered ring compounds. Facet and FOPA are highly cardiotoxic. In Tris formulations, they are trapped as stable oxazolidine adducts which release the free aldehydes at physiological pH thus explaining the higher cardiotoxicity of FU in Tris solutions compared to that of FU in NaOH solutions.

  16. In vivo cell synchrony in the L1210 mouse leukaemia studied with 5-fluorouracil or 5-fluorouracil followed by cold thymidine infusion.

    PubMed Central

    Camplejohn, R. S.; Schultze, B.; Maurer, W.

    1977-01-01

    [3H]-TdR and [3]-udR labelling indices and mitotic indices were followed in tumour-bearing mice after application of either 5-fluorouracil (FU) alone or of FU followed by cold TdR infusion. With FU alone, accumulation of cells at the beginning of S was found, but there was no indication of a synchronous passage of the accumulated cells further round the cycle. When FU injection was followed by cold TdR infusion, a synchronous passage of the accumulated cells through the cycle was observed. However, there was a large variation in the response of individual mice to this treatment. PMID:861145

  17. 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.

  18. Bugs and Drugs: Oncolytic Virotherapy in Combination with Chemotherapy

    PubMed Central

    Wennier, Sonia Tusell; Liu, Jia; McFadden, Grant

    2015-01-01

    Single agent therapies are rarely successful in treating cancer, particularly at metastatic or end stages, and survival rates with monotherapies alone are generally poor. The combination of multiple therapies to treat cancer has already driven significant improvements in the standard of care treatments for many types of cancers. The first combination treatments exploited for cancer therapy involved the use of several cytotoxic chemotherapy agents. Later, with the development of more targeted agents, the use of novel, less toxic drugs, in combination with the more classic cytotoxic drugs has proven advantageous for certain cancer types. Recently, the combination of oncolytic virotherapy with chemotherapy has shown that the use of these two therapies with very distinct anti-tumor mechanisms may also lead to synergistic interactions that ultimately result in increased therapeutic effects not achievable by either therapy alone. The mechanisms of synergy between oncolytic viruses (OVs) and chemotherapeutic agents are just starting to be elucidated. It is evident, however, that the success of these OV-drug combinations depends greatly on the particular O V, the drug(s) selected, and the cancer type targeted. This review summarizes the different OV-drug combinations investigated to date, including the use of second generation armed OVs, which have been studied with the specific purpose of generating synergistic interactions with particular chemotherapy agents. The known mechanisms of synergy between these OV-drug combinations are also summarized. The importance of further investigating these mechanisms of synergy will be critical in order to maximize the therapeutic efficacy of OV-drug combination therapies in the future. PMID:21740354

  19. Bugs and drugs: oncolytic virotherapy in combination with chemotherapy.

    PubMed

    Wennier, Sonia Tusell; Liu, Jia; McFadden, Grant

    2012-07-01

    Single agent therapies are rarely successful in treating cancer, particularly at metastatic or end stages, and survival rates with monotherapies alone are generally poor. The combination of multiple therapies to treat cancer has already driven significant improvements in the standard of care treatments for many types of cancers. The first combination treatments exploited for cancer therapy involved the use of several cytotoxic chemotherapy agents. Later, with the development of more targeted agents, the use of novel, less toxic drugs, in combination with the more classic cytotoxic drugs has proven advantageous for certain cancer types. Recently, the combination of oncolytic virotherapy with chemotherapy has shown that the use of these two therapies with very distinct anti-tumor mechanisms may also lead to synergistic interactions that ultimately result in increased therapeutic effects not achievable by either therapy alone. The mechanisms of synergy between oncolytic viruses (OVs) and chemotherapeutic agents are just starting to be elucidated. It is evident, however, that the success of these OV-drug combinations depends greatly on the particular OV, the drug(s) selected, and the cancer type targeted. This review summarizes the different OV-drug combinations investigated to date, including the use of second generation armed OVs, which have been studied with the specific purpose of generating synergistic interactions with particular chemotherapy agents. The known mechanisms of synergy between these OV-drug combinations are also summarized. The importance of further investigating these mechanisms of synergy will be critical in order to maximize the therapeutic efficacy of OV-drug combination therapies in the future.

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

    PubMed

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

    2012-10-01

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

  1. Effects of systemic hyperthermia and intrahepatic infusion with 5-fluorouracil.

    PubMed

    Daly, J M; Smith, G; Frazier, O H; Dudrick, S J; Copeland, E M

    1982-03-15

    Potential hepatotoxicity from systemic hyperthermia (43 degrees C) +/- simultaneous hepatic artery infusion with 5-FU was evaluated in an animal model. Twenty-two dogs had aorta-vena caval shunts (8 mm Dacron grafts) placed, and 10 of these dogs had silastic catheters inserted in their hepatic arteries. Two weeks later, Group I (n = 8) was heated to 43 degrees C for one hour (distal esophageal + intrahepatic temperature) using the shunts and blood-heat exchangers; Group II (n = 6) was heated to 43 degrees C for one hour with simultaneous intrahepatic infusion of 5-FU (10 mg/kg); Group III (n = 8) was shamheated (37 degrees C) and underwent a one hour intrahepatic infusion with 5-FU (10 mg/kg). Serum alkaline phosphatase, SGOT, SPGT (IU/ml) and bilirubin were measured, and liver biopsies were obtained at 0 and 1 hour, at one and seven days. Mean SGOT levels increased significantly (P less than 0.05) in Group II from 19 +/- 2 to 31 +/- 6 and 63 +/- 18 at one hour and one day; these levels rose slightly in Group I from 31 +/- 5 to 40 +/- 8 and 47 +/- 8 at one hour and one day. Hepatocellular enzyme levels returned to normal at seven days in both groups. Mean SGOT and SGPT levels remained similar in Group III at all time periods. No significant differences in mean serum alkaline phosphatase or bilirubin levels were noted. There was no histologic evidence of hepatocellular necrosis at any time period. Survival was 6/8, 5/6 and 8/8 dogs in Groups I, II, and III, respectively. Systemic hyperthermia to 43 degrees C for one hour in dogs does not adversely affect serum hepatic enzymes or cell structure; reversible serum hepatic enzyme changes occurred when hyperthermia was combined with hepatic artery infusion with 5-FU.

  2. Effects of Ultrasound Irradiation on the Release Profile of 5-fluorouracil from Magnetic Polylactic co-glycolic Acid Nanocapsules

    PubMed Central

    Abed, Z.; Beik, J.; Khoee, S.; Khoei, S.; Shakeri-Zadeh, A.; Shiran, M.B.

    2016-01-01

    Background: Drug nano-carriers are one of the most important tools for targeted cancer therapy so that undesired side effects of chemotherapy drugs are minimized. In this area, the use of ultrasound can be helpful in controlling drug release from nanoparticles to achieve higher treatment efficiency. Objective: Here, we studies the effects of ultrasound irradiation on the release profile of 5-fluorouracil (5-Fu) loaded magnetic poly lactic co-glycolic acid (PLGA) nanocapsules. Methods: 5-Fu loaded magnetic PLGA nanocapsules were synthesized by multiple emulsification method. Particle size was measured by dynamic light scattering (DLS) and transmission electron microscope (TEM). The pattern of drug release was assessed with and without 3 MHz ultrasound waves at intensities of 0.3, 0.5 and 1 w/cm2 for exposure time of 5 and 10 min in phosphate-buffered saline (PBS). Results: The size of nanoparticles was about 70 nm. Electron microscope images revealed the spherical shape of nanoparticles. The results demonstrated that the intensity and exposure time of ultrasound irradiation have significant effects on the profile of drug release from nanoparticles. Conclusion: It may be concluded that the application of ultrasound to control the release profile of drug loaded nanocapsules would be a promising method to develop a controlled drug delivery strategy in cancer therapy. PMID:27853726

  3. CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype

    PubMed Central

    Paschall, Amy V.; Yang, Dafeng; Lu, Chunwan; Redd, Priscilla S.; Choi, Jeong-Hyeon; Heaton, Christopher M.; Lee, Jeffrey R.; Nayak-Kapoor, Asha; Liu, Kebin

    2016-01-01

    The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment selectively enriches a subset of CD133+ colon cancer cells in vitro. 5-FU chemotherapy also increases CD133+ tumor cells in human colon cancer patients. However, sorted CD133+ colon cancer cells exhibit no increased resistance to 5-FU, and CD133 levels exhibit no correlation with colon cancer patient survival or cancer recurrence. Genome-wide analysis of gene expression between sorted CD133+ colon cancer cells and 5-FU-selected colon cancer cells identifies 207 differentially expressed genes. CD24 is one of the genes whose expression level is lower in the CD133+ and 5-FU-resistant colon cancer cells as compared to CD133+ and 5-FU-sensitive colon cancer cells. Consequently, CD133+CD24lo cells exhibit decreased sensitivity to 5-FU. Therefore, we determine that CD133+CD24lo phenotype defines 5-FU-resistant human colon cancer stem cell-like cells. PMID:27659530

  4. 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

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

    PubMed

    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.

  6. The herbal extract, Iberogast, improves jejunal integrity in rats with 5-Fluorouracil (5-FU)-induced mucositis.

    PubMed

    Wright, Tessa H; Yazbeck, Roger; Lymn, Kerry A; Whitford, Eleanor J; Cheah, Ker Y; Butler, Ross N; Feinle-Bisset, Christine; Pilichiewicz, Amelia N; Mashtoub, Suzanne; Howarth, Gordon S

    2009-05-01

    There is an acute need for the development of effective therapies for mucositis, a debilitating side effect of cancer chemotherapy. Iberogast is a herbal extract reported to possess anti-inflammatory properties. We investigated Iberogast for its potential to reduce the severity of 5-Fluorouracil (FU)-induced mucositis in rats. Rats were allocated to three treatment groups (n = 8) and gavaged daily with a 10% solution of Iberogast or water from day 0 to day 8. Rats were injected intraperitoneally with 5-FU (150 mg/kg) or saline on day 6, and killed after 72 h. In vivo and in vitro sucrase activity was assessed by (13)C-sucrose breath test (SBT) and sucrase assay respectively. Intestinal disease severity was determined by histological assessment of villus height and crypt depth. Significant increases in villus height (277 +/- 9 microm) and crypt depth (67 +/- 3 microm) were observed in 5-FU + Iberogast-treated rats compared with 5-FU + Water (224 +/- 13 microm and 48 +/- 2 microm respectively; p < 0.05). Sucrase activity was significantly reduced in all 5-FU groups compared to control. Significant reductions in SBT and sucrase activity were observed in all 5-FU groups compared with Saline + Water controls (p < 0.05). We conclude that although Iberogast partially improved the histopathological features of 5-FU induced mucositis, it conferred no significant protection as indicated by the assessed endpoints.

  7. 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.

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

    PubMed

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

    2016-12-01

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

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

    PubMed

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

    2016-10-01

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

  10. 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.

  11. Melanonychia induced by topical treatment of periungual warts with 5-fluorouracil.

    PubMed

    De Anda, Mariana Catalina; Domínguez, Judith Guadalupe

    2013-03-15

    Periungal and subungual warts are benign epidermal neoplasms caused by human papillomaviruses. They represent a challenge for management because of resistance to treatment. 5-flourouracil is an antimetabolite that interferes with DNA synthesis and inhibits RNA formation. We present a 32-year-old female with subungual and periungual warts of the fingers of both hands and first right toe. She was treated with 5-fluorouracil twice daily under occlusion plus 20 percent urea. After a month she presented with grayish transverse melanonychia along and parallel to the lunula with some maceration of the periungal folds. Nail pigmentation may be a consequence of dermal deposition by systemic drugs and less frequently by topical drugs. In this case melanonychia was induced by the topical application of 5-fluorouracil. The brown-grayish pigmentation, with parallel involvement of the lunula of all the nails treated, presented like that induced by systemically administered cytotoxic drugs.

  12. Chemotherapy

    Cancer.gov

    Chemotherapy is a type of cancer treatment that uses drugs to kill cancer cells. Learn how chemotherapy works against cancer, why it causes side effects, and how it is used with other cancer treatments.

  13. Combination chemotherapy and radiotherapy in non-Hodgkin's lymphomata.

    PubMed Central

    Bonadonna, G.; De Lena, M.; Lattuada, A.; Milani, F.; Monfardini, S.; Beretta, G.

    1975-01-01

    The results obtained with intensive chemotherapy and intensive chemotherapy plus radiotherapy in non-Hodgkin's lymphomata are reported. A quintuple drug regimen (mechloretamine, adriamycin, bleomycin, vincristine and prednisone) in histiocytic lymphomata (Stage III and IV) yielded complete remissions in 53% and complete plus partial remissions in 77%. These figures were 44% and 64% respectively in lymphocytic lymphoma. In Stage III complete responders after combination chemotherapy were subsequently irradiated (involved field irradiation). The median duration of complete remission after completion of radiotherapy was 9-5 months in histiocytic and 12-0 months in lymphocytic lymphomata. At 2 years actuarial survival in Stage III and IV was better in patients with the lymphocytic type and with nodular pattern than with histiocytic and diffuse patterns. A more recent trial compares, in Stage IV patients, cyclophosphamide, vincristine and prednisone (CVP) versus adriamycin, bleomycin and prednisone (ABP). Although the number of evaluable patients is still limited, there appears to be no difference in the response rate between CVP and ABP. In Stages I and II, 6 cycles of CVP were given as adjuvant treatment after radiotherapy. At the present moment, there is no statistical difference in the relapse rate between the group of patients treated with radiotherapy alone and that with radiotherapy plus CVP. PMID:52367

  14. Chemotherapy

    MedlinePlus

    ... to Know Central Venous Catheters Track Your Chemotherapy Side Effects [PDF] Common Concerns About Chemotherapy Get information about common concerns people have when getting chemotherapy, and learn more about related topics. Is It Safe to Keep My Pet While I’m Being Treated for ... Drug Use ...

  15. Post-5-fluorouracil human marrow: stem cell characteristics and renewal properties after autologous marrow transplantation.

    PubMed

    Stewart, F M; Temeles, D; Lowry, P; Thraves, T; Grosh, W W; Quesenberry, P J

    1993-05-01

    The effect of 5-fluorouracil (5-FU) pretreatment on human bone marrow (BM) progenitor/stem cells and recovery of hematopoiesis after autologous marrow transplant was studied. Twenty-one patients were treated with 5-FU (15 mg/kg to 45 mg/kg) intravenously (IV) for 1 to 3 days administered 6 to 22 days before BM harvest. Post-FU marrow was infused into 15 patients after high-dose cyclophosphamide, carmustine (BCNU), and VP-16 (CBV). Seventeen patients (historical controls) were treated with CBV and autologous BM transplantation but did not receive 5-FU before marrow harvest. The groups were comparable for diagnosis and prior therapy. In the 5-FU-treated group and control group, median recovery times for platelet count to 50,000/mm3 were 20 and 30 days, respectively (P = .007), and for platelet count to 100,000/mm3, 23 and 38 days, respectively (P = .007), while neutrophil recovery was not significantly altered. In vitro cultures with 1 to 7 growth factors (interleukin-1 [IL-1], IL-3, IL-4, IL-6, colony-stimulating factor-1 [CSF-1], granulocyte-macrophage colony-stimulating factor [GM-CSF], and G-CSF) were performed. In 8 of 10 patients whose marrow was studied before and after 5-FU treatment, the numbers of CFU-C responsive to the combination of GM-CSF and IL-3 was increased 6.15-fold by 5-FU pretreatment. In 4 of these patients, thymidine suicide of GM-CSF- and IL-3-stimulated CFU-C ranged from 17% to 42%. High proliferative potential colony-forming cell (HPP-CFC) was observed in low frequency in normal marrow and patient's marrow before 5-FU treatment. In 11 of 16 patients pretreated with 5-FU, increased numbers of HPP-CFC were noted. GM-CSF and IL-3 interacted synergistically to stimulate HPP-CFC. Multifactor combinations, especially GM-CSF + G-CSF + IL-3 + IL-6 + IL-1 + CSF-1 did not increase total colony count or classic HPP-CFC but did result in altered morphology, producing huge, loose colonies. The marrow from patients pretreated with 5-FU is enriched with

  16. Topical Mitomycin-C versus Subconjunctival 5-Fluorouracil for Management of Bleb Failure

    PubMed Central

    Pakravan, Mohammad; Miraftabi, Arezoo; yazdani, Shahin; Koohestani, Nasim; yaseri, Mehdi

    2011-01-01

    Purpose To compare the efficacy and safety of topical mitomycin-C (MMC) drops with that of subconjunctival 5-fluorouracil (5-FU) injections for management of early bleb failure after trabeculectomy or combined phacoemulsification and trabeculectomy with posterior chamber intraocular lens implantation (PT+PCIOL). Methods In a randomized comparative study, 37 eyes of 37 patients with impending early bleb failure received MMC 0.02% eye drops for 2 or 4 weeks (19 eyes) or subconjunctival 5-FU injections, 5 mg per dose (18 eyes). Complete success was defined as 5 < IOP ≤ 18 mmHg without medications. Results Baseline characteristics were comparable between the study groups. However, there were more cases of combined PT+PCIOL in the MMC group [11 (57.9%) eyes versus 3 (16.7%) eyes, P = 0.017]. Mean preoperative IOP was 20.5±8.85 mmHg in the MMC group and 25.82±11.35 mmHg in the 5-FU group (P = 0.129), which was decreased to 13.2±6.1 and 10.6±4.8 mmHg respectively after 12 months (P = 0.159). There was no significant difference between the study groups in terms of bleb extent (P = 0.170), height (P = 0.178) or vascularity (P = 0.366). At the end of the study, complete success was achieved in 13 eyes (68.4%) in the MMC group and 14 eyes (77.8%) in the 5-FU group (P = 0.714). The survival of success at 8 months (median follow-up) was 89.5% and 86.5% in the MMC and 5-FU groups respectively; the number of glaucoma medications (P = 0.707) and best-corrected visual acuity (P = 0.550) were also comparable. Complication rates were similar in the study groups (P = 0.140). Conclusion Topical MMC 0.02% has comparable safety and efficacy to subconjunctival 5-FU injections for management of early bleb failure. Topical MMC 0.02% drops are more convenient and can be initiated first, while 5-FU injections may be reserved for eyes with an insufficient response to topical MMC. PMID:22454715

  17. Preoperative concurrent 5-Fluorouracil infusion, Mitomycin C and pelvic radiation therapy in tethered and fixed rectal carcinoma

    SciTech Connect

    Chan, A.; Wong, A.; Langevin, J.; Khoo, R. )

    1993-04-02

    This is a Phase 1/2 study of preoperative concurrent radiation and chemotherapy in tethered and fixed rectal carcinoma. This study examined the curative resectability, the acute toxicities during chemo-radiation and the surgical complications. Between 1986 and 1990, 46 patients were treated with preoperative pelvic radiation (4,000 cGy in 20 fractions in 4 weeks), 5-Fluorouracil infusion (20 mg/m[sup 2], days 1--4 and 15--18) and Mitomycin C (8 mg/m[sup 2], day 1). This was followed by surgery 6 to 8 weeks later. 30 patients had tethered tumors and 16 patients had fixed tumors. After preoperative chemo-radiation, 41 patients (89%) underwent curative resection. Two patients (4%) had no residual tumor found (T0N0M0). Seven patients (15%) had nodal metastases. Two patients developed grade 3 neutropenia (WBC = 1--2 [times] 10[sup 9]/L) during chemo-radiation. Five patients had delay in perineal wound healing. One patient had an anastomotic leak. Four patients developed stomal stenosis which required surgical revision. The 2-year actuarial survival was 73%. The 2-year local relapse rate was 16%. Patients with fixed carcinoma had a higher incidence of local failure (28% vs. 10%) and the difference was statistically significant (p = 0.0036). The 2-year distant failure rate was 41%, and the rates were similar for both tethered and fixed carcinomas. Preoperative pelvic radiation, chemotherapy and surgery could achieve a curative resection rate of 89% in tethered and fixed rectal carcinomas. However, distant metastases remained the major cause of failure. 42 refs., 6 figs., 4 tabs.

  18. Toxicity and efficacy of 5-fluorouracil and capecitabine in a patient with TYMS gene polymorphism: A challenge or a dilemma?

    PubMed

    Shahrokni, Armin; Rajebi, Mohammad Reza; Saif, Muhammad Wasif

    2009-10-01

    5-Fluorouracil (5-FU) is an antimetabolite that acts during the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS), thus preventing DNA synthesis, which leads to imbalanced cell growth and ultimately cell death. 5-FU and its oral prodrug capecitabine are used in the treatment of a number of solid tumors, including colorectal, breast, gastric, pancreatic, prostate, and bladder cancers. Common side effects include leukopenia, diarrhea, stomatitis, nausea, vomiting, and alopecia. Hand-foot syndrome (HFS) is a relatively common side effect of cytotoxic chemotherapy. It is more frequently associated with 5-FU, capecitabine, and cytarabine. This article reports on the case of a 55-year-old black man with metastatic colorectal carcinoma that was refractory to recommended treatment measures who developed grade 3 HFS after treatment with modified FOLFOX6 (leucovorin [LV]/5-FU/oxaliplatin) and bFOL (bolus 5-FU/LV/oxaliplatin) regimens. Treatment was discontinued despite excellent response to chemotherapy. The patient had progression of disease on IROX (irinotecan/oxaliplatin) and irinotecan/cetuximab regimens. He was started on gemcitabine/capecitabine and developed HFS again, which was controlled with aggressive skin care and vitamin B6 treatment. Full sequencing of the dihydropyrimidine dehydrogenase (DPYD) gene and analysis of the human TS gene (TYMS) promoter region was performed. Pharmacogenetic testing revealed 2R/2R genotype of TYMS gene, which is associated with up to a 2.5-fold risk of toxicity to 5-FU therapy. Hand-foot syndrome has proven to be a dose-limiting toxicity of 5-FU, especially of capecitabine, leading to significant morbidity. Hand-foot syndrome seems to be dose dependent, and both peak drug concentration and total cumulative dose determine its occurrence. Genetic variations such as polymorphic abnormality of TYMS are potential causative factors for a significant portion of serious

  19. The Clinical Significance of MiR-429 as a Predictive Biomarker in Colorectal Cancer Patients Receiving 5-Fluorouracil Treatment

    PubMed Central

    Dong, Sheng-jian; Cai, Xiao-jun; Li, Shu-jin

    2016-01-01

    Background 5-Fluorouracil (5-FU) based treatment is the standard therapy for metastatic colorectal cancer (CRC), but the development of chemoresistance is inevitable. Increasing evidence shows that dysregulation of microRNAs (miRNAs) is involved in malignant transformation. Thus, it is imperative that we find new diagnostic and prognostic marker for chemotherapy in CRC. Material/Methods For clinical parameter analysis, 78 CRC tissues and adjacent normal tissues and 45 serum specimens from CRC patients were included in this study. For chemo-response analysis, 116 primary tissues were collected from the patients receiving first-line 5-FU treatment. Quantitative Real-Time PCR (qRT-PCR) was used to detect microRNAs expression. Results The expression of miR-429 was significantly increased in both serum and primary tissues from CRC patients, and enhanced miR-429 level was associated with tumor size, lymph node metastasis, and TNM stage. The diagnostic and prognostic values were also confirmed in CRC by using primary tissues. For patients receiving 5-FU-based treatment, miR-429 levels were significantly lower in responding group. The proportions of patients that did not experience response to therapy were higher in primary tumors with high miR-429 expression levels as compared with primary tumors with low miR-429 expression levels. Finally, Kaplan-Meier survival analysis showed that miR-429 is an independent prognostic indicator for chemo-response to 5-FU therapy among CRC patients. Conclusions High level of miR-429 expression was correlated with enhanced malignant potential and poor prognosis of CRC patients. Furthermore, miR-429 could affect the chemo-sensitivity of CRC patients to 5-FU therapy and was associated with poor response to 5-FU-based chemotherapy in patients with CRC. PMID:27654003

  20. Targeting Cancer using Polymeric Nanoparticle mediated Combination Chemotherapy

    PubMed Central

    Gad, Aniket; Kydd, Janel; Piel, Brandon; Rai, Prakash

    2016-01-01

    Cancer forms exhibiting poor prognosis have been extensively researched for therapeutic solutions. One of the conventional modes of treatment, chemotherapy shows inadequacy in its methodology due to imminent side-effects and acquired drug-resistance by cancer cells. However, advancements in nanotechnology have opened new frontiers to significantly alleviate collateral damage caused by current treatments via innovative delivery techniques, eliminating pitfalls encountered in conventional treatments. Properties like reduced drug-clearance and increased dose efficacy by the enhanced permeability and retention effect deem nanoparticles suitable for this application. Optimization of size, surface charge and surface modifications have provided nanoparticles with stealth properties capable of evading immune responses, thus deeming them as excellent carriers of chemotherapeutic agents. Biocompatible and biodegradable forms of polymers enhance the bioavailability of chemotherapeutic agents, and permit a sustained and time-dependent release of drugs which is a characteristic of their composition, thereby providing a controlled therapeutic approach. Studies conducted in vitro and animal models have also demonstrated a synergism in cytotoxicity given the mechanism of action of anticancer drugs when administered in combination providing promising results. Combination therapy has also shown implications in overcoming multiple-drug resistance, which can however be subdued by the adaptable nature of tumor microenvironment. Surface modifications with targeting moieties can therefore feasibly increase nanoparticle uptake by specific receptor-ligand interactions, increasing dose efficacy which can seemingly overcome drug-resistance. This article reviews recent trends and investigations in employing polymeric nanoparticles for effectively delivering combination chemotherapy, and modifications in delivery parameters enhancing dose efficacy, thus validating the potential in this

  1. Treatment of solar keratoses with a 5-fluorouracil and salicylic acid varnish.

    PubMed

    Goncalves, J C

    1975-01-01

    In an attempt to avoid the side-effects of treating solar keratoses with 5% 5-fluorouracil (5-FU) ointment, a new pharmacological varnish containing 5% 5-FU and 5-10% salicylic acid to collodium was tried. Twenty patients with such lesions were treated. A drop of the varnish was applied on each lesion every 3 weeks. Only one to five applications on facial lesions were necessary to obtain apparent cure in all patients. Lesions reappeared in four patients, but were cured after a second and similar treatment. The keratoses of the hands were more resistant and needed seven applications in one patient and nine in the other.

  2. Angina induced by 5-fluorouracil infusion in a patient with normal coronaries.

    PubMed

    Tajik, Reza; Saadat, Habib; Taherkhani, Maryam; Movahed, Mohammad Reza

    2010-01-01

    This article reviews the occurrence of angina in patients treated with 5-fluorouracil (5-FU) without significant coronary artery disease. We present a case followed by a review of the literature. A 43-year-old man with a history of colon cancer developed typical angina during intravenous infusion of 5-FU. His electrocardiogram (ECG) showed tall T waves during his angina episode. His angina and ECG changes reoccurred during a second 5-FU infusion. His coronary angiography was normal. This case is consistent with a rare occurrence of 5-FU-induced angina despite normal coronaries. Physician should be aware of this important side effect of 5-FU infusion.

  3. Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina.

    PubMed

    Stewart, T; Pavlakis, N; Ward, M

    2010-04-01

    In this case series we present a variety of different cardiac toxicities with 5-fluorouracil and its pro-drug capecitabine, including myocardial infarction, cardiomyopathy, sinoatrial and atrioventricular node dysfunction, takotsubo cardiomyopathy and QT prolongation with torsade-de pointes ventricular tachycardia. We stress the fact that while vasospasm is a well-recognized side-effect of this class of chemotherapeutic agent, broader cardiotoxicity is commonly seen and an increased awareness of the range of toxicity is necessary if repeat toxicity is to be avoided.

  4. Is 5-fluorouracil-induced vasospasm a Kounis syndrome? A diagnostic challenge.

    PubMed

    Karabay, C Y; Gecmen, C; Aung, S M; Guler, A; Candan, O; Batgerel, U; Kalayci, A; Kirma, C

    2011-11-01

    Cardiovascular hypersensitivity is a rare and well-documented side-effect of 5-FU (5-fluorouracil). Besides the common complications such as angina pectoris and myocardial infarction, it can also cause cardiogenic shock, and supraventricular and ventricular arrhythmias. Studies have reported that FU-induced angina most commonly occurred due to vasospasm. In our case, 9 hours after stopping the infusion of 5-FU, the patients developed symptoms and electrocardiographic (ECG) findings consistent with acute myocardial infarction. We intend to share this rare case and discuss whether this late complication after 5-FU infusion is an FU-induced vasospasm or rather an allergic reaction leading to Kounis syndrome.

  5. Determination of Moisture Content in 5-Fluorouracil using Diffuse Reflectance Infrared Spectroscopy

    NASA Astrophysics Data System (ADS)

    Singh, Parul; Jangir, Deepak Kumar; Mehrotra, Ranjana; Kandpal, H. C.

    2008-11-01

    Determination of moisture content in pharmaceuticals is very important, as moisture is mainly responsible for the degradation of drugs. The degraded drug has not only reduced efficacy but is also hazardous for health. The objective of the present work is to replace the Karl Fischer (KF) titration method used for moisture analysis with a method that is rapid, involves no toxic materials and is more effective. Diffuse reflectance infrared spectroscopy, which is explored as a potential alternate for various applications, is investigated for moisture analysis in 5-Fluorouracil, an anticancer drug.

  6. Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug.

    PubMed Central

    Lemaire, L.; Malet-Martino, M. C.; de Forni, M.; Martino, R.; Lasserre, B.

    1992-01-01

    The cardiotoxicity of 5-fluorouracil (FU) was attributed to impurities present in the injected vials. One of these impurities was identified as fluoroacetaldehyde which is metabolised by isolated perfused rabbit hearts into fluoroacetate (FAC), a highly cardiotoxic compound. FAC was also detected in the urine of patients treated with FU. These impurities were found to be degradation products of FU that are formed in the basic medium employed to dissolve this compound. To avoid chemical degradation of this antineoplastic drug, the solution of FU that will be injected should be prepared immediately before use. PMID:1637660

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

    NASA Astrophysics Data System (ADS)

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

    2017-02-01

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

  8. 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.

  9. Pancytopenia and Severe Gastrointestinal Toxicities Associated with 5-Fluorouracil in a Patient with Thymidylate Synthase (TYMS) Polymorphism

    PubMed Central

    Wang, Bo; Walsh, Shannon J

    2016-01-01

    5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50-year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5’TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a

  10. Replacing 5-fluorouracil by capecitabine in localised squamous cell carcinoma of the anal canal: systematic review and meta-analysis

    PubMed Central

    Souza, Karla T; Pereira, Allan AL; Araujo, Raphael L; Oliveira, Suilane Coelho Ribeiro; Hoff, Paulo M; Riechelmann, Rachel P

    2016-01-01

    Background The standard treatment for localised squamous cell carcinoma of the anal canal (SCCAC) is chemoradiotherapy (CRT) with infusional 5-fluorouracil (5-FU) and mitomycin. Because 5-FU and capecitabine have offered similar efficacy in many phase-III trials of solid tumours, studies have tested capecitabine in this setting of SCCAC. However, these studies are small and have reported variable results. Therefore, a systematic review and meta-analysis was performed. Methods Medline, Scopus and Embase were searched for studies that evaluated the efficacy outcomes of capecitabine used as a substitute of 5-FU in the CRT of localised SCCAC. The primary endpoint was complete response rate (CRR) at 6 months. Metaprop analysis of reported CRR-based on pooled estimates of proportions with corresponding 95% confidence intervals (95%CI) were calculated on the base of the Freeman-Tukey double arcsine transformation. Results We retrieved 300 studies, of which six met our eligibility criteria. The capecitabine dose ranged from 500 mg/m2 to 825 mg/m2 BID for 5 days per week during radiation. With a total of 218 patients, the median follow-up was 21.5 months (14–23). The pooled analysis of three trials (N = 132 patients) reported a CRR at 6 months of 88% (83%–94%), considering all clinical stages. The pooled analysis of overall CRR (N = 218 patients), evaluated at different intervals, showed an overall CRR of 91% (87%–95%). Rates of locoregional relapse varied from 3.2% to 21%. The majority of patients completed the planned radiotherapy dose (93.5%–100%) and any chemotherapy interruption was reported in up to 55.8% of patients. Conclusions Capecitabine is an acceptable and more convenient alternative to infusional 5-FU in the CRT for localised SCCAC, offering similar clinical CRR to those reported by phase-III trials. PMID:28105070

  11. Drug-specific [sup 19]F NMR and dynamic [sup 18]F PET imaging of the cytostatic agent 5-fluorouracil

    SciTech Connect

    Bellemann, M.E.; Brix, G.; Haberkorn, U.; Ostertag, H.J.; Lorenz, W.J. )

    1994-12-01

    The spatial distribution of the antineoplastic agent 5-fluorouracil (5-FU) has been mapped both with [sup 19]F NMR and [sup 18]F PET imaging techniques. For [sup 19]F NMR imaging of 5-FU and its major catabolite [alpha]-fluoro-[beta]-alanine (FBAL), a fast gradient-echo pulse sequence was employed. A chemical-shift selective saturation pulse was used to suppress either the 5-FU or the FBAL resonance before the other component of the [sup 19]F NMR spectrum was images. This approach yielded selective 5-FU and FBAL NMR images free of chemical-shift artifacts in readout and slice-selection direction. In phantom experiments, [sup 19]F 5-FU and FBAL images with a spatial resolution of 12.5 x 12.5 x 20 mm[sup 3] were obtained in 32 min from model solutions with drug and catabolite concentrations similar to those estimated in animals and patients undergoing i.v. chemotherapy with 5-FU. The biodistribution of 5-[[sup 18]F]FU in rats shortly after administration of the drug demonstrated the good vascularization of the transplanted tumors. The metabolic turnover of the cytostatic agent started about 10--20 min p.i. and was predominant in the tumor and liver tissue. The rapid adjustment of the [sup 18]F metabolite concentrations in the transplanted tumors to a steady state provides evidence of anabolic tumor activity, which supports the hypothesis of 5-FU trapping in malignant cells based on [sup 19]F NMR spectroscopy data. The high uptake of 5-[[sup 18]F]FU in the liver, on the other hand, mainly reflects the catabolization of 5-FU to the noncytotoxic FBAL, which leads to a reduced bioavailability of the drug.

  12. Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon.

    PubMed

    Sakai, Hiroyasu; Sagara, Atsunobu; Matsumoto, Kenjiro; Jo, Ara; Hirosaki, Akiko; Takase, Kazuhide; Sugiyama, Ryoto; Sato, Ken; Ikegami, Daigo; Horie, Syunji; Matoba, Motohiro; Narita, Minoru

    2014-09-01

    Diarrhea is a common side effect experienced by cancer patients undergoing clinical chemotherapy, such as with 5-fluorouracil (5-FU). However, the precise mechanisms underlying 5-FU-induced diarrhea remain unclear. In the present study, we examined the role of neutrophil in 5-FU-induced diarrhea. Mice were given 5-FU (50mg/kg, i.p.) daily for 4 days. Sivelestat sodium (100 or 300 mg/kg, i.p., neutorophil elastase inhibitor) or SB225002 (3 or 9 mg/kg, i.p., CXCR2 antagonist) was administered before the administration of 5-FU. Gene expression levels of aquaporin (AQP) 4 and 8, CXCL1, CXCL2, CXCL3, neutrophil elastase (Elane) and myeloperoxidase (MPO) in the colon were examined by real-time RT-PCR. The neutrophil (Ly-6G positive cell) number in the mucosa of colon was measured by flow-cytometric analysis. Administration of 5-FU induced diarrhea and decreased the expression levels of AQP 4 and 8 in the colon. Under the present conditions, the expression levels of CXCL1, CXCL2, CXCL3, the neutrophil markers Elane and MPO, as well as Ly-6G-positive neutrophils, in the colon were significantly increased by 5-FU. Neutrophil recruitment with decreased levels of AQP 4 and 8 were dramatically inhibited by either sivelestat sodium or SB225002. Furthermore, these reagents reduced the 5-FU-induced body weight loss and diarrhea. These findings provide evidence that neutrophil recruitment and neutrophil elastase may decrease the levels of AQP 4 and 8 in the colon of mice treated with 5-FU and contribute to the pathophysiology of 5-FU-induced body weight loss and diarrhea.

  13. Amphiphilic dendritic nanomicelle-mediated co-delivery of 5-fluorouracil and doxorubicin for enhanced therapeutic efficacy.

    PubMed

    Han, Rui; Sun, Yuan; Kang, Chen; Sun, Huijing; Wei, Wenguang

    2017-02-01

    Combination cancer therapy has attracted considerable attention due to its enhanced antitumor efficacy and reduced toxicity granted by synergistic effects over monotherapy. The application of nanotechnology is expected to achieve coencapsulation of multiple anticancer agents with enhanced therapeutic efficacy. Herein, a unique nanomicelle based on amphiphilic dendrimer (AmD) consisting of a hydrophilic polyamidoamine dendritic shell and a hydrophobic polylactide core is developed for effectively loading and shuttling 5-fluorouracil (5-Fu) and doxorubicin (Dox). The yielded drug-encapsulated dendritic nanomicelle (5-Fu/Dox-DNM) has a modest average size of 68.6 ± 3.3 nm and shows pH-sensitive drug release manner. The parallel activity of 5-Fu and Dox show synergistic anticancer efficacy. The IC50 value of 5-Fu/Dox-DNM toward human breast cancer (MDA-MB-231) cells was 0.25 μg/mL, presenting an 11.2-fold and 6.1-fold increase in cytotoxicity compared to Dox-DNM and 5-Fu-DNM, respectively. Furthermore, 5-Fu/Dox-DNM significantly inhibits the progression of tumor growth in the MDA-MB-231 xenograft tumor mice model. In conclusion, we have demonstrated that our AmD-based combination therapeutic system has promising potential to open an avenue for coencapsulation of multiple chemotherapeutic agents to promote superior anticancer effect.

  14. Chemotherapy

    MedlinePlus

    ... needs plenty of rest to recover from chemotherapy. Scale back on strenuous stuff, and make time to ... teeth very gently to avoid bleeding. Once you've finished chemo, it's still important to visit the ...

  15. Primary Vaginal Adenocarcinoma Arising in Vaginal Adenosis After CO2 Laser Vaporization and 5-Fluorouracil Therapy

    PubMed Central

    Paczos, Tamera A.; Ackers, Stacey; Odunsi, Kunle; Lele, Shashikant; Mhawech-Fauceglia, Paulette

    2016-01-01

    Summary We present a case of a 45-year-old woman with a long-standing history of persistent cervical dysplasia that resulted in a hysterectomy. Subsequent vaginal smears revealed high-grade vaginal intraepithelial neoplasia (VAIN III) on Pap smear with positive human papilloma virus (HPV) testing. Over the course of 2 years, the patient underwent 2 CO2 laser vaporization procedures of the upper vagina and intermittent 5-fluorouracil therapy. A biopsy performed at the time of the second laser procedure revealed endocervical-type well-differentiated adenocarcinoma, associated with VAIN III. HPV in situ hybridization for HPV types 16 and 18 was positive in both the glandular and squamous mucosa. The patient has no known history of intrauterine diethylstilbestrol exposure or mullerian developmental abnormalities. Subsequently, the patient underwent a radical upper vaginetcomy with bilateral pelvic lymph nodes dissection and bilateral salpingo-oophorectomy. The vaginectomy specimen showed residual adenocarcinoma associated with VAIN-III and extensive vaginal adenosis with free resection margins. This is the second reported case in the literature of adenocarcinoma arising in vaginal adenosis after 5-fluorouracil. Herein, we highlight these important findings and shed some light on the pathogenesis of vaginal adenosis and the subsequent development of vaginal adenocarcinoma. PMID:20173507

  16. Primary vaginal adenocarcinoma arising in vaginal adenosis after CO2 laser vaporization and 5-fluorouracil therapy.

    PubMed

    Paczos, Tamera A; Ackers, Stacey; Odunsi, Kunle; Lele, Shashikant; Mhawech-Fauceglia, Paulette

    2010-03-01

    We present a case of a 45-year-old woman with a long-standing history of persistent cervical dysplasia that resulted in a hysterectomy. Subsequent vaginal smears revealed high-grade vaginal intraepithelial neoplasia (VAIN III) on Pap smear with positive human papilloma virus (HPV) testing. Over the course of 2 years, the patient underwent 2 CO(2) laser vaporization procedures of the upper vagina and intermittent 5-fluorouracil therapy. A biopsy performed at the time of the second laser procedure revealed endocervical-type well-differentiated adenocarcinoma, associated with VAIN III. HPV in situ hybridization for HPV types 16 and 18 was positive in both the glandular and squamous mucosa. The patient has no known history of intrauterine diethylstilbestrol exposure or mullerian developmental abnormalities. Subsequently, the patient underwent a radical upper vaginetcomy with bilateral pelvic lymph nodes dissection and bilateral salpingo-oophorectomy. The vaginectomy specimen showed residual adenocarcinoma associated with VAIN-III and extensive vaginal adenosis with free resection margins. This is the second reported case in the literature of adenocarcinoma arising in vaginal adenosis after 5-fluorouracil. Herein, we highlight these important findings and shed some light on the pathogenesis of vaginal adenosis and the subsequent development of vaginal adenocarcinoma.

  17. Magnetic glass ceramics for sustained 5-fluorouracil delivery: characterization and evaluation of drug release kinetics.

    PubMed

    Abdel-Hameed, S A M; El-Kady, A M; Marzouk, M A

    2014-11-01

    In the present study, magnetic glass ceramics in the system Fe2O3 ∙ TiO2 ∙ P2O5 ∙ SiO2 ∙ MO (M=Mg, Ca, Mn, Cu, Zn or Ce) are prepared. The effect of adding different cations on the thermal behavior, developed phases, microstructure and magnetic properties is studied using differental thermal analysis (DTA), X-ray diffraction analysis (XRD), transmission electron microscope (TEM), FT-infrared transmission (FT-IR) and vibrating sample magnetometer (VSM) respectively. The magnetic glass ceramics are tested as delivery systems for 5-fluorouracil. Modeling and analysis of release kinetics are addressed. The application of Higuchi square root of time model and the first order release model indicated that, 5-FU is released by diffusion controlled mechanisms, and that its released rate depends greatly on the concentration of loaded drug during the loading stage. The obtained results suggested that, the prepared magnetic glass ceramics can be used for cancer treatment by hyperthermia and/or by localized delivery of therapeutic doses of 5-fluorouracil.

  18. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity

    PubMed Central

    2014-01-01

    Background Cardiotoxicity is a serious side effect to treatment with 5-fluorouracil (5-FU), but the underlying mechanisms are not fully understood. The objective of this systematic review was to evaluate the pathophysiology of 5-FU- induced cardiotoxicity. Methods We systematically searched PubMed for articles in English using the search terms: 5-FU OR 5-fluorouracil OR capecitabine AND cardiotoxicity. Papers evaluating the pathophysiology of this cardiotoxicity were included. Results We identified 27 articles of 26 studies concerning the pathophysiology of 5-FU-induced cardiotoxicity. The studies demonstrated 5-FU-induced: hemorrhagic infarction, interstitial fibrosis and inflammatory reaction in the myocardium; damage of the arterial endothelium followed by platelet aggregation; increased myocardial energy metabolism and depletion of high energy phosphate compounds; increased superoxide anion levels and a reduced antioxidant capacity; vasoconstriction of arteries; changes in red blood cell (RBC) structure, function and metabolism; alterations in plasma levels of substances involved in coagulation and fibrinolysis and increased endothelin-1 levels and N-terminal-pro brain natriuretic peptide levels. Based on these findings the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia. Conclusions There is no evidence for a single mechanism responsible for 5-FU-induced cardiotoxicity, and the underlying mechanisms might be multifactorial. Further research is needed to elucidate the pathogenesis of this side effect. PMID:25186061

  19. 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

  20. 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.

  1. Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Ulahannan, Susanna V; Brahmer, Julie R

    2011-01-01

    Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC. PMID:21469981

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

    NASA Astrophysics Data System (ADS)

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

    2012-11-01

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

  3. 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

  4. 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

  5. In vitro anticancer evaluation of 5-fluorouracil lipid nanoparticles using B16F10 melanoma cell lines

    NASA Astrophysics Data System (ADS)

    Shenoy, Vikram S.; Gude, Rajiv P.; Murthy, Rayasa S. Ramachandra

    2013-05-01

    The present study is aimed to investigate the formulation and in vitro anticancer activities of solid lipid nanoparticles (SLNs) of 5-fluorouracil (5-FU) prepared using glyceryl monostearate (GMS) and cetyl palmitate (CP) by hot homogenization method. The lipids were selected based on the partition coefficient of 5-FU in lipids. The lipid nanoparticles were optimized for process and formulation parameters. The optimized nanoparticles were characterized for their zeta potential, morphology, release kinetics, and anticancer activity. Higher entrapments were achieved using a combination of emulsifiers. The zeta potential of the optimized CP and GMS SLN formulation were -8.26 and -9.35 mV, respectively. Both the optimized formulations were spherical. The in vitro release studies of SLNs of both the lipid carriers followed Peppas-Korsenmeyer equation when carried out at pH 3.5 and 7.4. The chemosensitivity assay carried out in B16F10 cell lines revealed that CP SLNs had better cytotoxicity than 5-FU solution and GMS SLNs at 48 h of incubation. Subtoxic concentration of 5-FU-loaded CP SLNs (0.12 μg/mL) possessed comparable antimigrational activity, colony inhibition activity, and cytopathic as that of 5-FU solution effects. The results indicated that encapsulating 5-FU in CP would be a promising delivery system for delivering 5-FU.

  6. High glucose-induced resistance to 5-fluorouracil in pancreatic cancer cells alleviated by 2-deoxy-D-glucose.

    PubMed

    Cheng, Yao; Diao, Dongmei; Zhang, Hao; Guo, Qi; Wu, Xuandi; Song, Yongchun; Dang, Chengxue

    2014-03-01

    Abnormal glucose metabolism from hyperglycemia or diabetes aggravates the progression of pancreatic cancer. It is unknown whether high glucose has an impact on the antitumor effect of 5-fluorouracil (5-Fu) and whether targeting aberrant glucose metabolism using 2-deoxy-D-glucose (2-DG) may reverse this effect in high-glucose microenvironments. The cell viability of AsPC-1 and Panc-1 was analyzed by MTT assay following 5-Fu treatment at different glucose concentrations. Altered sensitivity to 5-Fu by 2-DG was also analyzed. LY294002 was used to inhibit PI3K-Akt signaling to determine the mechanism involved. In response to glucose, 5-Fu-induced cell growth inhibition was attenuated in a dose-dependent manner, accompanied with activated p-Akt, while 2-DG enhanced 5-Fu-induced cell growth inhibition. Moreover, blocking the PI3K/Akt pathway by LY294002 effectively eliminated 2-DG-induced apoptosis. In conclusion, high glucose weakens the antitumor effect of 5-Fu via PI3K/Akt signaling. Using 2-DG in combination with 5-Fu significantly increased their therapeutic effectiveness in high-glucose microenvironments.

  7. New insights into the RNA-based mechanism of action of the anticancer drug 5'-fluorouracil in eukaryotic cells.

    PubMed

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

    2013-01-01

    5-Fluorouracil (5FU) is a chemotherapeutic drug widely used in treating a range of advanced, solid tumours and, in particular, colorectal cancer. Here, we used high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5FU in the eukaryotic model Schizosaccharomyces pombe. This approach combined with real-time quantitative PCR analysis allowed us to detect splicing defects of a significant number of intron-containing mRNA, in addition to identify some rRNA and tRNA processing defects after 5FU treatment. Interestingly, our studies also revealed that 5FU specifically induced the expression of certain genes implicated in the processing of mRNA, tRNA and rRNA precursors, and in the post-transcriptional modification of uracil residues in RNA. The transcription of several tRNA genes was also significantly induced after drug exposure. These transcriptional changes might represent a cellular response mechanism to counteract 5FU damage since deletion strains for some of these up-regulated genes were hypersensitive to 5FU. Moreover, most of these RNA processing genes have human orthologs that participate in conserved pathways, suggesting that they could be novel targets to improve the efficacy of 5FU-based treatments.

  8. Synthesis of different sized and porous hydroxyapatite nanorods without organic modifiers and their 5-fluorouracil release performance.

    PubMed

    Ji, Yuqin; Wang, Aili; Wu, Gang; Yin, Hengbo; Liu, Shuxin; Chen, Bujun; Liu, Fanggang; Li, Xiaoyun

    2015-12-01

    Porous biocompatible hydroxyapatite (HAP) nanorods of various sizes were synthesized by the combination of chemical precipitation and hydrothermal method without the use of organic modifiers. The HAP nanorod samples were characterized by powder X-ray diffraction, transmission electron microscopy, and N2 adsorption/desorption techniques. HAP nanorods with average diameters and average lengths ranging from 8.5 to 26.6 nm and from 23.1 to 49.7 nm, respectively, could be controllably synthesized via these methods. Low autoclaving temperature and high pH value favored the formation of relatively small HAP nanorods. The TEM images showed that the nanorods possessed porous structures with average pore diameters ranging from 1.6 to 2.7 nm. These HAP nanoparticles effectively prolonged the release time of 5-fluorouracil up to 24h. The as-synthesized HAP nanorods displayed no cytotoxicity to bone marrow stem cells at low HAP concentration, indicating that these nanorod materials could serve as potential carriers for novel drug release systems.

  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

    2016-02-19

    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.

  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.

  11. Multicenter phase II study of infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first-line treatment in patients with metastatic colorectal cancer (CELINE trial)

    PubMed Central

    Kotake, Masanori; Aoyama, Toru; Munemoto, Yoshinori; Doden, Kenji; Kataoka, Masato; Kobayashi, Kenji; Nishimura, Genichi; Fujita, Hidehito; Nakamura, Keishi; Takehara, Akira; Tanaka, Chihiro; Sakamoto, Junichi; Nagata, Naoki; Oba, Koji; Kondo, Ken

    2017-01-01

    The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX-6)] in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Sixty patients with a median age of 64 years (range, 38–82 syears) received a biweekly intravenous infusion of cetuximab (500 mg/m2 on day 1) followed by FOLFOX-6 (2-hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2, and 5-FU as a 400 mg/m2 bolus followed by a 46-hour 2,400 mg/m2 infusion on days 1–3). Patient response rate was 70%, with 95% disease control rates. The median progression-free survival was 13.8 months. Thirteen patients (21.7%) were able to undergo resection of previously unresectable metastases, with the aim of curing them. The median follow-up was 22.7 months, and median overall survival was 31.0 months. Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated. The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX-6 was well tolerated and had a manageable safety profile for the first-line treatment of KRAS wild-type metastatic colorectal cancer. Efficacy was comparable to other treatment regimens. The results support the administration of biweekly cetuximab in combination with FOLFOX-6, which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers.

  12. 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

  13. Photocatalytic oxidation of 5-fluorouracil and cyclophosphamide via UV/TiO2 in an aqueous environment.

    PubMed

    Lin, Hank Hui-Hsiang; Lin, Angela Yu-Chen

    2014-01-01

    Cytostatic drugs are a class of pharmaceuticals that are increasingly used in cancer therapies; 5-fluorouracil is one of the most commonly used cytostatic (antineoplastic) drugs in the world. This study applied photocatalytic oxidation to remove 5-fluorouracil. Degussa P25 showed a higher photocatalytic degradation efficiency for 5-fluorouracil removal than Aldrich TiO2 and ZnO. Under optimal conditions (20 mg L(-1) TiO2 at pH 5.8), 200 μg L(-1) 5-fluorouracil can be removed within 2 h (k = 0.0375 min(-1)). 5-fluorouracil was found to be decomposed by near-surface OH free radicals produced from valence holes (hvb(+)). At a relatively high concentration, 5-fluorouracil (27.6 mg L(-1)) is >99.9% removed within 4 h by 300 mg L(-1) Degussa P25, while 24 h is required to reach complete mineralization with 96.7% fluoride recovery. Cyclophosphamide is another widely used cancer drug that follows a similar decomposition pathway. Cyclophosphamide (27.6 mg L(-1)) was also >99.9% eliminated within 4 h, but dechlorination and mineralization reached only 79.9% and 55.1%, respectively, after 16 h of irradiation. Together with the results for Microtox(®), it is suggested that the oxidation products of cyclophosphamide are even more recalcitrant and toxic. For engineering practices, despite the fact that photocatalytic oxidation can rapidly remove target antineoplastic, it is also important to further evaluate the treatment efficiency of the photoproducts.

  14. Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer.

    PubMed

    Moehler, M; Eimermacher, A; Siebler, J; Höhler, T; Wein, A; Menges, M; Flieger, D; Junginger, T; Geer, T; Gracien, E; Galle, P R; Heike, M

    2005-06-20

    An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m(-2), LV 500 mg m(-2), 24-h 5-FU 2000 mg m(-2), and ELF comprised three once-daily doses of etoposide 120 mg m(-2), LV 300 mg m(-2), 5-FU 500 mg m(-2). In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29-1.13, P = 0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33-0.97; P = 0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P = 0.4542), and overall survival was 10.8 vs 8.3 months (P = 0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.

  15. Development of an LC-MS/MS assay for the quantitative determination of the intracellular 5-fluorouracil nucleotides responsible for the anticancer effect of 5-fluorouracil.

    PubMed

    Derissen, Ellen J B; Hillebrand, Michel J X; Rosing, Hilde; Schellens, Jan H M; Beijnen, Jos H

    2015-06-10

    5-Fluorouracil (5-FU) and its oral prodrug capecitabine are among the most widely used chemotherapeutics. For cytotoxic activity, 5-FU requires cellular uptake and intracellular metabolic activation. Three intracellular formed metabolites are responsible for the antineoplastic effect of 5-FU: 5-fluorouridine 5'-triphosphate (FUTP), 5-fluoro-2'-deoxyuridine 5'-triphosphate (FdUTP) and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). In this paper, we describe the development of an LC-MS/MS assay for quantification of these active 5-FU nucleotides in peripheral blood mononuclear cells (PBMCs). Because the intracellular 5-FU nucleotide concentrations were very low, maximization of the release from the cell matrix and minimization of interference were critical factors. Therefore, a series of experiments was performed to select the best method for cell lysis and nucleotide extraction. Chromatography was optimized to obtain separation from endogenous nucleotides, and the effect of different cell numbers was examined. The assay was validated for the following concentration ranges in PBMC lysate: 0.488-19.9 nM for FUTP, 1.66-67.7 nM for FdUTP and 0.748-30.7 nM for FdUMP. Accuracies were between -2.2 and 7.0% deviation for all analytes, and the coefficient of variation values were ≤ 4.9%. The assay was successfully applied to quantify 5-FU nucleotides in PBMC samples from patients treated with capecitabine and patients receiving 5-FU intravenously. FUTP amounts up to 3054 fmol/10(6) PBMCs and FdUMP levels up to 169 fmol/10(6) PBMCs were measured. The FdUTP concentrations were below the lower limit of quantification. To our knowledge, this is the first time that 5-FU nucleotides were quantified in cells from patients treated with 5-FU or capecitabine without using a radiolabel.

  16. 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.

  17. 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.

  18. Chemotherapy

    MedlinePlus

    ... cell death (apoptosis). Types There are two main types of chemotherapy drugs: Cytostatic: These drugs prevent cells from reproducing. They include: Anti-angiogenesis agents/Angiogenesis inhibitors—These drugs prevent the development of blood vessels around the tumor that provide it with ...

  19. 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.

  20. 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

  1. Design and synthesis of novel camptothecin/5-fluorouracil conjugates as cytotoxic agents.

    PubMed

    Liu, Ying-Qian; Dai, Wei; Yang, Liu; Li, Hong-Yu

    2011-11-01

    In an effort to overcome several limitations associated with the synthesis of camptothecin (CPT), seven conjugates (10a-10g) composed of CPT and a 5-fluorouracil derivative joined by suitable dipeptide linkages were synthesised, and their cytotoxic activity against four human tumour cell lines as well as an in vitro pharmacokinetic determination of their lactone stability were studied. Among these compounds, most tested conjugates showed cytotoxic activities comparable or superior to CPT-11 (2), but they were less potent when compared with CPT (1). Interestingly, all of the compounds showed selective inhibitory activities against BGC-823, with IC₅₀ values lower than 0.1 µmol, which is more potent than CPT-11 (2). Also, the in vitro pharmacokinetic determination of the lactone levels of the representative compound 10b showed that the biological life span of their lactone forms in human and mouse plasma were significantly increased when compared with their mother compound CPT (1).

  2. Preliminary evaluation of molecular imprinting of 5-fluorouracil within hydrogels for use as drug delivery systems.

    PubMed

    Singh, Baljit; Chauhan, Nirmala

    2008-09-01

    Molecular imprinting is a new and rapidly evolving technique used to create synthetic receptors and it possesses great potential in a number of applications in the life sciences. Keeping in mind the therapeutic importance of 5-fluorouracil (5-FU) and the technological significance of molecular imprinting polymers, the present study is an attempt to synthesize 2-hydroxyethylmetacrylate- and acrylic acid-based 5-FU imprinted hydrogels. For the synthesis of these hydrogels, N,N'-methylenebisacrylamide was used as a crosslinker, ammonium persulfate as an initiator and N,N,N',N'-tetramethylethylenediamine as an accelerator. Both molecular imprinted polymers (MIPs) and non-imprinted polymers were synthesized at the optimum crosslinker concentration obtained from swelling studies and used to study their recognition affinity, their swelling and the in vitro release dynamics of the drug. It was observed from this study that the recognition affinity of MIPs is increased when these are synthesized in a high concentration template solution.

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

    PubMed

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

    2015-11-01

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

  4. Synthesis and properties of Mg{sub 2}Al layered double hydroxides containing 5-fluorouracil

    SciTech Connect

    Wang Zhongliang; Wang Enbo . E-mail: wangenbo@public.cc.jl.cn; Gao Lei; Xu Lin

    2005-03-15

    A pharmaceutically active compound, 5-fluorouracil (5-FU) has been firstly intercalated into layered double hydroxide with the restructure method. Powder X-ray diffraction and spectroscopic analysis indicate that 5-FU molecule is stabilized in the host interlayer by electrostatic interaction and intermolecular interaction, and that the orientation of 5-FU is different when changing the pattern of aging treatment or the swelling agent. The release studies show that a rapid release of the drug during the first 40min is followed by a more sustained one, and that the total amount of drug released from hybrid material into the aqueous solution is almost 87% and 74% at pH 4 and 7, respectively. The studies mentioned above suggest that layered double hydroxide might be used as the basis of a tunable drug delivery carrier.

  5. 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.

  6. A DFT study of 5-fluorouracil adsorption on the pure and doped BN nanotubes

    NASA Astrophysics Data System (ADS)

    Soltani, Alireza; Baei, Mohammad T.; Tazikeh Lemeski, E.; Kaveh, Sara; Balakheyli, Hanzaleh

    2015-11-01

    The electronic and adsorption properties of the pristine, Al-, Ga-, and Ge-doped BN nanotubes interacted with 5-fluorouracil molecule (5-FU) were theoretically investigated in the gas phase using the B3LYP density functional theory (DFT) calculations. It was found that the adsorption behavior of 5FU molecule on the pristine (8, 0) and (5, 5) BNNTs are electrostatic in nature. In contrast, the 5FU molecule (O-side) implies strong adsorption on the metal-doped BNNTs. Our results indicate that the Ga-doped presents high sensitivity and strong adsorption with the 5-FU molecule than the Al- and Ge-doped BNNTs. Therefore, it can be introduced as a carrier for drug delivery applications.

  7. 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

  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. 'Smart' gold nanoshells for combined cancer chemotherapy and hyperthermia.

    PubMed

    Liang, Zhongshi; Li, Xingui; Xie, Yegui; Liu, Shunying

    2014-04-01

    Nanomaterials that circulate in the body have great potential in the diagnosis and treatment of diseases. Here we report that 'smart' gold nanoshells can carry a drug payload, and that their intrinsic near-infrared (NIR) plasmon resonance enables the combination of chemotherapeutic and hyperthermia therapies. The 'smart' gold nanoshells (named DOX/A54@GNs) consist of (a) gold nanoshells (GNs) with NIR plasmon resonance, which not only act as nanoblocks but also produce local heat to allow hyperthermia; (b) an anticancer drug, doxorubicin (DOX), which was conjugated onto the nanoblocks by pH-dependent biodegradable copolymer thiol poly(ethylene glycol) derivatives via carbamate linkage; and (c) the targeting peptide A54 (AGKGTPSLETTP) to facilitate its orientation to liver cancer cells and enhance cellular uptake. The conjugated DOX was released from the DOX/A54@GNs much more rapidly in an acidic environment (pH 5.3) than in a neutral environment (pH 7.4), which is a desirable characteristic for intracellular tumor drug release. DOX-modified GNs showed pH-dependent release behavior, and the in vitro cell uptake experiment using ICP-AES and microscopy showed greater internalization of A54-modified GNs in the human liver cancer cell line BEL-7402 than of those without A54. Flow cytometry and fluoroscopy analysis were conducted to reveal the enhanced cell apoptosis caused by the A54-modified GNs under combined chemotherapeutic and hyperthermia therapies. These results imply that DOX/A54@GNs could be used as a multifunctional nanomaterial system with pH-triggered drug-releasing properties for tumor-targeted chemotherapy and hyperthermia.

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

    PubMed

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

    2017-02-01

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

  11. 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.

  12. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality.

    PubMed

    Farrell, C L; Bready, J V; Rex, K L; Chen, J N; DiPalma, C R; Whitcomb, K L; Yin, S; Hill, D C; Wiemann, B; Starnes, C O; Havill, A M; Lu, Z N; Aukerman, S L; Pierce, G F; Thomason, A; Potten, C S; Ulich, T R; Lacey, D L

    1998-03-01

    Keratinocyte growth factor (KGF) stimulates the proliferation and differentiation of epithelial cells including those of the gastrointestinal tract. Although chemotherapeutics and radiation exposure kill rapidly proliferating tumor cells, rapidly dividing normal cells of the host's gastrointestinal tract are also frequently damaged, leading to the clinical condition broadly termed "mucositis." In this report, recombinant human KGF used as a pretreatment in several mouse models of chemotherapy and/or radiation-induced gastrointestinal injury significantly improved mouse survival. Using multiple-dose 5-fluorouracil, methotrexate, and radiation in combination and total body radiation alone models, KGF increased survival by 55% or greater. In the models that used chemotherapy with or without radiation, KGF significantly ameliorated weight loss after injury and accelerated weight gain during recovery. The basis of these systemic benefits appears to be due in part to the trophic effects of the growth factor on the intestinal epithelium because KGF pretreatment caused an increase in measures of mucosal thickness (villus height and crypt depth) that persisted during the course of 5-fluorouracil chemotherapy. Treatment with KGF also afforded a 3.5-fold improvement in crypt survival in the small intestine, suggesting that KGF also has a direct effect on the crypt stem cells. These data indicate that KGF may be therapeutically useful to lessen the intestinal side effects of current cancer therapy regimens.

  13. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study

    PubMed Central

    Schultheis, B.; Folprecht, G.; Kuhlmann, J.; Ehrenberg, R.; Hacker, U. T.; Köhne, C. H.; Kornacker, M.; Boix, O.; Lettieri, J.; Krauss, J.; Fischer, R.; Hamann, S.; Strumberg, D.; Mross, K. B.

    2013-01-01

    Background Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective). Patients and methods Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h, folinic acid 400 mg/m2, and either oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2. On days 4–10, patients received regorafenib 160 mg orally once daily. Results The median duration of treatment was 108 (range 2–345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand–foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42–281 days). Conclusion Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics. PMID:23493136

  14. Mixed beam radiotherapy and combination chemotherapy in localized pancreatic adenocarcinoma - preliminary results

    SciTech Connect

    Bukowski, R.M.; Gahbauer, R.; Rodriquez-Antunez, A.; Hermann, R.

    1982-07-01

    A pilot study of mixed beam radiotherapy (fast neutrons alternating with photons) followed by combination chemotherapy with SMF (streptozotocin, 5-flouoruracil, mitomycin C) in localized pancreatic cancer was performed. Thirteen patients were treated and a median survival of 10.0 months was noted (range 5-30+). Toxicity was mild to moderate. Further studies of radiation and chemotherapy are indicated.

  15. 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.

  16. Effects of adenosine A(3) receptor agonist on bone marrow granulocytic system in 5-fluorouracil-treated mice.

    PubMed

    Hofer, Michal; Pospísil, Milan; Vacek, Antonín; Holá, Jirina; Znojil, Vladimír; Weiterová, Lenka; Streitová, Denisa

    2006-05-24

    The purpose of the experiments reported was to investigate effects of N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), a selective adenosine A(3) receptor agonist, on the granulocytic system in femoral marrow of mice depleted by the cytotoxic drug 5-fluorouracil. In the phase of the highest cell depletion IB-MECA was injected i.p. at single doses of 200 nmol/kg given either once or twice daily in 2- and 4-day regimens starting on day 1 after 5-fluorouracil administration; the effects were evaluated on days 3 and 5, respectively. The general effect of IB-MECA in all these experiments was an enhancement of the counts of morphologically recognizable proliferative granulocytic cells, interpreted as evidence of the differentiation of committed progenitor cells. A more expressive effect was observed after IB-MECA injected twice daily. It was found that the induction of the strong differentiation pressures by IB-MECA given twice daily shortly after 5-fluorouracil treatment can be counterproductive due to the preponderance of differentiaton processes over the proliferation control. In additional experiments, it has been shown that the use of the 2-day administration of IB-MECA given twice daily in the recovery phase, i.e., on days 5 and 6 after 5-fluorouracil administration, does not induce stimulatory effects. Thus, the dosing and timing of IB-MECA treatment determines its effectivity in stimulating granulopoiesis under conditions of myelosuppression.

  17. TOWARD A BIOLOGICALLY BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICITY OF 5-FLUOROURACIL IN THE RAT: A MATHEMATICAL CONSTRUCT

    EPA Science Inventory

    Biologically based dose-response (BBDR) models comprise one way to incorporate mechanistic information into a dose-response assessment to be used for risk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of ...

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

    PubMed Central

    2012-01-01

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

  19. 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.

  20. Apoptotic activity of 5-fluorouracil in breast cancer cells transformed by low doses of ionizing α-particle radiation.

    PubMed

    Ponce-Cusi, Richard; Calaf, Gloria M

    2016-02-01

    Globally, breast cancer in women is the leading cause of cancer death. This fact has generated an interest to obtain insight into breast tumorigenesis and also to develop drugs to control the disease. Ras is a proto-oncogene that is activated as a response to extracellular signals. As a member of the Ras GTPase superfamily, Rho-A is an oncogenic and a critical component of signaling pathways leading to downstream gene regulation. In chemotherapy, apoptosis is the predominant mechanism by which cancer cells die. However, even when the apoptotic machinery remains intact, survival signaling may antagonize the cell death by signals. The aim of this study was to evaluate 5-fluorouracil (5-FU) in cells transformed by low doses of ionizing α-particle radiation, in breast cancer cell lines on these genes, as well as apoptotic activity. We used two cell lines from an in vitro experimental breast cancer model. The MCF-10F and Tumor2 cell lines. MCF-10F was exposed to low doses of high linear energy transfer (LET) α-particles radiation (150 keV/µm). Tumor2, is a malignant and tumorigenic cell line obtained from Alpha5 (60cGy+E/60cGy+E) injected into the nude mice. Results indicated that 5-FU decreased H-ras, Rho-A, p53, Stat1 and increased Bax gene expression in Tumor2 and decreased Rac1, Rho-A, NF-κB and increased Bax and caspase-3 protein expression in Tumor2. 5-FU decreased H-ras, Bcl-xL and NF-κB and increased Bax gene expression. 5-FU decreased Rac1, Rho-A protein expression and increased Bax and caspase-3 protein expression in MDA-MB-231. Flow cytometry indicated 21.5% of cell death in the control MCF-10F and 80% in Tumor2 cell lines. It can be concluded that 5-FU may exert apoptotic activity in breast cancer cells transformed by low doses of ionizing α-particles in vitro regulating genes of Ras family and related to apoptosis such as Bax, Bcl-xL and NF-κB expression.

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor-induced angiogenesis.

    PubMed

    Singleton, Patrick A; Garcia, Joe G N; Moss, Jonathan

    2008-06-01

    Many patients with cancer receive combinations of drug treatments that include 5-fluorouracil (5-FU) and bevacizumab. Therapeutic doses of 5-FU are often associated with unwanted side effects, and bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that methylnaltrexone (MNTX), a peripheral antagonist of the mu-opioid receptor, exerts a synergistic effect with 5-FU and bevacizumab on inhibition of vascular endothelial growth factor (VEGF)-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC(50) of approximately 100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC(50) of 5-FU from approximately 5 micromol/L to approximately 7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC(50) of bevacizumab on inhibition of EC migration from approximately 25 to approximately 6 ng/mL. These synergistic effects were not observed with naltrexone, a tertiary mu-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased receptor protein tyrosine phosphatase mu activity, which was independent of mu-opioid receptor expression. Silencing receptor protein tyrosine phosphatase mu expression (small interfering RNA) in human EC inhibited both synergy between MNTX and bevacizumab or 5-FU and increased VEGF-induced tyrosine phosphorylation of Src and p190 RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory protein, RhoA, whereas silencing Src, Akt, or RhoA blocked VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of 5-FU and bevacizumab, which could improve index.

  7. 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

  8. 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

  9. 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.

  10. Self-assembling peptide nanofibers containing phenylalanine for the controlled release of 5-fluorouracil

    PubMed Central

    Ashwanikumar, Narayanan; Kumar, Nisha Asok; Saneesh Babu, Padma S; Sivakumar, Krishnankutty C; Vadakkan, Mithun Varghese; Nair, Parvathi; Hema Saranya, Ilamathi; Asha Nair, Sivakumari; Vinod Kumar, Gopalakrishnapillai S

    2016-01-01

    The study shows that RADA-F6 peptide with pH-responsive self-assembling nature can be effectively used as a drug delivery system for the sustained release of a potent anticancer drug 5-fluorouracil (5-FU) at basic pH. As 5-FU contains the aromatic pyrimidine ring, RADA-F6 system is suitable for entrapping an aromatic drug due to effective π–π stacking with phenylalanine and be able to show better controlled release behavior. The stability and controlled release nature of RADA-F6 in different conditions followed by 5-FU entrapment at in silico conditions was confirmed by molecular dynamics simulation taking RADA-16 as control. Cytotoxicity of the drug-loaded RADA-F6 was measured by MTT assay and cellular uptake by confocal microscopy. Physicochemical characterization and further Western blot analysis and flow cytometric studies confirm that RADA-F6 can be successfully used as an efficient vector for pH-sensitive, controlled 5-FU delivery system. PMID:27822037

  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. 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.

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

    PubMed

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

    2016-12-21

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

  14. Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis.

    PubMed

    Cascinu, S; Fedeli, A; Fedeli, S L; Catalano, G

    1994-07-01

    Recently, a randomised study demonstrated the utility of oral cooling (cryotherapy) in the prevention of 5-fluorouracil (5FU)-induced stomatitis. In order to verify these results a confirmatory study, using identical treatment regimen, was initiated. 84 patients treated with a 5-FU-containing regimen were randomised to a control arm or to receive oral cryotherapy. End point evaluation was obtained by a global assessment of the physician's judgement and patients' description of mucositis severity graded 0-4. Mucositis was significantly reduced by cryotherapy considering both the first cycle of therapy (the mean toxicity score for cryotherapy was 0.59 and it was 1.1 for the control group, P < or = 0.05) and all the chemotherapeutic courses (the mean toxicity score for cryotherapy was 0.36 when it was 0.69 for the control group, P < or = 0.05). In conclusion, the present study confirms that cryotherapy can decrease 5FU-induced stomatitis and should be recommended for patients receiving bolus 5FU-containing regimens.

  15. 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.

  16. [Prevention of severe toxicity from capecitabine, 5-fluorouracil and tegafur by screening for DPD-deficiency].

    PubMed

    Deenen, Maarten J; Cats, Annemieke; Mandigers, Caroline M P W; Soesan, Marcel; Terpstra, Wim E; Beijnen, Jos H; Schellens, Jan H M

    2012-01-01

    Capecitabine, 5-fluorouracil and tegafur form the group called the fluoropyrimidines, which is one of the most frequently prescribed group of anti-cancer drugs for the treatment of (metastatic) colorectal, gastric and breast cancer. The primary enzyme responsible for the inactivation of the fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD). Consequently, patients with an inborn partial DPD deficiency, induced, for example by the polymorphism DPYD*2A, are highly prone to severe, potentially lethal toxicity following a standard dose of fluoropyrimidines. In this article, based on three representative case reports and our prospective study in patients with cancer, we demonstrate the clinical value of prospective screening for DPD deficiency in patients being treated with fluoropyrimidine-based anti-cancer therapy. The results show that upfront genotyping for DPYD*2A followed by a fluoropyrimidine dose reduction of 50% (on average) in patients heterozygous polymorphic for DPYD*2A, significantly reduces the incidence of severe to potentially lethal toxicity compared to historical control patients given full-dose therapy.

  17. 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.

  18. The potential protective role of taurine against 5-fluorouracil-induced nephrotoxicity in adult male rats.

    PubMed

    Yousef, Hany N; Aboelwafa, Hanaa R

    2017-02-08

    Nephrotoxicity is common with the use of the chemotherapeutic agent 5-Fluorouracil (5-FU). The current study aimed to investigate the probable protective effect of taurine (TAU) against 5-FU-induced nephrotoxicity in rats using biochemical, histological and ultrastructural approaches. Twenty-four rats were equally divided into control, TAU, 5-FU and 5-FU+TAU groups. 5-FU significantly elevated levels of blood urea nitrogen (BUN), creatinine, and uric acid; while it reduced activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Also, 5-FU induced significant elevation in malondialdehyde (MDA) levels accompanied with marked decline in γ-glutamyltranspeptidase (GGT) and alkaline phosphatase (AP) levels in kidney tissues. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal renal structure, in addition to ultrastructural alterations represented by thickened and irregular glomerular basement membranes, congested glomerular capillaries, damaged lining fenestrated endothelium, mesangial cells hyperplasia with expanded mesangial matrix, and distorted podocyte's processes. Also, the proximal (PCT) and distal (DCT) convoluted tubules showed thickened basement membranes, destructed apical microvilli and loss of basal infoldings of their epithelial cells. Administration of TAU to 5-FU-treated rats reversed most of the biochemical, histological, and ultrastructural alterations. These results indicate that TAU has a protective effect against 5-FU-induced nephrotoxicity.

  19. Examination of the kinetics of degradation of the antineoplastic drug 5-fluorouracil by chlorine and bromine.

    PubMed

    Li, Wei; Tanumihardja, Jessica; Masuyama, Takaaki; Korshin, Gregory

    2015-01-23

    This study examined the degradation of the widely used antineoplastic drug 5-fluorouracil (5FU) by chlorine and bromine. 5FU was determined to interact readily with free chlorine and bromine but was stable in the presence of chloramine. The removal of 5FU followed a second-order kinetic pattern. Apparent rates (kapp) of 5FU removal by chlorine and bromine were strongly pH dependent and had maximum 14.8M(-1)s(-1) and 1.9×10(3)M(-1)s(-1)kapp values, respectively at pH 7. Modeling of the dependence of the kapp values vs. pH indicated the presence of a relatively acidic (pK 6.4 vs. 8.5 of 5FU per se) 5FU intermediate generated in the presence of halogen species. Spectrophotometric measurements confirmed the increased acidity of 5FU chlorination products and allowed proposing a degradation pathway of 5FU by chlorine. This pathway suggests that 5FU chlorination proceeds via chlorine incorporation at the 6th carbon in the heterocyclic ring of 5FU.

  20. [Review of pharmacokinetic monitoring of 5-Fluorouracil as a tool to increase efficacy and safety].

    PubMed

    Matus-Santos, Juan Antonio; Aguilar-Ponce, José Luis; Lara-Medina, Fernando Ulises; Herrera-Gómez, Ángel; Meneses-García, Abelardo; López-Gamboa, Mireya

    2016-01-01

    Recent progress in medical knowledge has indicated that both clinical and biological markers will determine the response to different medical treatments: age, gender and genetics will determine the success of treatment. Genetic variability in this respect is fundamental and determines efficiency and safety of drugs, as well as susceptibility and illness' development. Fortunately, personalized medicine now offers individually tailored treatment strategies for each patient's needs. This is of outmost importance in oncology, since treatment is per se toxic and the commonly found low serum drug concentrations result in low treatment efficacy. Personalized medicine will allow a better approach to this, until now, a poorly managed disease. In this review we intent to raise awareness of personalized medicine and of clinical pharmacologic monitoring, with the aim to achieve adequate levels of efficacy and safety in the use of the cytotoxic drug 5-Fluorouracil (5-FU). Additionally, the importance of pharmacogenomics for the use of 5-FU is discussed. We designed this discussion towards medical practitioners challenged with treatment decisions every day, together with their patients.

  1. 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.

  2. 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

    2015-01-08

    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.

  3. 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.

  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.

  5. Gold nanoparticles enhance 5-fluorouracil anticancer efficacy against colorectal cancer cells.

    PubMed

    Safwat, Mohamed A; Soliman, Ghareb M; Sayed, Douaa; Attia, Mohamed A

    2016-11-20

    5-Fluorouracil (5-FU), an antimetabolite drug, is extensively used in the treatment solid tumors. However, its severe side effects limit its clinical benefits. To enhance 5-FU anticancer efficacy and reduce its side effects it was loaded onto gold nanoparticles (GNPs) using two thiol containing ligands, thioglycolic acid (TGA) and glutathione (GSH). The GNPs were prepared at different 5-FU/ligand molar ratios and evaluated using different techniques. Anticancer efficacy of 5-FU/GSH-GNPs was studied using flow cytometry in cancerous tissue obtained from patients having colorectal cancer. The GNPs were spherical in shape and had a size of ∼9-17nm. Stability of the GNPs and drug release were studied as a function of salt concentration and solution pH. Maximum 5-FU loading was achieved at 5-FU/ligand molar ratio of 1:1 and 2:1 for TGA-GNPs and GSH-GNPs, respectively. GNPs coating with pluronic F127 improved their stability against salinity. 5-FU release from GNPs was slow and pH-dependent. 5-FU/GSH-GNPs induced apoptosis and stopped the cell cycle progression in colorectal cancer cells. They also had a 2-fold higher anticancer effect compared with free 5-FU. These results confirm the potential of GNPs to enhance 5-FU anticancer efficacy.

  6. 5-Fluorouracil delivery from metal-ion mediated molecularly imprinted cryogel discs.

    PubMed

    Çetin, Kemal; Denizli, Adil

    2015-02-01

    The objective of this study is to prepare imprinted cryogel discs for delivery of 5-fluorouracil. The coordinate bond interactions are utilized to accomplish a coordination complex between metal-chelate monomer N-methacryloyl-L-histidine and 5-FU with the assistance of Cu(2+) ion. The complex is copolymerized with hydroxyethyl methacrylate to produce poly(hydroxyethyl methacrylate-N-methacryloyl-(L)-histidine methyl ester) cryogel discs. The cryogel discs are characterized thoroughly by performing swelling tests, scanning electron microscopy, differential scanning calorimetry and X-ray diffraction studies. In vitro delivery studies are performed to investigate the effects of cross-linker ratio, medium pH and drug concentration. 5-FU imprinted cryogel discs have highly macroporous structures. Drug molecules are homogeneously dispersed in the 5-FU imprinted cryogel matrix. The cumulative release of 5-FU decreased by increasing the cross-linker density in the polymer matrix. Delivery rate of 5-FU varied with different pH values in a coordination complex since metal ion acts as a Lewis acid, and the ligand, i.e. 5-FU acts as a Lewis base. The cumulative release of 5-FU increased with increasing drug concentration in polymer matrix. The nature of the 5-FU transport mechanism is non-Fickian.

  7. 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.

  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. Chemotherapy of disseminated seminoma with combination of cis-diamminedichloroplatinum (II) and cyclophosphamide.

    PubMed

    Vugrin, D; Whitemore, W J; Batata, M

    1981-01-01

    Nine patients with metastatic seminoma who had received no prior chemotherapy were induced with a combination containing cis-platinum 120 mg/m2 I.V. and cyclophosphamide 600 mg/m2 I.V. for three to six treatments at 4-6 weeks intervals, and then received maintenance with cyclophosphamide 600 mg/m2 I.V. every 3-4 weeks to complete 2 years of chemotherapy. Eight patients entered complete remission: five with chemotherapy alone and three with chemotherapy and radiation or resection of residual disease. Seven patients remain in CR with a minimum follow up of 17 months. Chemotherapy is effective in treatment of metastatic seminoma.

  10. 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.

  11. Protective effect of Bu-Zhong-Yi-Qi decoction, the water extract of Chinese traditional herbal medicine, on 5-fluorouracil-induced intestinal mucositis in mice.

    PubMed

    Gou, H; Gu, L Y; Shang, B Z; Xiong, Y; Wang, C

    2016-12-01

    Intestinal mucositis is a serious toxic side effect of 5-fluorouracil (5-FU) treatment. Bu-Zhong-Yi-Qi decoction (BZYQD), a water extract of Chinese traditional herbal medicine, is widely used in chemotherapy in Asia as an alternative treatment to reduce the side effects of chemotherapy. However, the mechanism is unknown. To evaluate its mechanism, we investigated the effect of BZYQD on 5-FU-induced intestinal mucositis in mice, especially with regard to apoptosis in the intestinal mucosal epithelia. In the present study, mice were divided into three groups: control, 5-FU, and 5-FU + BZYQD. Mice in the 5-FU and 5-FU + BZYQD groups were administered 5-FU (100 mg/kg/day, intraperitoneally) for 6 days, and the mice in the latter group were given BZYQD (8 g/kg/day, intragastrically) beginning 4 days before 5-FU and continuing until the termination of the experiment. Loss in body weight and diarrhea during the 5-FU treatment were significantly attenuated by administration of BZYQD. The morphological signs of intestinal damage, including shortened villi height, crypt destruction, apoptosis, and necrosis, in intestinal mucosal epithelia were also reversed, accompanied by reduced neutrophil infiltration, nitrite levels, and inflammatory factors (tumor necrosis factor α and interleukin 1β) and increased levels of reduced glutathione. These results suggest that BZYQD inhibits 5-FU-induced intestinal mucositis, and this effect may be due to the reduction in apoptosis and necrosis in intestinal mucosal epithelia via the suppression of inflammatory cytokine upregulation. In conclusion, inhibiting cytokine-mediated apoptosis or necrosis can be the molecular mechanism by which BZYQD reduces the gastrointestinal side effects of cancer chemotherapy.

  12. 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

    2016-01-01

    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.

  13. 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.

  14. 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

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

    PubMed

    Hoshiba, Takashi; Tanaka, Masaru

    2016-11-01

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

  16. Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice.

    PubMed

    Kojouharov, Bojidar M; Brackett, Craig M; Veith, Jean M; Johnson, Christopher P; Gitlin, Ilya I; Toshkov, Ilia A; Gleiberman, Anatoli S; Gudkov, Andrei V; Burdelya, Lyudmila G

    2014-02-15

    Myelosuppression and gastrointestinal damage are common side effects of cancer treatment limiting efficacy of DNA-damaging chemotherapeutic drugs. The Toll-like receptor 5 (TLR5) agonist Entolimod has demonstrated efficacy in mitigating damage to hematopoietic and gastrointestinal tissues caused by radiation. Here, using 5-Fluorouracil (5-FU) treated mice as a model of chemotherapy-induced side effects, we demonstrated significant reduction in the severity of 5-FU-induced morbidity and increased survival accompanied by the improved integrity of intestinal tissue and stimulated the restoration of hematopoiesis. Entolimod-stimulated IL-6 production was essential for Entolimod's ability to rescue mice from death caused by doses of 5-FU associated with hematopoietic failure. In contrast, IL-6 induction was not necessary for protection and restoration of drug-damaged gastrointestinal tissue by Entolimod. In a syngeneic mouse CT26 colon adenocarcinoma model, Entolimod reduced the systemic toxicity of 5-FU, but did not reduce its antitumor efficacy indicating that the protective effect of Entolimod was selective for normal, non-tumor, tissues. These results suggest that Entolimod has clinical potential to broaden the therapeutic window of genotoxic anticancer drugs by reducing their associated hematopoietic and gastrointestinal toxicities.

  17. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2017-01-01

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

  20. Hyaluronidase enzyme core-5-fluorouracil-loaded chitosan-PEG-gelatin polymer nanocomposites as targeted and controlled drug delivery vehicles.

    PubMed

    Rajan, M; Raj, V; Al-Arfaj, Abdullah A; Murugan, A M

    2013-09-10

    This study examines the performance of novel hyaluronidase enzyme core-5-fluorouracil-loaded chitosan-polyethylene glycol-gelatin polymer nanocomposites, which were prepared using an ionic gelation technique, as targeted and controlled drug delivery vehicles. These hyaluronidase-loaded nanoparticles have recently been proposed as targeted and controlled drug delivery vehicle systems to tissues due to their ability to loosen the intercellular connective matrix of hyaluronic acid. The encapsulation efficiency and loading capacities of the nanoparticles demonstrated that these nanocomposites displayed sufficient binding ability, which depends on the pH and initial concentration of the drug. The cytotoxic effects of the chitosan-hyaluronidase-5-fluorouracil (CS-HYL-5-FU), chitosan-hyaluronidase-5-fluorouracil polyethylene glycol (CS-HYL-5-FU-PEG), and chitosan-hyaluronidase-5-fluorouracil polyethylene glycol-gelatin (CS-HYL-5-FU-PEG-G) nanoparticles were assessed using MTT assays, and the nanovectors were found to be less cytotoxic than the chemotherapeutic 5-FU after incubation for 3-12h. The particle sizes of the CS-HYL-5-FU, CS-HYL-5-FU-PEG and CS-HYL-5-FU-PEG-G polymer composites were between 300 and 580 nm, as determined by a Zetasizer. Scanning electron microscopy (SEM) analysis indicated that the nanocomposites exhibit a clear, smooth surface and fine morphology. Linkages of the polymers, enzyme, and drug were confirmed by FTIR spectroscopy. Atomic fluorescence microscopy (AFM) analysis confirmed the size of the polymer composite nanoparticles. Therefore, this work established that the drug can be successfully encapsulated in chitosan-polyethylene glycol-gelatin-accompanied hyaluronidase nanoparticles with a homogeneous distribution. These nanoparticles can be potential carriers for targeted and controlled drug delivery to cancer cells.

  1. 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.

  2. Synthesis, structural elucidation, biological, antioxidant and nuclease activities of some 5-Fluorouracil-amino acid mixed ligand complexes.

    PubMed

    Shobana, Sutha; Subramaniam, Perumal; Mitu, Liviu; Dharmaraja, Jeyaprakash; Arvind Narayan, Sundaram

    2015-01-05

    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. Phase II study of continuous infusional 5-fluorouracil with epirubicin and carboplatin (instead of cisplatin) in patients with metastatic/locally advanced breast cancer (infusional ECarboF): a very active and well-tolerated outpatient regimen.

    PubMed Central

    Bonnefoi, H.; Smith, I. E.; O'Brien, M. E.; Seymour, M. T.; Powles, T. J.; Allum, W. H.; Ebbs, S.; Baum, M.

    1996-01-01

    Infusional 5-fluorouracil (F) with cisplatin (C) and epirubicin (E), so-called infusional ECF, is a highly active new schedule against locally advanced or metastatic breast cancer. Cisplatin, however, is a major contributor to toxicity and usually requires inpatient treatment. In an attempt to overcome this, we have investigated the effect of substituting carboplatin for cisplatin in our original infusional ECF regimen. Fifty-two patients with metastatic (n = 36) or locally advanced/inflammatory (n = 16) breast cancer were treated with 5-fluorouracil 200 mg m-2 day-1 via a Hickman line using an ambulatory pump for for 6 months, with epirubicin 50 mg m-2 intravenously (i.v.) and carboplatin AUC5 i.v. every 4 weeks, for six courses (infusional ECarboF). The overall response rate (complete plus partial) was 81% (95% CI 67%-90%), with a complete response rate of 17% (95% CI 6-33%) in patients with metastatic disease and 56% (95% CI 30-80%) in patients with locally advanced disease. Median response duration and survival for metastatic disease was 8 and 14 months respectively, and two patients with locally advanced disease have relapsed. These results are very similar to those previously achieved with infusional ECF. Severe grade 3/4 toxicity was low. Infusional ECarboF is a highly active, well-tolerated, outpatient regimen effective against advanced/metastatic breast cancer and now warrants evaluation against conventional chemotherapy in high-risk early breast cancer. PMID:8562348

  4. Adsorption behavior of 5-fluorouracil on pristine, B-, Si-, and Al-doped C60 fullerenes: A first-principles study

    NASA Astrophysics Data System (ADS)

    Hazrati, Mehrnoosh Khodam; Hadipour, Nasser L.

    2016-02-01

    Since C60 fullerene has been enormously studied as a drug delivery vehicle, we investigated the interaction between C60 and 5-fluorouracil drug using density functional theory calculations. The electronic and structural properties were explored in terms of binding energies, frontier molecular orbitals, DOS and NBO. To manipulate 5-fluorouracil adsorption properties on the C60, we substituted a carbon atom with boron, silicon and aluminum. In contrast to the pristine C60, the binding energy of 5-fluorouracil to the doped fullerenes is much more negative and the HOMO-LUMO gaps are significantly enlarged. Our results suggest that doping may improve C60 drug delivery properties.

  5. 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.

  6. 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

  7. 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.

  8. Synthesis, in vitro cytotoxicity and radiosensitizing activity of novel 3-[(2,4-dinitrophenylamino)alkyl] derivatives of 5-fluorouracil.

    PubMed

    Khalaj, Ali; Abdi, Khosrou; Ostad, Seyed Nasser; Khoshayand, Mohammad Reza; Lamei, Navid; Nedaie, Hasan Ali

    2014-02-01

    Previously, it was reported that 3[3-(2,4-dinitrophenylamino)-propyl]-5-fluorouracil 8c unlike its components 5-fluorouracil (5-FU) 6 and 2,4-dinitroaniline 2 in HT-29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of 8c differing in the number of linking methylene groups were prepared and tested for in vitro cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound 8a was prepared in one pot by the reaction of 5-FU 6 with paraformaldehyde and 2,4-dinitroaniline 2 in the presence of the concentrated hydrochloric acid, and compounds 8b-f were prepared by the reaction of N-(bromoalkyl)-2,4-dinitrobenzeneamines 5b-f with 1-(t-butoxycarbonyl)-5-fluorouracil 7 followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and propidium iodide (PI)-digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds 8a-f induced time- and concentration-dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration-dependent radiocytotoxicity under hypoxic conditions.

  9. Selenium nanoparticles as a carrier of 5-fluorouracil to achieve anticancer synergism.

    PubMed

    Liu, Wen; Li, Xiaoling; Wong, Yum-Shing; Zheng, Wenjie; Zhang, Yibo; Cao, Wenqiang; Chen, Tianfeng

    2012-08-28

    A simple method for preparing 5-fluorouracil surface-functionalized selenium nanoparticles (5FU-SeNPs) with enhanced anticancer activity has been demonstrated in the present study. Spherical SeNPs were capped with 5FU through formation of Se-O and Se-N bonds and physical adsorption, leading to the stable structure of the conjugates. 5FU surface decoration significantly enhanced the cellular uptake of SeNPs through endocytosis. A panel of five human cancer cell lines was shown to be susceptible to 5FU-SeNPs, with IC(50) values ranging from 6.2 to 14.4 μM. Despite this potency, 5FU-SeNP possesses great selectivity between cancer and normal cells. Induction of apoptosis in A375 human melanoma cells by 5FU-SeNPs was evidenced by accumulation of sub-G1 cell population, DNA fragmentation, and nuclear condensation. The contribution of the intrinsic apoptotic pathway to the cell apoptosis was confirmed by activation of caspase-9 and depletion of mitochondrial membrane potential. Pretreatment of cells with a general caspase inhibitor z-VAD-fmk significantly prevented 5FU-SeNP-induced apoptosis, indicating that 5FU-SeNP induced caspase-dependent apoptosis in A375 cells. Furthermore, 5FU-SeNP-induced apoptosis was found dependent on ROS generation. Our results suggest that the strategy to use SeNPs as a carrier of 5FU could be a highly efficient way to achieve anticancer synergism. 5FU-SeNPs may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially melanoma.

  10. Design and evaluation of colon targeted modified pulsincap delivery of 5-fluorouracil according to circadian rhythm

    PubMed Central

    Patel, Dasharath M; Jani, Rushiraj H; Patel, Chhagan N

    2011-01-01

    Introduction: A modified pulsincap dosage form of 5-fluorouracil was developed to target drug to colorectal carcinoma according to daily oscillations of rate-limiting metabolizing enzyme dihydropyrimidine dehydrogenase. Materials and Methods: The capsule body was made water insoluble by exposing the body to formaldehyde vapor. A mixture of granules containing drug, superdisintegrant, and osmogen was filled in the capsule body. A hydrogel plug was fitted to the mouth of the treated body, and the untreated cap was fitted to the body which was coated with Eudragit S100. Developed formulations were evaluated for in vitro drug release in 1.2 pH (2 h), 6.8 pH (3 h), and 7.4 pH (up to 12 h) buffer solutions. A 23 full factorial design was used for optimization in which the type of hydrogel plug (X1), the type of osmogen (X2), and the type of superdisintegrant (X3) were selected as independent variables while, cap opening time, percentage drug released in 5(Q5), 6(Q6), and 12(Q12) h were taken as dependent variables. Results: Dissolution data were fitted to various models to ascertain the kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. The results of the F-statistics were used to select the most appropriate model. Conclusion: Formulation F1 containing sodium starch glycolate, potassium chloride, and hydroxypropyl methylcellulose K4M plug was considered optimum since it showed more similarity to the theoretical predicted dissolution profile (f2 = 77.33). The studies indicate that the formulation was effective in providing in vitro colon targeted release and controlled release after predetermined lag time. PMID:23071940

  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.

  12. Development and evaluation of nanostructured lipid carrier-based hydrogel for topical delivery of 5-fluorouracil.

    PubMed

    Rajinikanth, Paruvathanahalli Siddalingam; Chellian, Jestin

    The aim of this study was to develop a nanostructured lipid carrier (NLC)-based hydrogel and study its potential for the topical delivery of 5-fluorouracil (5-FU). Precirol(®) ATO 5 (glyceryl palmitostearate) and Labrasol(®) were selected as the solid and liquid lipid phases, respectively. Poloxamer 188 and Solutol(®) HS15 (polyoxyl-15-hydroxystearate) were selected as surfactants. The developed lipid formulations were dispersed in 1% Carbopol(®) 934 (poly[acrylic acid]) gel medium in order to maintain the topical application consistency. The average size, zeta potential, and polydispersity index for the 5-FU-NLC were found to be 208.32±8.21 nm, -21.82±0.40 mV, and 0.352±0.060, respectively. Transmission electron microscopy study revealed that 5-FU-NLC was <200 nm in size, with a spherical shape. In vitro drug permeation studies showed a release pattern with initial burst followed by sustained release, and the rate of 5-FU permeation was significantly improved for 5-FU-NLC gel (10.27±1.82 μg/cm(2)/h) as compared with plain 5-FU gel (2.85±1.12 μg/cm(2)/h). Further, skin retention studies showed a significant retention of 5-FU from the NLC gel (91.256±4.56 μg/cm(2)) as compared with that from the 5-FU plain gel (12.23±3.86 μg/cm(2)) in the rat skin. Skin irritation was also significantly reduced with 5-FU-NLC gel as compared with 5-FU plain gel. These results show that the prepared 5-FU-loaded NLC has high potential to improve the penetration of 5-FU through the stratum corneum, with enormous retention and with minimal skin irritation, which is the prerequisite for topically applied formulations.

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

    PubMed Central

    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

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

    SciTech Connect

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

    1986-03-01

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

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

    PubMed Central

    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

  17. Transcription and activity of 5-fluorouracil converting enzymes in fluoropyrimidine resistance in colon cancer in vitro.

    PubMed

    Mader, R M; Sieder, A E; Braun, J; Rizovski, B; Kalipciyan, M; Mueller, M W; Jakesz, R; Rainer, H; Steger, G G

    1997-12-01

    Cellular resistance to 5-fluorouracil (5-FU) is not completely understood. Since 5-FU shares the pyrimidine pathway with the physiological pyrimidines, we investigated the relationship between fluoropyrimidine metabolism, nucleic acid uptake and cytotoxicity of 5-FU in eight colon tumour cell lines including 5-FU-resistant subclones. The cytotoxicity of 5-FU was increased up to 423-fold when the anabolites 5-fluorouridine (FUrd), 5-fluorodeoxyuridine (FdUrd), and 5-fluorodeoxyuridine monophosphate (FdUMP) were compared with the parent drug in vitro. The enzymes uridine phosphorylase and thymidine phosphorylase were predictive for the cytotoxicity of 5-FU in 5/7 cell lines. Inhibition of uridine phosphorylase and thymidine phosphorylase by antisense strategies effectively antagonised 5-FU, abolishing 84% and 79% of its toxicity. The importance of thymidine phosphorylase was supported by a highly restricted enzyme activity in 5-FU-resistant cells. In 5-FU naive cells, a stimulating effect of 5-FU on thymidylate synthase mRNA and ribonucleotide reductase mRNA expression was observed. In these cells, antisense oligonucleotides to ribonucleotide reductase significantly reduced cell growth. Downregulation of ribonucleotide reductase mRNA in 5-FU-resistant subclones suggests different mechanisms in primary and secondary resistance to 5-FU. Most of the intracellular 5-FU was selectively incorporated into RNA (range: 45-91%) and generally spared DNA (range: 0.2-11%). In synthesising our data, we conclude that drug resistance could be overwhelmed through bypassing limiting steps in the activation of 5-FU. In the majority of colonic tumours, the activity of uridine phosphorylase and thymidine phosphorylase may have prognostic relevance for the cytotoxicity of 5-FU in vitro.

  18. 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.

  19. 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.

  20. 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

  1. Development and characterization of hyaluronic acid decorated PLGA nanoparticles for delivery of 5-fluorouracil.

    PubMed

    Yadav, Awesh K; Agarwal, Abhinav; Rai, Gopal; Mishra, Pradeep; Jain, Sanyog; Mishra, Anil K; Agrawal, Himanshu; Agrawal, Govind P

    2010-11-01

    The present investigation was aimed to develop and explore the prospective of engineered PLGA nanoparticles as vehicles for targeted delivery of 5-fluorouracil (5-FU). Nanoparticles of 5-FU-loaded hyaluronic acid-poly(ethylene glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA-FU) copolymer were prepared and characterized by FTIR, NMR, transmission electron microscopy, particle size analysis, DSC, and X-ray diffractometer measurement studies. The nanoparticulate formulation was evaluated for in vitro release, hemolytic toxicity, and hematological toxicity. Cytotoxicity studies were performed on Ehrlich ascites tumor (EAT) cell lines using MTT cell proliferation assay. Biodistribution studies of 99m Tc labeled formulation were conducted on EAT-bearing mice. The in vivo tumor inhibition study was also performed after i.v. administration of HA-PEG-PLGA-FU nanoparticles. The HA conjugated formulation was found to be less hemolytic but more cytotoxic as compared to free drug. The hematological data suggested that HA-PEG-PLGA-FU formulation was less immunogenic compared to plain drug. The tissue distribution studies displayed that HA-PEG-PLGA-FU were able to deliver a higher concentration of 5-FU in the tumor mass. In addition, the HA-PEG-PLGA-FU nanoparticles reduced tumor volume significantly in comparison with 5-FU. Thus, it was concluded that the conjugation of HA imparts targetability to the formulation, and enhanced permeation and retention effect ruled out its access to the non-tumor tissues, at the same time favored selective entry in tumors, thereby reducing the side-effects both in vitro and in vivo.

  2. 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.

  3. 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

  4. 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.

  5. Immunochemotherapy with interleukin-2, interferon- α and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study

    PubMed Central

    Herpen, C M L van; Jansen, R L H; Kruit, W H J; Hoekman, K; Groenewegen, G; Osanto, S; Mulder, P H M De

    2000-01-01

    In patients with metastatic renal cell carcinoma response rates of 7–26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-α (IFN-α), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993 a) Eur J Cancer29A: S6–8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m−2was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m−2t.i.w. in weeks 2 and 3. Recombinant human IFN-α 2a 6 MU m−2was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m−2t.i.w. in weeks 5–8. 5-FU (750 mg m−2) was given as a bolus injection intravenous once a week in weeks 5–8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1–5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1–153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9–20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8–22.4+) months. Median survival was 16.5 (range 1.8–30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-α, IL-2 and 5-FU, as described

  6. Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy.

    PubMed

    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.

  7. 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.

  8. 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

  9. Scalp cooling has no place in the prevention of alopecia in adjuvant chemotherapy for breast cancer.

    PubMed

    Tollenaar, R A; Liefers, G J; Repelaer van Driel, O J; van de Velde, C J

    1994-01-01

    35 patients were studied to determine the effectiveness of scalp hypothermia in the prevention of alopecia caused by adjuvant chemotherapy for breast cancer. Scalp hypothermia was induced by the newly developed Theracool cooling machine. The chemotherapeutic regimen consisted of one perioperative course of doxorubicin 50 mg/m2, cyclophosphamide 600 mg/m2 and 5-fluorouracil 600 mg/m2 (EORTC protocol 10854). Only 4 (11%) patients showed acceptable hair preservation (no or minor alopecia). 12 patients (34%) had moderate alopecia, all requiring a wig. 19 patients (54%) had complete alopecia. No scalp metastases were observed after scalp cooling. These results and a review of the literature suggest that scalp hypothermia to prevent alopecia may only be effective in a cytotoxic regimen containing an anthracycline as the sole alopecia-inducing agent. With current adjuvant chemotherapy for breast cancer, in which a combination of cyclophosphamide and an anthracycline is often used, there is no place for scalp hypothermia.

  10. Saireito (TJ-114), a Japanese traditional herbal medicine, reduces 5-fluorouracil-induced intestinal mucositis in mice by inhibiting cytokine-mediated apoptosis in intestinal crypt cells.

    PubMed

    Kato, Shinichi; Hayashi, Shusaku; Kitahara, Yumeno; Nagasawa, Koyo; Aono, Hitomi; Shibata, Junichiro; Utsumi, Daichi; Amagase, Kikuko; Kadowaki, Makoto

    2015-01-01

    Clinical chemotherapy frequently causes intestinal mucositis as a side effect, which is accompanied by severe diarrhea. We recently showed that the cytokine-mediated apoptotic pathway might be important for the development of intestinal mucositis induced by 5-fluorouracil (5-FU). Saireito, the traditional Japanese herbal (Kampo) medicine, is widely used to treat diarrhea and various inflammatory diseases in Japan. In the present study, we investigated the effect of saireito on 5-FU-induced intestinal mucositis in mice, especially in relation to apoptosis in the intestinal crypt. Male C57BL/6 mice were given 5-FU (50 mg/kg), i.p. once daily for 6 days. Intestinal mucositis was evaluated histochemically. Saireito (100-1000 mg/kg) was administered p.o. twice daily for 6 days. Repeated 5-FU treatment caused severe intestinal mucositis including morphological damage, which was accompanied by body weight loss and diarrhea. Daily administration of saireito reduced the severity of intestinal mucositis in a dose-dependent manner. Body weight loss and diarrhea during 5-FU treatment were also significantly attenuated by saireito administration. The number of apoptotic and caspase-3-activated cells in the intestinal crypt was increased, and was accompanied by up-regulated tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA within 24 h of the first 5-FU injection. However, all of these measures were significantly lower after saireito administration. These results suggest that saireito attenuates 5-FU-induced intestinal mucositis. This action may come from the reduction of apoptosis in the intestinal crypt via suppression of the up-regulation of inflammatory cytokines. Therefore, saireito may be clinically useful for the prevention of intestinal mucositis during cancer chemotherapy.

  11. Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil.

    PubMed

    Gao, Jing; Gao, Jin; Qian, Lan; Wang, Xia; Wu, Mingyuan; Zhang, Yang; Ye, Hao; Zhu, Shunying; Yu, Yan; Han, Wei

    2014-08-01

    Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract.

  12. A phase II study of sequential 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel in advanced breast cancer (Protocol PV BC 97/01)

    PubMed Central

    Riccardi, A; Pugliese, P; Danova, M; Brugnatelli, S; Grasso, D; Giordano, M; Bernardo, G; Giardina, G; Fava, S; Montanari, G; Pedrotti, C; Trotti, G; Rinaldi, E; Poli, M A; Tinelli, C

    2001-01-01

    Sequential administration of the association of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel could be better tolerated than the association of an anthracycline and paclitaxel while having a similar antitumour effect. 69 patients with advanced breast cancer previously untreated with anthracyclines or paclitaxel entered a phase II multicentre study in which FEC was followed by paclitaxel. Both regimens were administered 4 times every 21 days. The median follow-up is 20 months and 38/69 patients have died. Grade III–IV toxicity was acceptable. Leukopenia occurred in 26% of patients, thrombocytopenia in 2% and anaemia in 4%. One patient had reversible heart failure during FEC therapy. Peripheral neuropathy and arthralgia-myalgia occurred in 9% and 4% of patients, respectively and one patient had respiratory hypersensitivity during paclitaxel treatment. 9 patients did not complete therapy because of: treatment refusal (n= 1), cardiac toxicity (n= 1), early death during FEC chemotherapy (n= 1), major protocol violations (n= 4), hypersensitivity reaction (n= 1) and early death during paclitaxel chemotherapy (n= 1). The overall response rate was 65% (95% CI = 53–76), and 7% of patients had stable disease. Therapy was defined as having failed in 28% of patients because they were not evaluable (13%) or had progressive disease (15%). The median time to progression and survival are 13.2 and 23.5 months, respectively. Sequential FEC-paclitaxel is a suitable strategy for patients with metastatic breast cancer who have not been previously treated with anthracyclines and/or taxanes. In fact, it avoids major haematologic toxicity and has a good antitumour effect. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11461067

  13. Molecular chemotherapy of pancreatic cancer using novel mutant bacterial cytosine deaminase gene.

    PubMed

    Kaliberova, Lyudmila N; Della Manna, Debbie L; Krendelchtchikova, Valentina; Black, Margaret E; Buchsbaum, Donald J; Kaliberov, Sergey A

    2008-09-01

    The combination of molecular chemotherapy with radiation therapy has the potential to become a powerful approach for treatment of pancreatic cancer. We have developed an adenoviral vector (AdbCD-D314A) encoding a mutant bacterial cytosine deaminase (bCD) gene, which converts the prodrug 5-fluorocytosine (5-FC) into the active drug 5-fluorouracil. The aim of this study was to investigate AdbCD-D314A/5-FC-mediated cytotoxicity in vitro and therapeutic efficacy in vivo alone and in combination with radiation against human pancreatic cancer cells and xenografts. AdbCD-D314A/5-FC-mediated cytotoxicity alone and in combination with radiation was analyzed using crystal violet inclusion and clonogenic survival assays. CD enzyme activity was determined by measuring conversion of [3H]5-FC to [3H]5-fluorouracil after adenoviral infection of pancreatic cancer cells in vitro and pancreatic tumor xenografts by TLC. S.c. pancreatic tumor xenografts were used to evaluate the therapeutic efficacy of AdbCD-D314A/5-FC molecular chemotherapy in combination with radiation therapy. AdbCD-D314A infection resulted in increased 5-FC-mediated pancreatic cancer cell killing that correlated with significantly enhanced CD enzyme activity compared with AdbCDwt encoding wild-type of bCD. Animal studies showed significant inhibition of growth of human pancreatic tumors treated with AdbCD-D314A/5-FC in comparison with AdbCDwt/5-FC. Also, a significantly greater inhibition of growth of Panc2.03 and MIA PaCA-2 tumor xenografts was produced by the combination of AdbCD-D314A/5-FC with radiation compared with either agent alone. The results indicate that the combination of AdbCD-D314A/5-FC molecular chemotherapy with radiation therapy significantly enhanced cytotoxicity of pancreatic cancer cells in vitro and increased therapeutic efficacy against human pancreatic tumor xenografts.

  14. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck

    PubMed Central

    Budach, W; Hehr, T; Budach, V; Belka, C; Dietz, K

    2006-01-01

    Background Former meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria. Methods Randomised trials testing curatively intended RT (≥60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival. Results Thirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX). Conclusion RT combined with simultaneous 5-FU

  15. Conformal Therapy Improves the Therapeutic Index of Patients with Anal Canal Cancer Treated with Combined Chemotherapy and External Beam Radiotherapy

    SciTech Connect

    Vuong, Te . E-mail: te.vuong@muhc.mcgill.ca; Kopek, Neil; Ducruet, Thierry; Portelance, Lorraine; Faria, Sergio; Bahoric, Boris; Devic, Slobodan

    2007-04-01

    Purpose: To evaluate the clinical outcomes of three-dimensional conformal radiotherapy (3D-CRT) in patients with anal canal cancer, in terms of local control (LC), freedom from relapse (FFR), and overall survival (OS) rates, and to estimate long-term toxicity data. Methods and Materials: Sixty historical patients, treated with conventional radiation techniques (C-RT), were used as controls, and 62 consecutive patients were treated with 3D-CRT. Patients treated with 3D-CRT received 54 Gy in 30 fractions delivered continuously, compared with 45-58.9 Gy (median dose, 54 Gy) in a split course in patients treated with C-RT. Chemotherapy consisted of 5-fluorouracil with either mitomycin-C or cis-platinum given concurrently with radiation. Survival curves were performed using the Kaplan-Meier model, and the Cox proportional hazards model was used for multivariate analysis of risk factors. Results: No differences in stage and age distribution were observed between the two groups. Patients treated with 3D-CRT and C-RT had an actuarial 5-year LC rate of 85.1% and 61.1%, respectively (p = 0.0056); the FFR rate was 70.2% and 46.1% (p = 0.0166), and the OS rate was 80.7% and 53.9% (p = 0.0171). In multivariate analysis, factors of significance for LC were nodal (N) status (p < 0.001); for OS, 3D-CRT (p = 0.038), N status (p 0.011), and T status (p = 0.012); and for FFR, 3D-CRT (p = 0.024) and N status (p < 0.001). Conclusion: The use of 3D-CRT allows patients with anal canal cancer to complete radiation and chemotherapy without interruption for toxicity, with significant improvements in LC, FFR, and OS.

  16. 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

  17. Bcl-2/Bax protein ratio predicts 5-fluorouracil sensitivity independently of p53 status

    PubMed Central

    Mirjolet, J-F; Barberi-Heyob, M; Didelot, C; Peyrat, J-P; Abecassis, J; Millon, R; Merlin, J-L

    2000-01-01

    p53 tumour-suppressor gene is involved in cell growth control, arrest and apoptosis. Nevertheless cell cycle arrest and apoptosis induction can be observed in p53-defective cells after exposure to DNA-damaging agents such as 5-fluorouracil (5-FU) suggesting the importance of alternative pathways via p53-independent mechanisms. In order to establish relationship between p53 status, cell cycle arrest, Bcl-2/Bax regulation and 5-FU sensitivity, we examined p53 mRNA and protein expression and p53 protein functionality in wild-type (wt) and mutant (mt) p53 cell lines. p53 mRNA and p53 protein expression were determined before and after exposure to equitoxic 5-FU concentration in six human carcinoma cell lines differing in p53 status and displaying marked differences in 5-FU sensitivity, with IC 50 values ranging from 0.2–22.6 mM. 5-FU induced a rise in p53 mRNA expression in mt p53 cell lines and in human papilloma virus positive wt p53 cell line, whereas significant decrease in p53 mRNA expression was found in wt p53 cell line. Whatever p53 status, 5-FU altered p53 transcriptional and translational regulation leading to up-regulation of p53 protein. In relation with p53 functionality, but independently of p53 mutational status, after exposure to 5-FU equitoxic concentration, all cell lines were able to arrest in G1. No relationship was evidenced between G1 accumulation ability and 5-FU sensitivity. Moreover, after 5-FU exposure, Bax and Bcl-2 proteins regulation was under p53 protein control and a statistically significant relationship (r= 0.880,P= 0.0097) was observed between Bcl-2/Bax ratio and 5-FU sensitivity. In conclusion, whatever p53 status, Bcl-2 or Bax induction and Bcl-2/Bax protein ratio were correlated to 5-FU sensitivity. © 2000 Cancer Research Campaign PMID:11044365

  18. Development and evaluation of nanostructured lipid carrier-based hydrogel for topical delivery of 5-fluorouracil

    PubMed Central

    Rajinikanth, Paruvathanahalli Siddalingam; Chellian, Jestin

    2016-01-01

    The aim of this study was to develop a nanostructured lipid carrier (NLC)-based hydrogel and study its potential for the topical delivery of 5-fluorouracil (5-FU). Precirol® ATO 5 (glyceryl palmitostearate) and Labrasol® were selected as the solid and liquid lipid phases, respectively. Poloxamer 188 and Solutol® HS15 (polyoxyl-15-hydroxystearate) were selected as surfactants. The developed lipid formulations were dispersed in 1% Carbopol® 934 (poly[acrylic acid]) gel medium in order to maintain the topical application consistency. The average size, zeta potential, and polydispersity index for the 5-FU-NLC were found to be 208.32±8.21 nm, −21.82±0.40 mV, and 0.352±0.060, respectively. Transmission electron microscopy study revealed that 5-FU-NLC was <200 nm in size, with a spherical shape. In vitro drug permeation studies showed a release pattern with initial burst followed by sustained release, and the rate of 5-FU permeation was significantly improved for 5-FU-NLC gel (10.27±1.82 μg/cm2/h) as compared with plain 5-FU gel (2.85±1.12 μg/cm2/h). Further, skin retention studies showed a significant retention of 5-FU from the NLC gel (91.256±4.56 μg/cm2) as compared with that from the 5-FU plain gel (12.23±3.86 μg/cm2) in the rat skin. Skin irritation was also significantly reduced with 5-FU-NLC gel as compared with 5-FU plain gel. These results show that the prepared 5-FU-loaded NLC has high potential to improve the penetration of 5-FU through the stratum corneum, with enormous retention and with minimal skin irritation, which is the prerequisite for topically applied formulations. PMID:27785014

  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.

  20. [The usefulness and adverse events of bevacizumab combined with chemotherapy against advanced or recurrent colorectal cancer].

    PubMed

    Oga, Junichi; Sakata, Makiko; Sato, Sumito; Matsumura, Naoki; Hatakeyama, Toshiyuki; Nagayama, Hiroyuki; Sakurai, Osamu; Ishida, Yasuo; Hataya, Kiyoshi

    2010-06-01

    We examined clinical results of 35 patients on bevacizumab(BV)combined with chemotherapy at our hospital. The subjects were 35 patients with advanced or recurrent colorectal cancer who received BV combined with chemotherapy for approximately 2 years. Their median age was 66 years(41 to 86 years), PS was 2 or less for all; it was first-line therapy in 21 patients, second-line in 12 patients and thirdline in 2 patients. The concomitant chemotherapy was mFOLFOX 6 in 24 / patients, 5-FU/LV in 8 patients and FOLFIRI in 3 patients. Therapeutic efficacy was CR in 2 patients, PR in 10 patients, and the overall response rate was 35%. There were 7 adverse events of Grade 3 or higher, among which 4 events were leucopenia. Neither overall survival nor any concomitant chemotherapy reached the median periods. Moreover, the median periods of / progression-free survival in mFOLFOX6/FOLFIRI were 191 days. BV combined with chemotherapy should be actively introduced as first-line therapy against advanced or recurrent colorectal cancer because of its high therapeutic efficacy.

  1. Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer

    PubMed Central

    Leung, Linda; Loong, Herbert

    2012-01-01

    Treatment of advanced stage lung cancer is changing rapidly. With the new found knowledge on molecular targets such as the epidermal growth factor receptor (EGFR), effective therapy is now available in a selected population with the target mutation. Single-agent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for patients with activating-EGFR mutation such as base-pair deletion in exon 19 or point mutation at exon 21. At the same time, this class of drugs may be combined with chemotherapy. Studies on the concurrent combination of chemotherapy and EGFR-TKI confirmed a lack of efficacy. A phase II study on sequential intercalated combination has demonstrated an improvement in progression-free survival (PFS), but this needs to be validated by the ongoing phase III study. The third approach is to combine EGFR-TKI as maintenance therapy after tumour response or stable disease to cytotoxic chemotherapy. Two phase III studies have shown improvement in PFS, but the use of biomarkers for the selection of maintenance therapy remains debatable. Cetuximab is a monoclonal antibody against EGFR and its combination with chemotherapy was shown to improve overall survival in an unselected population. A new biomarker using the H-score will help to select patients for this combination. PMID:22754591

  2. Chemotherapy for colorectal cancer in the elderly.

    PubMed

    Kim, Jung Han

    2015-05-07

    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.

  3. Prognostic markers of survival after combined mitotane- and platinum-based chemotherapy in metastatic adrenocortical carcinoma.

    PubMed

    Malandrino, Pasqualino; Al Ghuzlan, Abir; Castaing, Marine; Young, Jacques; Caillou, Bernard; Travagli, Jean-Paul; Elias, Dominique; de Baere, Thierry; Dromain, Clarisse; Paci, Angelo; Chanson, Philippe; Schlumberger, Martin; Leboulleux, Sophie; Baudin, Eric

    2010-09-01

    To progress in the stratification of the first-line therapeutic management of metastatic adrenocortical carcinoma (ACC), we searched for prognostic parameters of survival in patients treated with combined mitotane- and cisplatinum-based chemotherapy as first-line. We retrospectively studied prospectively collected parameters from 131 consecutive patients with metastatic ACC (44 with a tissue specimen available) treated at the Gustave Roussy Institute with mitotane- and platinum-based chemotherapy. Fifty-five patients with clinical, pathological, and morphological data available together with treatment characteristics including detailed follow-up were enrolled. Plasma mitotane levels and ERCC1 protein staining were analyzed. Response was analyzed according to RECIST criteria as well as overall survival (OS) from the start of cisplatinum-based chemotherapy. Parameters impacting on OS were evaluated by univariate analysis, and then analyzed by multivariate analysis. Using a landmark method, OS according to response to chemotherapy was analyzed. Objective response to combined mitotane- and cisplatinum-based chemotherapy was 27.3%. Median OS was 1 year. In the univariate analysis, resection of the primary, time since diagnosis, mitotane monotherapy as single first-line treatment, number of affected organs, plasma mitotane above 14 mg/l, and objective response were predictors of survival. In the multivariate analysis, mitotane level > or =14 mg/l and objective response to platinum-based chemotherapy were found to be independent predictors of survival (P=0.03 and <0.001). Our study suggests a prognostic role for mitotane therapy and objective response to platinum-based chemotherapy.

  4. Progress in systemic chemotherapy of primary breast cancer: an overview.

    PubMed

    Hortobagyi, G N

    2001-01-01

    Substantial progress has been made in the multidisciplinary management of primary breast cancer during the last 30 years. Adjuvant chemotherapy has been shown to significantly reduce the annual risk of cancer recurrence and mortality, and these effects persist even 15 years after diagnosis. Combination chemotherapy is superior to single-agent therapy and anthracycline-containing regimens. Those that combine an anthracycline with 5-fluorouracil and cyclophosphamide are more effective than regimens without an anthracycline. Six cycles of a single regimen appear to provide optimal benefit. Dose reductions below the standard range are associated with inferior results. Dose increases that require growth factor or hematopoietic stem cell support are under investigation; at this time, the existing results provide no compelling reason to use this strategy outside a clinical trial. Regimens using fixed crossover designs with two non-cross-resistant regimens are being evaluated. The addition of a taxane to anthracycline-containing regimens is currently under intense scrutiny, and preliminary analysis of the first three clinical trials has shown encouraging, albeit not compelling, results. For patients with estrogen receptor-positive breast cancer, the sequential administration of chemotherapy and 5 years of tamoxifen therapy provides additive benefits. No compelling evidence exists to combine ovarian ablation with chemotherapy. Most side effects and toxic effects are self-limited, although premature menopause requires monitoring and preventive interventions to preserve bone mineral density. The small risk of acute leukemia is of concern, and additional research to develop safer regimens is clearly indicated. The overall effect of optimal local/regional treatment combined with an anthracycline-containing adjuvant chemotherapy and a taxane (and, for patients with estrogen receptor-positive tumors, 5 years of tamoxifen therapy) is a greater than 50% reduction in annual risks of

  5. 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

  6. [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.

  7. 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

  8. Interaction of fluorescence dyes with 5-fluorouracil: A photoinduced electron transfer study in bulk and biologically relevant water

    NASA Astrophysics Data System (ADS)

    Kuchlyan, Jagannath; Banik, Debasis; Kundu, Niloy; Roy, Arpita; Sarkar, Nilmoni

    2014-10-01

    The interactions of widely used chemotherapeutic drug, 5-fluorouracil (5FU) with coumarin dyes have been investigated for the first time using steady-state and time-resolved fluorescence spectroscopic measurements. The fluorescence quenching along with the decrease in lifetimes of excited state of coumarin derivatives with gradual addition of 5FU is explained by photoinduced electron transfer (PET) mechanism. Our studies were performed in bulk water and confined water of AOT (aerosol OT) reverse micelle to investigate the effect of confinement on PET dynamics. The feasibility of PET reaction for coumarin-5FU systems is investigated calculating the standard free energy changes using the Rehm-Weller equation.

  9. Solvent effects on the steady-state absorption and fluorescence spectra of uracil, thymine and 5-fluorouracil.

    PubMed

    Gustavsson, Thomas; Sarkar, Nilmoni; Bányász, Akos; Markovitsi, Dimitra; Improta, Roberto

    2007-01-01

    We report a comparison of the steady-state absorption and fluorescence spectra of three representative uracil derivatives (uracil, thymine and 5-fluorouracil) in alcoholic solutions. The present results are compared with those from our previous experimental and computational studies of the same compounds in water and acetonitrile. The effects of solvent polarity and hydrogen bonding on the spectra are discussed in the light of theoretical predictions. This comparative analysis provides a more complete picture of the solvent effects on the absorption and fluorescence properties of pyrimidine nucleobases, with special emphasis on the mechanism of the excited state deactivation.

  10. 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,

  11. EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models.

    PubMed

    Laurila, Niina; Koivunen, Jussi P

    2015-07-01

    Acquired resistance to EGFR TKIs is the most important limiting factor for treatment efficiency in EGFR-mutant NSCLC. Although the continuation of EGFR TKI beyond disease progression in combination with chemotherapy is often suggested as a strategy for treating acquired resistance, the optimal treatment sequence for EGFR TKI and chemotherapy is unknown. In the current work, NSCLC cell lines PC9ER, H1975 and HCC827GR, representing the acquired TKI resistance genotypes (T790M, cMET), were exposed to a chemotherapeutic agent, cisplatin or paclitaxel, in combination with EGFR TKIs (erlotinib, WZ4002) in vitro and analysed for cytotoxicity and apoptotic response. The result showed that all the combinations of EGFR TKIs with a chemotherapeutic agent tested had a synergistic effect on cytotoxicity and increased the apoptotic response. The sequences involving a chemotherapeutic agent concurrently with an EGFR TKI or preceding it were the most efficient strategies. Our in vitro models suggest that the combination of an EGFR TKI and chemotherapy is beneficial in cases of acquired EGFR TKI resistance. Furthermore, the sequence of chemotherapy followed by EGFR TKI is significantly more powerful than the reversed order, so that an intercalated approach is likely to be the most active strategy in clinical use and ought to be tested in a randomized clinical trial.

  12. 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.

  13. 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

  14. The First Case of Severe Takotsubo Cardiomyopathy Associated with 5-Fluorouracil in a Patient with Abnormalities of Both Dihydropyrimidine Dehydrogenase (DPYD) and Thymidylate Synthase (TYMS) Genes

    PubMed Central

    Smith, Melissa; Maloney, Antonio

    2016-01-01

    5-Fluorouracil (5-FU) is the backbone of the chemotherapy regimens approved for treatment of many malignancies, especially colorectal cancer (CRC). The incidence of cardiotoxicity associated with 5-FU ranges between 1.5% to 18% and is most commonly manifested as anginal symptoms. Cardiomyopathy is very rarely reported with 5-FU and capecitabine. A 35-year-old Caucasian male with T3, N1, M0 rectal cancer after the initial neoadjuvant chemoradiation with 5FU/LV followed by surgical abdominoperineal resection (APR), began mFOLFOX6 in the adjuvant setting. Following the first treatment, he developed severe cardiomyopathy, with a drop in ejection fraction (EF) to 19% from normal. The cardiac workup showed no ischemic or other etiologies to explain this cardiac event. He was a nonsmoker and only occasionally drank alcohol. He had no previous or family history of heart disease and had normal cholesterol level. He was treated for severe congestive heart failure (CHF). When the patient presented to us for second opinion, we decided to examine him for dihydropyrimidine dehydrogenase (DPD) deficiency and thymidylate synthase (TYMS) polymorphism. The patient was found to be heterozygous for the c.85T>C mutation, resulting in reduced DPYD enzymatic activity and homozygous for TYMS 5’TSER genotype 2R/2R *f. Our group first identified and reported P453L (1358C>T) type DPYD germline mutation in a patient who developed 5-FU induced cardiotoxicity. In this paper, we describe the first case of cardiomyopathy related to DPD deficiency and homozygous polymorphism of TYMS in a patient with colon cancer following 5-FU containing regimen. Fluorouracil-related cardiomyopathy has to be anticipated and treated to prevent the serious consequence of cardiac dysfunction. The prospective testing for DPD deficiency in patients might prevent DPD-deficient patients from severe toxicity or even death, and therefore the development of a unified screening method is warranted. PMID:27752409

  15. Synthesis of F16 conjugated with 5-fluorouracil and biophysical investigation of its interaction with bovine serum albumin by a spectroscopic and molecular modeling approach.

    PubMed

    Xiang, Chen; Li, Dong-Wei; Qi, Zu-De; Jiang, Feng-Lei; Ge, Yu-Shu; Liu, Yi

    2013-01-01

    5-Fluorouracil (5-FU) has been widely used as a chemotherapy agent in the treatment of many types of solid tumors. Investigation of its antimetabolites led to the development of an entire class of fluorinated pyrimidines. However, the toxicity profile associated with 5-FU is significant and includes diarrhea, mucositis, hand-foot syndrome and myelosuppression. In aiming at reducing of the side effects of 5-FU, we have designed and synthesized delocalized lipophilic cations (DLCs) as a vehicle for the delivery of 5-FU. DLCs accumulate selectively in the mitochondria of cancer cells because of the high mitochondrial transmembrane potential (ΔΨm). Many DLCs exhibited anti-cancer efficacy and were explored as potential anti-cancer drugs based on their selective accumulation in the mitochondria of cancer cells. F16, the DLC we used as a vehicle, is a small molecule that selectively inhibits tumor cell growth and dissipates mitochondrial membrane potential. The binding of the conjugate F16-5-FU to bovine serum albumin (BSA) was investigated using spectroscopic and molecular modeling approaches. Fluorescence quenching constants were determined using the Stern-Volmer equation to provide a measure of the binding affinity between F16-5-FU and BSA. The activation energy of the interaction between F16-5-FU and BSA was calculated and the unusually high value was discussed in terms of the special structural block indicated by the molecular modeling approach. Molecular modeling showed that F16-5-FU binds to human serum albumin in site II, which is consistent with the results of site-competitive replacement experiments. It is suggested that hydrophobic and polar forces played important roles in the binding reaction, in accordance with the results of thermodynamic experiments.

  16. Curcumin Inhibits 5-Fluorouracil-induced Up-regulation of CXCL1 and CXCL2 of the Colon Associated with Attenuation of Diarrhoea Development.

    PubMed

    Sakai, Hiroyasu; Kai, Yuki; Oguchi, Aya; Kimura, Minami; Tabata, Shoko; Yaegashi, Miyabi; Saito, Taiki; Sato, Ken; Sato, Fumiaki; Yumoto, Tetsuro; Narita, Minoru

    2016-12-01

    The compound 5-fluorouracil (5-FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5-FU in mice. Curcumin has anti-inflammatory, antitumour and antioxidant properties. Therefore, we examined the effect of curcumin on 5-FU-induced diarrhoea development and CXCL1 and CXCL2 up-regulation in the colon. Mice were given 5-FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5-FU and administered 30 min. before the administration of 5-FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real-time RT-PCR. Curcumin reduced the 5-FU-induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up-regulated by 5-FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5-FU application in vitro. The 5-FU-induced up-regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay-117082 and bortezomib, nuclear factor kappa B (NF-κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element-binding protein-histone acetyltransferase (HAT) inhibitor. In conclusion, these findings suggested that curcumin prevented the development of diarrhoea by inhibiting NF-κB and HAT activation.

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

    PubMed

    Filgueiras, Marcelo de Carvalho; Morrot, Alexandre; Soares, Pedro Marcos Gomes; Costa, Manoel Luis; Mermelstein, Cláudia

    2013-01-01

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

  18. 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

    2016-06-14

    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.

  19. 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.

  20. 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.

  1. Outcome of early clinical trials of the combination of hydroxychloroquine with chemotherapy in cancer.

    PubMed

    Poklepovic, Andrew; Gewirtz, David A

    2014-08-01

    The premise of inhibiting autophagy to overcome resistance to chemotherapy has been investigated in 5 clinical phase I trials combining hydroxychloroquine with vorinostat, temsirolimus, temozolomide, or bortezomib. These studies have provided a number of insights relating to the tolerability of the combination treatments. In addition, these studies should provide guidance in the planning and design of future trials to directly determine whether the strategy of autophagy inhibition could prove useful in the treatment of various malignancies.

  2. Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment.

    PubMed

    Bose, A; Elyagoby, A; Wong, T W

    2014-07-01

    In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 μg 5-FU/g rat colon content vs 4.66 μg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.

  3. Experimental and theoretical studies on the coordination chemistry of the N1-hexyl substituted pyrimidines (uracil, 5-fluorouracil and cytosine).

    PubMed

    Barceló-Oliver, Miquel; Baquero, Beatriz Adriana; Bauzá, Antonio; García-Raso, Angel; Vich, Roberto; Mata, Ignasi; Molins, Elies; Terrón, Angel; Frontera, Antonio

    2013-06-07

    N(1)-Hexyl substituted pyrimidines were shown to present solubility properties closer to the real bases than the commonly used methyl and ethyl derivatives, yielding bi-layered structures in the solid state. The study of their coordination capabilities, mainly with Ag(I) and Hg(II), is presented in order to prove their reactivity. A series of coordination complexes, namely, [Hg(N(1)-hexyl-5-fluorouracilate)2]4·6H2O (1), (Ag(+))·[Ag(N(1)-hexyl-5-fluorouracilate)2](-) (2), [Ag(NO3)(N(1)-hexyluracil-κO(4))4] (3), [ZnBr2(N(1)-hexylcytosine)2] (4), [CdBr2(N(1)-hexylcytosine)2] (5), [HgBr2(N(1)-hexylcytosine)2] (6) and [CoBr2(N(1)-hexylcytosine)2] (7), have been synthesized in good yields and X-ray characterized. The presence of the hexyl chains and the fluorine atoms causes the formation of interesting 3D architectures in the solid state. Their structures have been further characterized by infrared spectra (IR) and elemental analyses. In addition, DFT-D3 calculations are used to study interesting noncovalent interactions observed in the solid state, like fluorine-fluorine, fluorine-π and hydrophobic interactions.

  4. Eradication of keloids: Surgical excision followed by a single injection of intralesional 5-fluorouracil and botulinum toxin

    PubMed Central

    Wilson, Adel Michel

    2013-01-01

    BACKGROUND: Keloids may complicate wound healing secondary to trauma, inflammation or surgical incision. Although various treatment modalities have been used with variable degrees of success, overall recurrence rates have remained unacceptably high. METHODS: The present study involved 80 patients with keloids of at least one-years’ duration. Following total surgical excision of the keloid, a single dose of 5-fluorouracil was injected into the edges of the healing wound on postoperative day 9 together with botulinum toxin. The concentration of 5-fluorouracil used was 50 mg/mL and approximately 0.4 mL was infiltrated per cm of wound tissue, with the total dose <500 mg. The concentration of botulinum toxin was 50 IU/mL with the total dose <140 IU. RESULTS: Patients were followed-up for 17 to 24 months and a recurrence rate of 3.75% was found, which was significantly lower than in previously reported studies using other therapeutic modalities. CONCLUSION: The author recommends that this treatment be routinely applied to all keloids because it is significantly more effective than those described by other authors. PMID:24431948

  5. Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

    PubMed Central

    Twitty, Chris G.; Diago, Oscar R.; Hogan, Daniel J.; Burrascano, Cindy; Ibanez, Carlos E.; Jolly, Douglas J.; Ostertag, Derek

    2016-01-01

    Toca 511 is a modified retroviral replicating vector based on Moloney γ-retrovirus with an amphotropic envelope. As an investigational cancer treatment, Toca 511 preferentially infects cancer cells without direct cell lysis and encodes an enhanced yeast cytosine deaminase that converts the antifungal drug 5-fluorocytosine to the anticancer drug, 5-fluorouracil. A panel of established human cancer cell lines, derived from glioblastoma, colon, and breast cancer tissue, was used to evaluate parameters critical for effective anticancer activity. Gene transfer, cytosine deaminase production, conversion of 5-fluorocytosine to 5-fluorouracil, and subsequent cell killing occurred in all lines tested. We observed >50% infection within 25 days in all lines and 5-fluorocytosine LD50 values between 0.02 and 6 μg/ml. Although we did not identify a small number of key criteria, these studies do provide a straightforward approach to rapidly gauge the probability of a Toca 511 and 5-fluorocytosine treatment effect in various cancer indications: a single MTS assay of maximally infected cancer cell lines to determine 5-fluorocytosine LD50. The data suggest that, although there can be variation in susceptibility to Toca 511 and 5-fluorocytosine because of multiple mechanistic factors, this therapy may be applicable to a broad range of cancer types and individuals. PMID:26467507

  6. Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types.

    PubMed

    Twitty, Chris G; Diago, Oscar R; Hogan, Daniel J; Burrascano, Cindy; Ibanez, Carlos E; Jolly, Douglas J; Ostertag, Derek

    2016-02-01

    Toca 511 is a modified retroviral replicating vector based on Moloney γ-retrovirus with an amphotropic envelope. As an investigational cancer treatment, Toca 511 preferentially infects cancer cells without direct cell lysis and encodes an enhanced yeast cytosine deaminase that converts the antifungal drug 5-fluorocytosine to the anticancer drug, 5-fluorouracil. A panel of established human cancer cell lines, derived from glioblastoma, colon, and breast cancer tissue, was used to evaluate parameters critical for effective anticancer activity. Gene transfer, cytosine deaminase production, conversion of 5-fluorocytosine to 5-fluorouracil, and subsequent cell killing occurred in all lines tested. We observed >50% infection within 25 days in all lines and 5-fluorocytosine LD50 values between 0.02 and 6 μg/ml. Although we did not identify a small number of key criteria, these studies do provide a straightforward approach to rapidly gauge the probability of a Toca 511 and 5-fluorocytosine treatment effect in various cancer indications: a single MTS assay of maximally infected cancer cell lines to determine 5-fluorocytosine LD50. The data suggest that, although there can be variation in susceptibility to Toca 511 and 5-fluorocytosine because of multiple mechanistic factors, this therapy may be applicable to a broad range of cancer types and individuals.

  7. Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

    PubMed Central

    Botticelli, Andrea; Borro, Marina; Onesti, Concetta Elisa; Strigari, Lidia; Gentile, Giovanna; Cerbelli, Bruna; Romiti, Adriana; Occhipinti, Mario; Sebastiani, Claudia; Lionetto, Luana; Marchetti, Luca; Simmaco, Maurizio; Marchetti, Paolo; Mazzuca, Federica

    2016-01-01

    Background 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival. Materials and Methods Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome. Results 133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed. Conclusion 5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes. PMID:27656891

  8. Thermosensitive gemcitabine-magnetoliposomes for combined hyperthermia and chemotherapy.

    PubMed

    Ferreira, Roberta V; Martins, Thaís Maria da Mata; Goes, Alfredo Miranda; Fabris, José D; Cavalcante, Luis Carlos D; Outon, Luis Eugenio Fernandez; Domingues, Rosana Z

    2016-02-26

    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%.

  9. 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%.

  10. Chan-Yu-Bao-Yuan-Tang and 5-fluorouracil synergistically induce apoptosis by means of the caspase-3 signaling pathway in lung and cervical cancer cells.

    PubMed

    Zeng, Fang; Liu, Xiaoguang; Li, Yuncheng; Chen, Gang; Wang, Yekai; Zhou, Shiquan; Zhu, Wangyu; Huang, Yanyan; Zhou, Jiehang; Li, Shibo; Zhang, Yongkui

    2011-01-01

    Previous clinical studies have shown the safety and efficacy of the traditional Chinese medicinal herbal aqueous extract Chan-Yu-Bao-Yuan-Tang (CYBYT) for the treatment of lung and cervical cancer patients. Used in combination with 5-fluorouracil (5-Fu), CYBYT has been observed to be particularly effective in cancer treatment. Herein, the combined anticancer effect and the underlying mechanisms of 5-Fu and CYBYT in the human lung cancer cell line A549 and the human cervical cancer cell line HeLa were investigated in vitro. The MTT assay, Annexin V-FITC staining and Western blotting were applied to identify cell viability, the stages of apoptosis and the expression of signaling proteins, respectively. The results indicated that CYBYT and 5-Fu, alone or in combination, significantly inhibited proliferation and induced marked apoptosis in A549 and HeLa cells, but had no significant inhibitory effects on normal human IMR-90 fibroblasts. The rate of mid and late apoptosis or necrosis was greater after 5-Fu treatment compared to treatment with CYBYT or the combination of agents; however, the early apoptotic rate showed opposite results. CYBYT and 5-Fu, alone or in combination, up-regulated cleaved caspase-3 expression in a time-dependent manner, with CYBYT being more effective than 5-Fu. Taken together, our data show that the pro-apoptotic activity of the two-drug combination was much stronger than that of CYBYT or 5-Fu alone; CYBYT combined with 5-Fu had synergistic effects at lower concentrations and promoted apoptosis, while the combined treatment also decreased the cytotoxic side effects of 5-Fu.

  11. The use of capecitabine in the combined-modality therapy for rectal cancer.

    PubMed

    Liauw, Stanley L; Minsky, Bruce D

    2008-03-01

    Locally advanced rectal adenocarcinoma is treated by combined-modality therapy, which consists of surgery, chemotherapy, and radiation therapy. A series of randomized trials established a preferred treatment sequence of preoperative radiation therapy and 5-fluorouracil(5-FU)-based chemotherapy, total mesorectal excision, and adjuvant 5-FU-based chemotherapy for patients with stage II/III disease. Capecitabine is an oral prodrug of 5-FU that has potential advantages compared with intravenous 5-FU, including ease of administration and potentially increased therapeutic effect. Capecitabine is converted by a 3-step enzymatic process; the last step involves the enzyme thymidine phosphorylase, which is overexpressed in tumor tissues and is stimulated by concurrent radiation therapy. Over the past 5 years, several phase I/II trials of capecitabine-based therapy were reported. This review discusses the evolution of combined-modality therapy for rectal cancer with specific attention given to the use of capecitabine in conjunction with radiation therapy.

  12. Scoring of Prognostic Parameters in Patients with Unresectable Advanced or Recurrent Colorectal Cancer Undergoing Chemotherapy

    PubMed Central

    Ikeguchi, Masahide; Shimoda, Ryugo; Yamamoto, Manabu; Maeta, Yoshihiko; Ashida, Keigo; Saito, Hiroaki

    2013-01-01

    Background Suitable chemotherapy is needed to prolong the survival of patients with unresectable advanced or recurrent colorectal cancer. We scored the periodical changes of several prognostic markers during chemotherapy in patients with this type of cancer to discern the effectiveness of chemotherapy. Methods Twenty consecutive patients with unresectable advanced or recurrent colorectal cancer were enrolled. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/leucovorin. Neutrophil/lymphocyte ratio (NLR), serum C-reactive protein (CRP), serum carcinoembryonic antigen (CEA) and serum albumin (ALB) were compared between the two periods (before chemotherapy and 3 months after it was started) in each patient. The scoring system was as follows: points are added when a patient shows a decrease of NLR, CRP and CEA and an increase of ALB at 3 months after the start of chemotherapy with a possible final score of +4. On the other hand, points are reduced if a patient shows an elevation of NLR, CRP and CEA and a decrease of ALB at 3 months after the start of chemotherapy with a possible final score of −4. Results At 3 months after the start of first line chemotherapy, 13 patients showed positive scores but 7 patients showed zero or minus scores. According to our scoring system, we found the mean survival time (MST) of the 13 patients with plus scores was 34 months and this was significantly better than that of the 7 patients who showed zero or minus scores (P = 0.0008). Conclusion Our new scoring system is useful but when we find that first line chemotherapy is ineffective, we need to change it to second line chemotherapy as soon as possible. That may be the best treatment for patients with unresectable advanced or recurrent colorectal cancer. PMID:24179314

  13. Immunobiological effects of gemcitabine and capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma

    PubMed Central

    Middleton, Gary; Greenhalf, William; Costello, Eithne; Shaw, Victoria; Cox, Trevor; Ghaneh, Paula; Palmer, Daniel H; Neoptolemos, John P

    2016-01-01

    Background: Preclinical studies suggest that chemotherapy may enhance the immune response against pancreatic cancer. Methods: The levels of granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) and the associated inflammatory marker C-reactive protein (CRP) were assessed in 38 patients receiving gemcitabine and capecitabine combination chemotherapy for advanced pancreatic cancer within the TeloVac trial. Apoptosis (M30) and total immune response (delayed-type hypersensitivity and/or T-cell response) were also assessed and levels of apoptosis induction correlated with immune response. The telomerase GV1001 vaccine was given either sequentially (n=18) or concomitantly (n=24) with the combination chemotherapy. Results: There were no differences between baseline and post-treatment levels of CRP (P=0.19), IL-6 (P=0.19) and GM-CSF (P=0.71). There was a positive correlation between post-chemotherapy CRP and IL-6 levels (r=0.45, P=0.005) and between CRP with carbohydrate antigen-19-9 (CA19-9) levels at baseline (r=0.45, P=0.015) and post treatment (r=0.40, P=0.015). The change in CRP and IL-6 levels was positively correlated (r=0.40, P=0.012). Hazard ratios (95% CI) for baseline CA19-9 (1.30 (1.07–1.59), P=0.009) and CRP (1.55 (1.00–2.39), P=0.049) levels were each independently predictive of survival. The M30 mean matched differences between pre- and post-chemotherapy showed evidence of apoptosis in both the sequential (P=0.058) and concurrent (P=0.0018) chemoimmunotherapy arms. Respectively, 5 of 10 and 9 of 20 patients had a positive immune response but there was no association with apoptosis. Conclusions: Combination gemcitabine and capecitabine chemotherapy did not affect circulating levels of GM-CSF, IL-6 and CRP. Chemotherapy-induced apoptosis was not associated with the immunogenicity induced by the GV1001 vaccine in advanced pancreatic cancer. PMID:26931369

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

    PubMed

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

    2015-10-01

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

  15. 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.

  16. A retrospective study on TS mRNA expression and prediction of the effects of adjuvant oral 5-fluorouracil in breast cancer

    PubMed Central

    AKI, FUMINORI; BANDO, YOSHIMI; TAKAHASHI, TETSUYUKI; UEHARA, HISANORI; NUMOTO, SATOSHI; ITO, SUEYOSHI; SASA, MITSUNORI; IZUMI, KEISUKE

    2010-01-01

    Nucleic acid-metabolizing enzymes, such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT), have attracted attention as candidates for response determinants of 5-fluorouracil (5-FU). Whether the expression levels of these enzymes can be adopted as valuable parameters for 5-FU sensitivity in breast cancer has yet to be elucidated. In the present study, intratumoral mRNA expression of TS, DPD, TP and OPRT were determined in formalin-fixed paraffin-embedded surgical specimens collected from 217 breast cancer patients, using the Danenberg Tumor Profile method, which combines microdissection and real-time-polymerase chain reaction. The significance of these enzymes as prognostic and 5-FU efficacy-predicting factors was evaluated. Our data showed that a low DPD expression is related to a high nuclear grade and other factors including hormone receptor-negativity. Low expression levels of TP were found in hormone receptor-negative tumors. TS and OPRT expression were not related to various clinicopathological factors, but patients with a high TS mRNA expression showed a significantly poorer prognosis in cases where 5-FU was not administered. The efficacy of 5-FU was more significant when administered for more than 6 months in the group with a high TS mRNA expression. These data suggest that TS mRNA expression in breast cancer tissue is an ideal predictor of outcomes for patients with no administration of 5-FU, and of the efficacy of 5-FU. PMID:22870098

  17. Synthesis of glycyrrhetinic acid-modified chitosan 5-fluorouracil nanoparticles and its inhibition of liver cancer characteristics in vitro and in vivo.

    PubMed

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

    2013-09-17

    Nanoparticle drug delivery (NDDS) is a novel system in which the drugs are delivered to the site of action by small particles in the nanometer range. Natural or synthetic polymers are used as vectors in NDDS, as they provide targeted, sustained release and biodegradability. Here, we used the chitosan and hepatoma cell-specific binding molecule, glycyrrhetinic acid (GA), to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by Fourier transformed infrared spectroscopy (FT-IR) and ¹H-nuclear magnetic resonance (¹H-NMR). By combining GA-CTS and 5-FU (5-fluorouracil), we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 217.2 nm, a 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. We demonstrated that the nanoparticle accumulated in the liver. In vitro data indicated that it had a dose- and time-dependent anti-cancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. Additionally, GA-CTS/5-FU significantly inhibited the growth of drug-resistant hepatoma, which may compensate for the drug-resistance of 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited tumor growth, resulting in increased survival time.

  18. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: the Gastrointestinal Tumor Study Group. [X ray

    SciTech Connect

    Moertel, C.G.; Frytak, S.; Hahn, R.G.

    1981-10-15

    One-hundred-ninety-four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high-dose (6000 rads) radiation therapy alone, to moderate-dose (4000 rads) radiation + 5-fluorouracil (5-FU), and to high-dose radiation plus 5-FU. Median survival with radiation alone was only 5 1/2 months from date of diagnosis. Both 5-FU-containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Survival differences between 4000 rads plus 5-FU and 6000 rads plus 5-FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level. The toxic reactions related to the treatment are discussed.

  19. 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

  20. Combined laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a patient with peritoneal mesothelioma.

    PubMed

    Esquivel, Jesus; Averbach, Andrew

    2009-08-01

    The role of minimally invasive, laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported by several centers around the world, mainly to palliate intractable ascites in patients with extensive peritoneal surface malignancies who are not candidates for a complete cytoreduction. In this paper, we report on the first case of combined laparoscopic cytoreductive surgery and HIPEC with curative intent in a patient with limited peritoneal mesothelioma.

  1. 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.

  2. β-Carotene synergistically enhances the anti-tumor effect of 5-fluorouracil on esophageal squamous cell carcinoma in vivo and in vitro.

    PubMed

    Zhang, Yanting; Zhu, Xiangzhan; Huang, Tuanjie; Chen, Lei; Liu, Yanxia; Li, Qinghua; Song, Jishi; Ma, Shanshan; Zhang, Kun; Yang, Bo; Guan, Fangxia

    2016-11-02

    Recently, we reported that β-carotene exhibited anticancer activity against human esophageal squamous cell carcinoma cells in vitro. In the present study, we examined a novel therapeutic strategy by combining β-carotene with 5-fluorouracil (5-FU) in human esophageal cancer in vitro and in vivo, and elucidated the underlying mechanisms. We found that the combination of 5-FU and β-carotene displayed greater growth inhibitory effects than did either compound alone in esophageal squamous cell carcinoma (ESCC) cells. In addition, the combination of 5-FU and β-carotene displayed greater tumor growth inhibition in an Eca109 xenograft mouse model than did a single agent with low systemic toxicity. β-Carotene enhanced 5-FU-induced apoptosis. TUNEL staining revealed that the rate of TUNEL-positive cells was markedly increased in tumor tissues after treatment with 5-FU and β-carotene. Western blotting and immunohistochemistry revealed the down-regulation of Bcl-2 and PCNA and the up-regulation of Bax and caspase-3 in tumor tissues. Further studies demonstrated that the combined administration of 5-FU and β-carotene significantly down-regulated the protein levels of Cav-1, p-AKT, p-NF-κB, p-mTOR and p-p70S6K in Eca109 cells more effectively than did 5-FU alone. These data suggested that the combined therapy of 5-FU and β-carotene exerted synergistic antitumor effects in vivo and in vitro and could constitute a novel therapeutic treatment for ESCC.

  3. 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

  4. 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.

  5. Real time in vitro regulation of DNA methylation using a 5-fluorouracil conjugated DNA-based stimuli-responsive platform.

    PubMed

    Mao, Xiuhai; Wei, Ming; Zhu, Chengfeng; Lu, Jianxin; Gao, Jimin; Simon, Anna J; Shi, Jiye; Huang, Qing; Fan, Chunhai

    2013-04-10

    DNA methylation, catalyzed by methylases, plays a critical role in many biological processes, and many methylases have been regarded as promising targets for antimicrobial drugs. In this work, we report a stimulus responsive, self-regulating anticancer drug release platform, comprising a multifunctional DNA that upon methylation by methyltransferase (MTase) releases 5-fluorouracil (5-Fu) and in turn inhibits subsequent expression of MTase. The multifunctional DNA with anticancer drug are first methylated by DNA adenine methylation (DAM) methyltransferase (MTase) and then cut by the methylation-sensitive restriction endonuclease Dpn I. Removal of duplex from the functional DNA by the methylation/cleavage process will release the anticancer drug, resulting in inhibition of the activity of DAM in turn. Consequently, the enzyme activity of DAM MTase can be self-regulated. Furthermore, we found that the inhibition efficiency of 5-Fu significantly increase as it is functionalized with DNA.

  6. 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.

  7. Comparative Analysis of the Antineoplastic Activity of C60 Fullerene with 5-Fluorouracil and Pyrrole Derivative In Vivo

    NASA Astrophysics Data System (ADS)

    Lynchak, O. V.; Prylutskyy, Yu I.; Rybalchenko, V. K.; Kyzyma, O. A.; Soloviov, D.; Kostjukov, V. V.; Evstigneev, M. P.; Ritter, U.; Scharff, P.

    2017-01-01

    The antitumor activity of pristine C60 fullerene aqueous solution (C60FAS) compared to 5-fluorouracil (5-FU) and pyrrole derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2.5-dione (MI-1) cytostatic drugs was investigated and analyzed in detail using the model of colorectal cancer induced by 1.2-dimethylhydrazine (DMH) in rats. The number, size, and location of the tumors were measured, and the pathology was examined. It was found that the number of tumors and total lesion area decreased significantly under the action of C60FAS and MI-1. Because these drugs have different mechanisms of action, their simultaneous administration can potentially increase the effectiveness and significantly reduce the side effects of antitumor therapy.

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

    NASA Astrophysics Data System (ADS)

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

    2013-11-01

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

  9. Kinetics of membrane binding and dissociation of 5-fluorouracil by pulsed-field-gradient 19F NMR

    NASA Astrophysics Data System (ADS)

    Yoshii, Noriyuki; Okamura, Emiko

    2009-06-01

    The kinetics of membrane binding and dissociation of an anticancer drug, 5-fluorouracil (5FU) is quantified by high resolution NMR with the pulsed-field-gradient technique. The 19F NMR signal of 5FU is analyzed at 293-313 K by the solution of Bloch equation with exchange terms. The rate constants of 5FU binding and dissociation are 0.2 and 4.1 s -1 at 303 K. The 5FU motion in the vertical direction to the membrane surface is restricted as compared with the lateral diffusion, judging from the activation energy (57 kJ/mol) larger than the lateral diffusion in membrane (26 kJ/mol [E. Okamura, N. Yoshii, J. Chem. Phys. 129 (2008) 215102]).

  10. A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil.

    PubMed

    Méndez, Miguel; Salut, Antonieta; García-Girón, Carlos; Navalon, Marta; Diz, Pilar; García López, Maria José; España, Pilar; de la Torre, Ascensión; Martínez del Prado, Purificación; Duarte, Isabel; Pujol, Eduardo; Arizcun, Alberto; Cruz, Juan Jesús

    2003-11-01

    This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.

  11. Combining anti-miR-155 with chemotherapy for the treatment of lung cancers.

    PubMed

    Van Roosbroeck, Katrien; Fanini, Francesca; Setoyama, Tetsuro; Ivan, Cristina; Rodriguez-Aguayo, Cristian; Fuentes-Mattei, Enrique; Xiao, Lianchun; Vannini, Ivan; Redis, Roxana; D'Abundo, Lucilla; Zhang, Xinna; Nicoloso, Milena S; Rossi, Simona; Gonzalez-Villasana, Vianey; Rupaimoole, Rajesha; Ferracin, Manuela; Morabito, Fortunato; Neri, Antonino; Ruvolo, Peter; Ruvolo, Vivian R; Pecot, Chad V; Amadori, Dino; Aruzzo, Lynne; Calin, Steliana; Wang, Xuemei; You, M James; Ferrajoli, Alessandra; Orlowski, Robert Z; Plunkett, William; Lichtenberg, Tara; Davuluri, Ramana V; Berindan-Neagoe, Ioana; Negrini, Massimo; Wistuba, Ignacio I; Hagop, Kantarjian; Sood, Anil K; Lopez-Berestein, Gabriel; Keating, Michael J; Fabbri, Muller; Calin, George A

    2016-11-30

    Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia and acute lymphoblastic leukemia. Results We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism, and demonstrate that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions Our findings support the existence of a miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.

  12. 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

  13. An intravitreal biodegradable sustained release naproxen and 5-fluorouracil system for the treatment of experimental post-traumatic proliferative vitreoretinopathy

    PubMed Central

    Cardillo, J A; Farah, M E; Mitre, J; Morales, P H; Costa, R A; Melo, L A S; Kuppermann, B; Jorge, R; Ashton, P

    2004-01-01

    Background/aims: To determine the potential of an intravitreal sustained release naproxen and 5-fluorouracil (NA/5-FU) codrug for the treatment of experimental proliferative vitreoretinopathy (PVR) in a model for trauma associated tractional retinal detachment (TRD). Methods: Sustained release pellets were prepared by covalently linking naproxen to 5-fluorouracil. Drug release was tested in vitro and toxic effects were evaluated by electroretinography and light microscopy. Traumatic PVR was induced in pigmented rabbits by performing a scleral laceration, followed by repair and intravitreal injection of 0.4 ml of autologous blood. Thirty six eyes were treated with a sustained release implant containing 1.5 mg NA/5-FU as a codrug and 36 control eyes were submitted to surgery alone. Eyes were evaluated for TRD by serial indirect ophthalmoscope examination at different time points followed by postmortem fundus evaluation of the enucleated eye Results: The NA/5-FU pellets were found to provide linear release of 5-FU and naproxen over the 30 day duration of the in vitro release test. Both the severity of PVR grade and the percentage of eyes with moderate or worse tractional detachment were significantly lower in eyes treated with the codrug pellet. There were no drug related toxic effects evident on histopathological or electroretinograph examination of eyes containing the NA/5-FU pellet. Conclusions: The results suggest that this NA/5-FU codrug device effectively inhibits the progression of PVR in a rabbit trauma model that closely resembles PVR in humans. Additional studies to add knowledge to these initial findings and to clarify the potential of the codrug device for the treatment of human PVR are warranted. PMID:15317716

  14. Scutellaria barbata D. Don extract synergizes the antitumor effects of low dose 5-fluorouracil through induction of apoptosis and metabolism.

    PubMed

    Xu, Huanli; Yu, Jinmei; Sun, Yan; Xu, Xiaona; Li, Li; Xue, Ming; Du, Guanhua

    2013-07-15

    Traditional Chinese medicines have been recognized as a new source of anticancer drugs or chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects. This study aimed to investigate the antitumor effects of combined Scutellaria barbata D. Don extract (SBE) and 5-FU treatment in vitro and in vivo and the potential mechanisms. SBE was prepared and analyzed by HPLC. Tumor growth inhibition both in vitro and in vivo, cell apoptosis, apoptosis related protein expressions (P53, bid, bax, bcl-2), caspase-3 activities and 5-FU related enzymes were assessed. SBE could significantly synergize the antitumor effects of low dose 5-FU both in vivo and in vitro. SBE could increase the apoptosis inducing effect of low dose 5-FU in both Bel-7402 and HCT-8 cells. Also, caspase-3 activities, P53 and bax expressions were significantly increased, while bid and bcl-2 expressions were significantly decreased in drug combination groups, compared with individual drug treatment groups. Furthermore, SBE could significantly decrease the mRNA levels of dihydropyrimidine dehydrogenase. These results showed that combined treatment with SBE and low dose 5-FU can significantly inhibit the tumor growth both in vitro and in vivo, which might be related with apoptosis and regulations of 5-FU metabolism.

  15. Malignant Esophagogastric Junction Obstruction: Efficacy of Balloon Dilation Combined with Chemotherapy and/or Radiation Therapy

    SciTech C