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Sample records for 5-fluorouracil combination chemotherapy

  1. Phase I dose-escalation study of docetaxel, nedaplatin, and 5-fluorouracil combination chemotherapy in patients with advanced esophageal cancer.

    PubMed

    Miyazaki, Tatsuya; Sohda, Makoto; Tanaka, Naritaka; Suzuki, Shigemasa; Ieta, Keisuke; Sakai, Makoto; Sano, Akihiko; Yokobori, Takehiko; Inose, Takanori; Nakajima, Masanobu; Fukuchi, Minoru; Ojima, Hitoshi; Kato, Hiroyuki; Kuwano, Hiroyuki

    2013-04-01

    More effective protocols are needed for unresectable and recurrent esophageal cancer. Therefore, we conducted a phase I trial to establish the recommended dose of docetaxel, nedaplatin, and 5-fluorouracil (DNF) as combination chemotherapy. Fourteen patients with esophageal cancer were enrolled and received DNF combination therapy at different dose levels according to the treatment and examination plan. Dose-limiting toxicities (DLTs) included febrile neutropenia. DLTs occurred in 3/5 patients at level 4. The recommended doses (level 3) of DNF were 60 mg/m(2) (day 1), 70 mg/m(2) (day 1), and 700 mg/m(2) (days 1-5), respectively, given at 3-week intervals. In conclusion, DNF combined chemotherapy for advanced esophageal cancer was associated with relatively minor adverse events and was safely administered at the recommended dose. A phase II study is now underway.

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

    PubMed

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

    2013-11-01

    The present investigation aimed to develop magnetoliposome nanoparticles loaded with 5-fluorouracil by following a reproducible thin film hydration technique. The physicochemical characterization (including electron microscopy analysis, dynamic light scattering, infrared spectrometry, X-ray diffractometry, electrophoresis, and surface thermodynamics) suggested that superparamagnetic magnetite nuclei were successfully embedded into a multilamellar lipid vesicle. Magnetic responsiveness of these nanocomposites was quantitatively analyzed by determining the hysteresis cycle and qualitatively confirmed by microscopic visualizations. A high frequency alternating electromagnetic field was further used to define their heating properties. The absence of cytotoxicity in human colon fibroblast CCD-18 and in human colon carcinoma T-84 cell lines and excellent hemocompatibility of these core/shell particles were demonstrated. Additionally, 5-fluorouracil incorporation was investigated by two procedures: (i) entrapment into the nanoparticulate matrix and (ii) surface deposition onto already formed magnetoliposome particles. The former method reported greater drug loading values and a sustained release profile. Interestingly, 5-fluorouracil release was also triggered by the heating properties of the nanoparticles (hyperthermia-triggered drug release). Hence, we put forward that magnetoliposome particles hold important properties, that is, magnetically targeted delivery, hyperthermia inducing capability, high 5-fluorouracil loading capability, and hyperthermia-triggered burst drug release, suggestive of their potential for a combined antitumor therapy against colon cancer. PMID:23485475

  3. [Dose-intensive chemotherapy with continuous infusion 5-fluorouracil].

    PubMed

    Tichler, T; Ghodsizade, E; Katz, A; Rath, P; Berger, R; Brenner, H

    1999-11-01

    54 patients with advanced malignancy refractory to chemotherapy were studied to evaluate efficacy and toxicity of continuous infusion of 5-fluorouracil (5FU) given for 3 weeks. We report results of the first 156 courses given in combination with other drugs. 19 (37%) of the 54 responded, including 3 (6%) with complete response. Toxicity was acceptable, with mucositis in 13 (26%) and 3 (6%) with grade II-III toxicity. Results and toxicity profile were compatible with further disease-oriented studies using this dose-intensive program.

  4. [Successful treatment of locally advanced squamous cell carcinoma of the esophagus by combination chemotherapy with 5-fluorouracil plus nedaplatin following tracheal stent tube placement-a case report].

    PubMed

    Nishimura, Junya; Kubo, Naoshi; Lee, Tomohiro; Shinto, Osamu; Sakurai, Katsunobu; Toyokawa, Takahiro; Tanaka, Hiroaki; Muguruma, Kazuya; Shibutani, Masatsune; Yamazoe, Sadaaki; Nagahara, Hisashi; Kimura, Kenjiro; Amano, Ryosuke; Ohtani, Hiroshi; Yashiro, Masakazu; Maeda, Kiyoshi; Ohira, Masaichi; Hirakawa, Kosei

    2013-11-01

    The patient was a 68-year-old man who complained of hoarseness and dyspnea. Upper gastrointestinal endoscopy revealed a type 3 tumor located in the middle thoracic esophagus at 30 cm from the incisor tooth that involved one-fourth of the circumference of the esophagus. Histopathological examination revealed moderately differentiated squamous cell carcinoma. Chest computed tomography( CT) revealed severe tracheal stenosis due to compression by a metastatic lymph node along the left recurrent laryngeal nerve. The patient was diagnosed as having cT4( 106recL-trachea), N2( 101L, 106recL, 106recR), M0, Stage IVa unresectable esophageal carcinoma. After insertion of a tracheal stent tube( spiral Z stent: diameter, 18 mm; length, 80 mm) to improve dyspnea, combination chemotherapy with 5-fluorouracil( 5-FU) plus nedaplatin was administered. Subsequent CT and endoscopy showed that the main tumor and the metastatic lymph node had significantly reduced in size and that complete response (CR) had been achieved. Thirty months after the initial treatment, the patient showed no sign of disease recurrence, after completion of 19 cycles of chemotherapy. The patient did not experience any severe adverse events. We report a case of a patient with locally advanced squamous cell carcinoma of the esophagus successfully treated with 5-FU/nedaplatin combination chemotherapy following tracheal stent tube placement.

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

    PubMed Central

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

    2002-01-01

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

  6. The role of additional chemotherapy with oral UFT in intravenous combination chemotherapy with cisplatin and 5-fluorouracil for human gastric cancer xenograft lines of well- and poorly- differentiated adenocarcinomas transplanted in nude mice.

    PubMed

    Tseng, C C; Nio, Y; Tsubono, M; Kawabata, K; Masai, Y; Hayashi, H; Fukumoto, M; Tobe, T

    1992-01-01

    In order to assess the role of maintenance chemotherapy with the oral anticancer agent UFT, a mixture of uracil and futraful, in the intensive intravenous chemotherapy for gastric cancer, nude mice transplanted with human gastric cancer xenografts were treated with intravenous 5-fluorouracil (5-FU) and cisplatin (CDDP), alone or in combination, with or without the oral anticancer agent UFT. UFT was given at its maximal clinical dose of 10 mg/kg of body weight daily for 2 weeks, while 5-FU and/or CDDP was intravenously administered at the dose of 20 mg/kg and 1.8 mg/kg of body weight respectively once a week, alone or in combination, for two weeks. The results revealed that 5-FU or CDDP alone were ineffective for both GC-YN, a well differentiated adenocarcinoma line, and GC-SF, a poorly differentiated adenocarcinoma line; however, UFT was effective for GC-SF. In combinations, only the three-agent combination 5-FU + CDDP + UFT (FPU) was effective for GC-YN; however, all the two-agent combinations and FPU were effective for GC-SF. FPU significantly suppressed the growth of GC-YN much more than all the other treatment groups. In contrast, although all combinations as well as UFT alone were effective for GC-SF, there was no significant difference among these effective groups. Moreover, no side effects were noted in combined use of UFT. This study suggests that oral UFT as a maintenance treatment may be beneficial in the combination chemotherapy for human gastric cancer.

  7. Sequential combination chemotherapy of high-grade non-Hodgkin's lymphoma with 5-fluorouracil, methotrexate, cytosine-arabinoside, cyclophosphamide, doxorubicin, vincristine, and prednisone (F-MACHOP).

    PubMed

    Guglielmi, C; Amadori, S; Anselmo, A P; Baroni, C D; Biagini, C; Cimino, G; Papa, G; Mandelli, F

    1987-01-01

    An intensive treatment program was developed to achieve durable remissions in a high proportion of previously untreated patients with advanced stages of diffuse high-grade non-Hodgkin's lymphoma (NHL). Fifty-six patients (15-68 years) received a course of F-MACHOP (5-fluorouracil, methotrexate, cytosine-arabinoside, cyclophosphamide, doxorubicin, vincristine, and prednisone) every 3-4 weeks for 6 courses. Cycle active drugs were sequentially administered to expose rapidly proliferating tumor cells to the synergistic effects of these agents throughout the cell cycle. Forty-three patients achieved complete remission (77%) and 80% of the complete responders are projected to be alive and disease-free at 4 1/2 years (median follow-up 33 months). Up to 70% of all patients are predicted to be alive at 5 years. Bulky tumor, "B"-symptoms and lymphoblastic histology were poor prognostic factors, particularly when associated with clinically detectable disease after three courses. Toxicity included transitory myelodepression in most patients (2 septic deaths). This protocol provides effective and tolerable therapy for the majority of patients with advanced stages of diffuse aggressive NHL.

  8. Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

    PubMed Central

    Fischel, J L; Formento, P; Ciccolini, J; Rostagno, P; Etienne, M C; Catalin, J; Milano, G

    2002-01-01

    The combination of 5-fluorouracil-folinic acid and oxaliplatin has led to a significant improvement of chemotherapy efficacy in advanced pretreated colorectal cancer. The objective of the present study was, considering the oxaplatin-5-fluorouracil-folinic acid combination, to examine the impact of one given drug on the cellular determinants of cytotoxic activity of the other drug. These cellular factors were analysed on the human colon cancer cell line WiDr in clinically relevant conditions of drug exposure (‘De Gramont’ schedule) with oxaliplatin-folinic acid during 2 h followed by 5-fluorouracil 48 h. The DNA binding of oxaliplatin was significantly reduced by the presence of 5-fluorouracil but this effect was time-dependent and after 50 h the platinum incorporated into DNA was identical in controls and in the drug combination. In the presence of oxaliplatin, there was less formation of FUH2 which is the first catabolite produced in the cascade of 5-fluorouracil metabolic degradation. The effects of drugs on cell cycle were quite different from one drug to the other with oxaliplatin inducing a shift towards G2 accumulation and 5-fluorouracil-folinic acid to a greater proportion of cells in G1–S. When oxaliplatin and 5-fluorouracil-folinic acid were combined the cell cycle effects were very similar to that of the 5-fluorouracil-folinic acid sequence alone. Oxaliplatin was able to reduce thymidylate synthase activity with a marked impact 28 h after the beginning of cell exposure to the drug. The 5-fluorouracil-folinic acid drug sequence led to a profound reduction in thymidylate synthase activity and this decrease was not markedly enhanced by the presence of oxaliplatin. Regarding apoptosis, changes in mitochondrial membrane permeability were observed in the presence of the tested drugs and the impact of 5-fluorouracil-folinic acid was greater than that of oxaliplatin. The addition of oxaliplatin did not amplify the action of 5-fluorouracil

  9. Preoperative docetaxel/cisplatin/5-fluorouracil chemotherapy in patients with locally advanced gastro-esophageal adenocarcinoma.

    PubMed

    Bayraktar, Ulas Darda; Bayraktar, Soley; Hosein, Peter; Chen, Emerson; Koniaris, Leonidas G; Rocha-Lima, Caio Max S; Montero, Alberto J

    2012-09-01

    Perioperative chemotherapy plus surgery improves survival compared to surgery alone in GE junctional (GEJ) and gastric adenocarcinomas. The docetaxel/cisplatin/5-fluorouracil (DCF) combination is superior to CF in patients with metastatic gastric cancer. We retrospectively evaluated the safety and efficacy of preoperative DCF chemotherapy in patients with locally advanced gastric and GEJ cancer. Twenty-one gastric and 10 gastroesophageal junctional (GEJ) cancer patients received 2-3 cycles of preoperative docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, 5-FU 750 mg/m(2) (continuous infusion) on days 1-5 every 3 weeks. Clinical response was evaluated by comparing pre- and postchemotherapy CT scans. Overall survival (OS) and progression-free survival (PFS) were calculated from the initiation of chemotherapy. None of the patients achieved complete clinical remission while 11 (35%) patients achieved partial clinical remission. Ten patients with GEJ cancer (100%) and 13 with gastric cancer (62%) underwent curative surgery (P = 0.023). Seventeen (55%) patients experienced grade 3-4 chemotherapy-related adverse events. The most common adverse events were anemia, nausea/vomiting, diarrhea, and febrile neutropenia. At a median follow-up of 17.0 months, median OS and PFS were 26.1 months (95% CI: 22.7-29.5) and 18.8 months (95% CI: 9.9-27.7), respectively. The DCF regimen is active in patients with gastric and GEJ adenocarcinoma in the preoperative setting.

  10. 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

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

    PubMed Central

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

    2016-01-01

    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.

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

    PubMed Central

    GUO, XU-FENG; YANG, ZI-RONG; WANG, JUN; LEI, XIAO-FEI; LV, XIAO-GUANG; DONG, WEI-GUO

    2015-01-01

    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. PMID:25434307

  13. Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

    PubMed Central

    Foley, John J.; Raffa, Robert B.

    2011-01-01

    Rationale The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date. Objective We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory. Materials and methods In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session. Results Methotrexate (1.0–32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3–75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering responserates or motivation to respond as measured by progressive ratio responding. Conclusion Taken together, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so. PMID:18463849

  14. 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.

  15. Treatment of advanced or recurrent endometrial carcinoma with combination of etoposide, cisplatin, and 5-fluorouracil: a phase II study.

    PubMed

    Pierga, J Y; Dieras, V; Paraiso, D; Dorval, T; Palangie, T; Beuzeboc, P; Jouve, M; Scholl, S M; Garcia-Giralt, E; Pouillart, P

    1996-01-01

    Forty-nine consecutive patients with metastatic or recurrent endometrial carcinoma were treated with a monthly combination chemotherapy consisting of VP 16-213 80 mg/m2 i.v. Days 1-3, 5-fluorouracil (5-FU) 600 mg/m2 i.v. Days 1-3, and cisplatin 35 mg/m2 i.v. Days 1-3. The objective response rate was 41% (95% CI, 27-54%) with 14.3% complete responses. The median survival duration was 14 months. The median response duration was 12 months. The estimated median survival for responders was 20 months. Three patients are still free of disease 5 years after treatment. The major toxic effects were myelosuppression (less than 25% of grade III and IV leucopenia, and 14% grade III and IV thrombocytopenia). Grade III peripheral neuropathy was observed in five patients. Cisplatin administration had to be stopped due to renal toxicity in six patients. No treatment-related deaths occurred. The combination of etoposide, 5 fluorouracil, and cisplatin is an effective regimen with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma.

  16. 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

  17. 5-Fluorouracil + cisplatin + mitomycin C is a relatively most effective combination against xenograft lines of human colorectal cancer.

    PubMed

    Kawabata, K; Nio, Y; Imamura, M

    1997-09-01

    5-Fluorouracil (5-FU) has been an accepted effective against colorectal cancer, but combination regimens resulted in a lesser effect than 5-FU alone. The present study was designed to evaluate the efficiency of various combination chemotherapies, including 5-FU, on human colorectal cancer xenograft lines (CC-KK and RC-TK), which had been passed by transplantation in nude mice. Eight anticancer agents [5-FU, mitomycin C (MMC), adriamycin (ADR), 4'-epirubicin (EPIR), carboquone (CQ), cisplatin, carboplatin and etoposide (VP-16)] and their combinations were evaluated at 2-4 times the clinical dose. When the agents were administered singly, 5-FU, EPIR and CQ were effective against CC-KK, and 5-FU, MMC, EPIR, ADR, CQ and carboplatin were effective against RC-TK. Of the two-agent combinations including 5-FU, cisplatin + 5-FU was the most effective against both CC-KK and RC-TK. However, of the three-agent combinations, only cisplatin + 5-FU + MMC was more effective against both lines than cisplatin + 5-FU. These results suggest that cisplatin + 5-FU + MMC may be the most useful regimen against colorectal cancers in clinical application.

  18. Combination effects of tamoxifen plus 5-fluorouracil on gastric cancer cell lines in vitro.

    PubMed

    Hosoya, Y; Kitoh, Y; Kobayashi, E; Okabe, R; Fujimura, A; Kanazawa, K

    1999-06-01

    We tested the effect of tamoxifen alone and tamoxifen plus 5-fluorouracil (5-FU) on proliferation of two different types of gastric cancer cell lines using the WST-1 method. A high dose of tamoxifen suppressed the proliferation of KATOIII cells (poorly differentiated adenocarcinoma), but MKN28 cells (well-differentiated adenocarcinoma) were not affected. The combination of the two drugs resulted in a synergistic anti-proliferative activity on KATOIII cells. On the other hand, in the combination therapy, tamoxifen stimulated MKN28 cells to proliferate in a dose-dependent manner. TGF-beta1 secretion was not changed in KATOIII cells by tamoxifen plus 5-FU treatment but was down-regulated in MKN28 cells. Both cancer cell lines were judged as intracellular estrogen receptor (ER) negative. These data suggest that the anti-proliferative effects of tamoxifen plus 5-FU on KATOIII cells were not dependent on ER expression or TGF-beta1 secretion. On the other hand, their proliferative effects on MKN28 cells might be, in part, caused by the reduced secretion of TGF-beta1. PMID:10403552

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

    PubMed

    Duke, Roseline; Ikpeme, Anthonia

    2015-01-01

    Background. Delayed postoperative suprachoroidal hemorrhage (DSCH) may occur following intraocular surgery for the treatment of glaucoma. It is considered to be a rare and debilitating event if not managed appropriately. Reported herewith is a case of Primary Congenital Glaucoma followed by DSCH with successful immediate surgical intervention and visual restoration. Patient and Method. An 8-month-old male child had bilateral Primary Congenital Glaucoma (PCG). Combined Trabeculotomy Trabeculectomy with 5-Fluorouracil (5FU) was performed. He developed delayed suprachoroidal hemorrhage (DSCH) within 24 hours after intraocular surgery which was drained. In addition, he developed exposure keratopathy and left amblyopia. Outcome. Resolution of the DSCH was seen with surgical drainage in addition to treatments for exposure keratopathy and amblyopia. These resulted in reduced intraocular pressure and improved visual acuities. Conclusion. There appears to be a difference in the overall management of PCG and DSCH between adults and children. A high index of suspicion as well as emergency surgical treatment for DSCH and associated conditions should be performed on pediatric patients that present with these challenges. PMID:26819790

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

    PubMed Central

    Duke, Roseline; Ikpeme, Anthonia

    2015-01-01

    Background. Delayed postoperative suprachoroidal hemorrhage (DSCH) may occur following intraocular surgery for the treatment of glaucoma. It is considered to be a rare and debilitating event if not managed appropriately. Reported herewith is a case of Primary Congenital Glaucoma followed by DSCH with successful immediate surgical intervention and visual restoration. Patient and Method. An 8-month-old male child had bilateral Primary Congenital Glaucoma (PCG). Combined Trabeculotomy Trabeculectomy with 5-Fluorouracil (5FU) was performed. He developed delayed suprachoroidal hemorrhage (DSCH) within 24 hours after intraocular surgery which was drained. In addition, he developed exposure keratopathy and left amblyopia. Outcome. Resolution of the DSCH was seen with surgical drainage in addition to treatments for exposure keratopathy and amblyopia. These resulted in reduced intraocular pressure and improved visual acuities. Conclusion. There appears to be a difference in the overall management of PCG and DSCH between adults and children. A high index of suspicion as well as emergency surgical treatment for DSCH and associated conditions should be performed on pediatric patients that present with these challenges. PMID:26819790

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

    PubMed

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

    2011-03-15

    German chamomile (Matricaria recutita L.) is a popular ingredient in herbal teas. In previous study, micromolar bisabololoxide A, one of main constituents in German chamomile, exerted cytotoxic action on rat thymocyte, a normal non-proliferative cell. This result prompted us to study the effect of bisabololoxide A on proliferative cancer cells and to seek the possibility of its use with 5-fluorouracil, an anticancer agent. In this study, the effect of micromolar bisabololoxide A on human leukemia K562 cells was cytometrically examined. Although the incubation of K562 cells with 10 μM bisabololoxide A for 72h did not significantly increase the percentage populations of dead cells and shrunken cells, the inhibitory action on the growth was obviously observed. It was not the case for the concentrations of less than 5 μM. The threshold concentration of bisabololoxide A to exert the cytotoxic action on K562 cells was ascertained to be 5-10 μM. Bisabololoxide A at 5-10 μM did not exert cytotoxic action on normal non-proliferative cells (rat thymocytes) in our previous study. Since the antiproliferative action of micromolar bisabololoxide A on cancerous cells was expected to be beneficial to cancer treatment, the modification of antiproliferative action of 5-fluorouracil (3-30 μM) by bisabololoxide A was studied. The combination of 5-fluorouracil and bisabololoxide further inhibited the growth of K562 cells although the additive inhibition of growth by bisabololoxide A became smaller as the concentration of 5-fluorouracil increased. Therefore, it is suggested that the simultaneous application of German chamomile containing bisabololoxide A may reduce the dose of 5-fluorouracil. PMID:20863677

  2. 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.

  3. Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study.

    PubMed

    Sasaki, Kazuhito; Tsuno, Nelson H; Sunami, Eiji; Kawai, Kazushige; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Murono, Koji; Tada, Noriko; Nirei, Takako; Takahashi, Koki; Kitayama, Joji

    2012-08-01

    Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer. PMID:22561420

  4. Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment

    PubMed Central

    MILCZAREK, MAGDALENA; FILIP-PSURSKA, BEATA; ŚWIĘTNICKI, WIESŁAW; KUTNER, ANDRZEJ; WIETRZYK, JOANNA

    2014-01-01

    In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\\RXR ligand binding domain of PRI-2205 may, in part, explain its very low

  5. 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

  6. 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

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

    PubMed Central

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

    2015-01-01

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

  8. Low Molecular Weight Procyanidins from Grape Seeds Enhance the Impact of 5-Fluorouracil Chemotherapy on Caco-2 Human Colon Cancer Cells

    PubMed Central

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

    2014-01-01

    Objective Grape seed procyanidins (PC) are flavan-3-ol oligomers and polymers known for their biological activity in the gut. Grape seed extract (GSE) have been reported to reduce intestinal injury in a rat model of mucositis. We sought to investigate effects of purified PC fractions differing in mean degree of polymerization (mDP) combined with 5-Fluorouracil (5-FU) chemotherapy on the viability of colon cancer cells (Caco-2). Design SixPC fractions (F1-F6) were isolated from Cabernet Sauvignon seeds at two ripeness stages: pre-veraison unripe (immature) and ripe (mature), utilizing step gradient, low-pressure chromatography on a Sephadex LH-20 resin. Fractions were tested on Caco-2 cells, alone and in combination with 5-FU. Eluted fractions were characterized by phloroglucinolysis and gel permeation chromatography. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) (MTT) assay. Results All isolated fractions significantly reduced Caco-2 cell viability compared to the control (P<0.05), but F2 and F3 (mDP 2–6) were the most active fractions (immature F2 = 32% mDP 2.4, F3 = 35% mDP 5.8 and mature F2 = 13% mDP 3.6 and F3 = 17% mDP 5.9; percentage of viable cells remaining) on Caco-2 cells. When combined with 5-FU, immature fractions F1-F3 enhanced the cell toxicity effects of 5-FU by 27–73% (P<0.05). Mature seed PC fractions (F1–F4) significantly enhanced the toxicity of 5-FU by 60–83% against Caco-2 cells (P<0.05). Moreover, some fractions alone were more potent at decreasing viability in Caco-2 cells (P<0.05; immature fractions = 65–68% and mature fractions = 83–87%) compared to 5-FU alone (37%). Conclusions PCs of mDP 2–6 (immature F1-F3 and mature F1 and F4)not only enhanced the impact of 5-FU in killing Caco-2 cells, but also surpassed standard 5-FU chemotherapy as an anti-cancer agent.The bioactivity of PC is therefore attributed primarily to lower molecular weight PCs. PMID

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

    PubMed

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

    2009-11-01

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

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

    PubMed

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

    2014-11-01

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

  11. Preservation of immune effector cell function following administration of a dose-intense 5-fluorouracil-chemotherapy regimen.

    PubMed

    Weiner, L M; Hudes, G R; Kitson, J; Walczak, J; Watts, P; Litwin, S; O'Dwyer, P J

    1993-01-01

    In a phase II clinical trial of 5-fluorouracil (5FU) plus N-(phosphonacetyl)-L-aspartate (PALA) therapy administration, a number of slowly developing clinical responses were observed. Because of this, a variety of immune parameters were sequentially studied in 21 patients on this trial. Of the 21 patients studied, 20 provided sufficient samples to compare baseline with subsequent values, 10 of the 20 patients responded to treatment. Responders and non-responders did not differ in any studied parameter at baseline. After 2 months of therapy, non-specific monocyte cytotoxicity (NSMC), antibody-dependent monocyte cytotoxicity (ADMC) and natural killer (NK) activity were higher in the entire study population, but these increases were not statistically significant. When responders and non-responders were evaluated separately, it was apparent that the trend was due solely to the changes observed in the responding patient population. When mean lysis values for each patient group were determined for each studied time point, it was possible to generate a mean area under the cytotoxicity/time curve (AUC) for each studied parameter. NSMC and ADMC did not differ in responders and non-responders. However, NK activity was significantly greater by mean AUC analysis (P = 0.006) in the responding group; NK activity was maintained in the responders, but decreased in non-responders. When lymphocyte and monocyte expression of the surface markers beta 2-microglobulin, HLA-DR, CD56, HNK-1, CD16 and interleukin-2 receptor were evaluated, there were no differences among responders and non-responders at baseline by mean AUC analysis or when comparing baseline with non-baseline values. It is concluded that although baseline immunological characteristics do not identify patients who are likely to respond to weekly 5FU and PALA, treatment is not associated with deleterious effects on the immune effector function parameters evaluated in this study, there being no effects on expression of a

  12. Long-term bresults of radiotherapy combined with nedaplatin and 5-fluorouracil for postoperative loco-regional recurrent esophageal cancer: update on a phase II study

    PubMed Central

    2012-01-01

    Background In 2006, we reported the effectiveness of chemoradiotherapy for postoperative recurrent esophageal cancer with a median observation period of 18 months. The purpose of the present study was to update the results of radiotherapy combined with nedaplatin and 5-fluorouracil (5-FU) for postoperative loco-regional recurrent esophageal cancer. Methods Between 2000 and 2004, we performed a phase II study on treatment of postoperative loco-regional recurrent esophageal cancer with radiotherapy (60 Gy/30 fractions/6 weeks) combined with chemotherapy consisting of two cycles of nedaplatin (70 mg/m2/2 h) and 5-FU (500 mg/m2/24 h for 5 days). The primary endpoint was overall survival rate, and the secondary endpoints were progression-free survival rate, irradiated-field control rate and chronic toxicity. Results A total of 30 patients were enrolled in this study. The regimen was completed in 76.7% of the patients. The median observation period for survivors was 72.0 months. The 5-year overall survival rate was 27.0% with a median survival period of 21.0 months. The 5-year progression-free survival rate and irradiated-field control rate were 25.1% and 71.5%, respectively. Grade 3 or higher late toxicity was observed in only one patient. Two long-term survivors had gastric tube cancer more than 5 years after chemoradiotherapy. Pretreatment performance status, pattern of recurrence (worse for patients with anastomotic recurrence) and number of recurrent lesions (worse for patients with multiple recurrent lesions) were statistically significant prognostic factors for overall survival. Conclusions Radiotherapy combined with nedaplatin and 5-FU is a safe and effective salvage treatment for postoperative loco-regional recurrent esophageal cancer. However, the prognosis of patients with multiple regional recurrence or anastomotic recurrence is very poor. PMID:23171077

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

    PubMed Central

    2009-01-01

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

  14. Anthracycline-based induction chemotherapy followed by concurrent cyclophosphamide, methotrexate and 5-fluorouracil and radiation therapy in surgically resected axillary node-positive breast cancer.

    PubMed

    Recchia, Francesco; Candeloro, Giampiero; Cesta, Alisia; DI Staso, Mario; Bonfili, Pierluigi; Gravina, Giovanni Luca; DI Cesare, Ernesto; Necozione, Stefano; Rea, Silvio

    2014-05-01

    The present study aimed to determine the toxicity and efficacy of 4 courses of anthracyclines-taxane (AT) chemotherapy followed by radiation therapy (XRT) concurrent with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in surgically resected axillary node-positive (N+) breast cancer. A total of 200 women with N+ breast cancer were treated with adriamycin and docetaxel followed by XRT concurrent with six courses of CMF. Two courses of dose-dense chemotherapy with ifosfamide, carboplatin and etoposide, supported by pegfilgrastim, were administered to patients with >5 histologically confirmed axillary lymph node metastases and patients with triple-negative disease. Additional treatments included 1 year of trastuzumab in human epidermal growth factor receptor 2-positive patients, 5 years of a luteinizing hormone-releasing hormone analogue in premenopausal women and 5 years of an aromatase inhibitor (AI) in estrogen receptor-positive (ER+) patients. The mean number of positive axillary lymph nodes was 4.4 (range, 2-37), 52% of the patients were premenopausal, 74% were ER+ and 26% had triple-negative disease. After a median follow-up of 73 months, grade 2 and 3 hematological toxicity was observed in 20% of the patients. The 10-year disease-free survival (DFS) and overall survival (OS) rates were 73 and 77%, respectively. There was no significant difference in DFS between ER+ and estrogen receptor-negative (ER-) patients (P>0.05), whereas the OS was better in ER+ vs. ER- patients (P<0.05) and in premenopausal vs. postmenopausal patients (P<0.005). In conclusion, induction AT concurrent CMF and XRT and dose-dense chemotherapy followed by AI in N+ high-risk breast cancer was associated with a low level of systemic and late cardiac toxicity and excellent local control, DFS and OS. PMID:24772320

  15. The effect of 5-fluorouracil/leucovorin chemotherapy on CpG methylation, or the confounding role of leukocyte heterogeneity: An illustration.

    PubMed

    Lemire, Mathieu; Zaidi, Syed H E; Zanke, Brent W; Gallinger, Steven; Hudson, Thomas J; Cleary, Sean P

    2015-12-01

    Blood-based epigenome-wide association studies that aim at comparing CpG methylation between colorectal cancer (CRC) patients and controls can lead to the discovery of diagnostic or prognostic biomarkers. Numerous confounders can lead to spurious associations. We aimed to see if 5-fluorouracil (5-FU)/leucovorin chemotherapy administered to cases prior to the collection of their blood has an effect on methylation. 304 patients who received treatment and 273 who did not were profiled on the HumanMethylation450 array. Association tests were adjusted for confounders, including proxies for leukocyte cell counts. There were substantial methylation differences between these two groups that vanished once the leukocyte heterogeneity was accounted for. We observed a significant decrease of T cells in the treatment group (CD4+: p=10(-6); CD8+: p=0.036) and significant increase of NK cells (p=0.05) and monocytes (p=0.0006). 5-FU/leucovorin has no effect on global and local blood-based methylation profiles, other than through differences in the leukocyte compositions that the treatment induced.

  16. Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients

    PubMed Central

    2010-01-01

    Background Severe toxicity to 5-fluorouracil (5-FU) based chemotherapy in gastrointestinal cancer has been associated with constitutional genetic alterations of the dihydropyrimidine dehydrogenase gene (DPYD). Methods In this study, we evaluated DPYD promoter methylation through quantitative methylation-specific PCR and screened DPYD for large intragenic rearrangements in peripheral blood from 45 patients with gastrointestinal cancers who developed severe 5-FU toxicity. DPYD promoter methylation was also assessed in tumor tissue from 29 patients Results Two cases with the IVS14+1G > A exon 14 skipping mutation (c.1905+1G > A), and one case carrying the 1845 G > T missense mutation (c.1845G > T) in the DPYD gene were identified. However, DPYD promoter methylation and large DPYD intragenic rearrangements were absent in all cases analyzed. Conclusions Our results indicate that DPYD promoter methylation and large intragenic rearrangements do not contribute significantly to the development of 5-FU severe toxicity in gastrointestinal cancer patients, supporting the need for additional studies on the mechanisms underlying genetic susceptibility to severe 5-FU toxicity. PMID:20809970

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

    PubMed Central

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

    2012-01-01

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

  18. 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.

  19. Cetuximab in combination with cisplatin and 5-Fluorouracil induces dramatic response in metastatic refractory squamous cell carcinoma of the anal canal

    PubMed Central

    Silva, Ninoska N.; Eng, Cathy

    2015-01-01

    Metastatic squamous cell carcinoma (SCC) of the anal canal is rare with limited data regarding treatment. Epidermal growth factor receptor (EGFR) expression has been observed in SCC of the anal canal and Kristen rat sarcoma vial oncogene (KRAS) mutations are rare. EGFR monoclonal antibodies, cetuximab and panitumumab, represent a potential option in this patient population. We report a metastatic SCC of the anal canal patient treated with cetuximab in combination with cisplatin plus 5-Fluorouracil (5-FU) that had a dramatic response. PMID:26487956

  20. 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

  1. 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.

  2. In vitro and in vivo studies on the combination of Brequinar sodium (DUP-785; NSC 368390) with 5-fluorouracil; effects of uridine.

    PubMed Central

    Peters, G. J.; Kraal, I.; Pinedo, H. M.

    1992-01-01

    Brequinar sodium (DUP-785; Brequinar) is a potent inhibitor of the pyrimidine de novo enzyme dihydroorotate dehydrogenase (DHO-DH), leading to a depletion of pyrimidine nucleotides, which could be reversed by uridine. In in vitro studies we investigated the effect of different physiological concentrations of uridine on the growth-inhibition by Brequinar, the effect of the nucleoside transport inhibitor, dipyridamole, and the combination of Brequinar and 5-fluorouracil (5FU). Uridine at 1 microM slightly reversed the growth inhibition by Brequinar, while the effect of 5-500 microM was greater. However, at Brequinar concentrations greater than 30 microM, uridine could not reverse the growth-inhibitory effects. Addition of dipyridamole could only partially prevent the reversing effects of uridine. The combination of Brequinar and 5FU was more than additive in the absence of uridine in the culture medium, but not in the presence of uridine. The combination of Brequinar and 5FU was tested in vivo in two murine colon tumour models, Colon 26 and Colon 38. Scheduling of both compounds appeared to be very important. In Colon 38 no potentiating effect of Brequinar could be observed. In contrast in Colon 26 a more than additive effect could be observed. Since uridine concentrations are considerably different in these tumours (higher in Colon 38), it was concluded from both the in vitro and in vivo experiments that uridine is an important determinant in combinations of Brequinar and 5FU. PMID:1739622

  3. 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.

  4. Adverse effects on cardiovascular status and lipid levels of albino Wistar rats treated with cisplatin and oxaliplatin in combination with 5 Fluorouracil.

    PubMed

    Najam, Rahila; Bano, Nusrat; Mirza, Talat; Hassan, Saba

    2014-09-01

    The study was designed to comparatively assess direct damages on cardiac tissues and aorta associated with abnormalities in lipid profile and cardiac biomarkers induced by two platinum cytotoxic compounds with and without 5FU (5Fluorouracil) in rats. Albino Wistar rats were treated with 5FU (15mg/kg), cisplatin (0.8mg/kg) and oxaliplatin (0.8mg/kg) in different dosing schedules. The changes in the lipid levels, CPK and Tropinin I levels, following treatment with single and combination schedules of CDDP, 5FU and Oxaliplatin were compared with the control group maintained on normal saline. Changes in LDL and cholesterol levels were highly significant in cisplatin and oxaliplatin treated rats. Myofibrillar loss and vascular wall thickening was seen in cisplatin treatment groups in the acute model of toxicity. The damages were mild but progressive. Tropinin I levels were raised well above diagnostic risk levels in the delayed model of toxicity in the rats treated with oxaliplatin in combination of 5FU, indicative of definite cardiotoxic potential of oxaliplatin in combination of 5FU mimicking the FOLFOX regimen.

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

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay

    2016-03-01

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

  6. Urachal Carcinoma with Choroidal, Lung, Lymph Node, Adrenal, Mammary, and Bone Metastases and Peritoneal Carcinomatosis Showing Partial Response after Chemotherapy Treatment with a Modified Docetaxel, Cisplatin and 5-Fluorouracil Regimen

    PubMed Central

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

    2016-01-01

    Urachal carcinoma (UC) is a rare tumor mainly affecting middle-aged males. Metastases occur most frequently in lymph nodes and the lungs. There are no standard adjuvant and metastatic treatments. We report the case of a 36-year-old female with UC treated with partial cystectomy who relapsed 3 years after surgery with left choroidal, lung, mediastinal lymph node, right adrenal, mammary, and bone metastases as well as peritoneal carcinomatosis. She obtained a partial response after 10 cycles of chemotherapy with a modified docetaxel, cisplatin and 5-fluorouracil (mTPF) regimen. This is the first report on the use of the mTPF regimen in UC and on the existence of choroidal, adrenal, and mammary metastases. PMID:27194981

  7. Expression of p53 protein as a predictor of the response to 5-fluorouracil and cisplatin chemotherapy in human gastrointestinal cancer cell lines evaluated with apoptosis by use of thin layer collagen gel.

    PubMed

    Matsuhashi, Nobuhisa; Saio, Masanao; Matsuo, Atsushi; Sugiyama, Yasuyuki; Saji, Shigetoyo

    2004-04-01

    Apoptosis of the target cells is an important index in the assessment of the efficacy of cancer chemotherapy. We previously established a new experimental technique in which cancer cells are distributed in thin collagen gel as one or two cell layers, and cultured with anti-cancer drugs. The cells are stained with fluorescent Hoechst 33258 (Ho) and photographed, then with hematoxylin and eosin (H&E) and again photographed. The results show that most cell death patterns can be determined by combining observations of Ho and H&E-stained cells without the necessity for judging the apoptosis by electron microscopy. 5-fluorouracil (5-FU) and cisplatin (CDDP) are important anti-cancer drugs in the treatment of a variety of cancers. 5-FU or CDDP alone have shown significant effects in the treatment of gastric and colon cancers, and in addition, it has been shown that the combination of 5-FU plus CDDP (FP) therapy produces synergism greater than 5-FU or CDDP alone in gastrointestinal cancer. In this study, we evaluated the efficacy and toxicity of FP therapy in the gastric cancer cell lines MKN45, MKN28, and KATOIII and the colon cancer cell lines HCT116 and COLO320, and examined the relationship between the response to FP therapy and apoptosis. Additionally, we performed transfection of normal p53 gene into p53 mutant MKN28 cells and analyzed the impact of the p53 gene on a sensitivity test. Wild-type p53 in MKN45, HCT116, and COLO320 cells underwent significantly (p<0.01) more apoptosis than MKN28 and KATOIII cells possessing p53 mutant- and deficient-type, respectively, in FP therapy. Transfection of p53 to MKN28 cells resulted in a significantly (p<0.01) higher apoptotic index. From these results, we conclude that the p53 pathway allows induction of apoptosis in gastrointestinal cancers in FP therapy treatment, and that identification of the p53 type of a patient's cancer can be used to predict the success of FP therapy. PMID:15010816

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

    PubMed Central

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

    2016-01-01

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

  9. 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.

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

    PubMed

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

    1997-12-01

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

  11. 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

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

    PubMed Central

    Liu, Yuguo; Luan, Lijuan; Wang, Xingli

    2015-01-01

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

  14. A genome-wide association study identifies WT1 variant with better response to 5-fluorouracil, pirarubicin and cyclophosphamide neoadjuvant chemotherapy in breast cancer patients

    PubMed Central

    Zhang, Hong; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Yin, C. Cameron; Xie, Yuntao

    2016-01-01

    Breast cancer is believed to result from the interplay of genetic and non-genetic risk factors, and individual genetic variation may influence the efficacy of chemotherapy. Here we conducted a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with response to anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer patients. In the discovery stage, we divided 92 patients who received anthracycline-based neoadjuvant chemotherapy into 2 groups according to pathologic response and performed a genome-wide study using Affymetrix SNP6.0 genechip. Of 389,795 SNPs associated with pathologic complete response (pCR), we identified 2 SNPs, rs6044100 and rs1799937, that were significantly associated with pCR after neoadjuvant chemotherapy. In the validation stage, genotype analysis of samples from an independent cohort of 401 patients who received anthracycline-based neoadjuvant regimens and 467 patients who received taxane-based regimens was performed using sequencing analysis. We found that only SNP rs1799937, located in the WT1 gene, was associated with pCR after anthracycline-based neoadjuvant therapy (AA vs GG; odds ratio [OR], 2.81; 95% confidence interval [CI], 1.13–6.98; P < 0.05) but not after taxane-based neoadjuvant therapy (AA vs GG; OR, 0.85; 95% CI, 0.36–2.04; P = 0.72). These results suggest that WT1 may be a potential target of anthracycline-based neoadjuvant therapy for breast cancer. PMID:26573232

  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. 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.

  17. 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.

  18. 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

  19. A phase II study of cisplatin, vindesine and continuously infused 5-fluorouracil in the treatment of advanced non-small-cell lung cancer. Osaka Lung Cancer Chemotherapy Study Group.

    PubMed Central

    Nakano, T.; Ikegami, H.; Nakamura, S.; Kawase, T.; Nishikawa, H.; Yokota, S.; Yoshida, M.; Tachibana, T.; Igarashi, T.; Komuta, K.; Higashino, K.

    1996-01-01

    Fifty-two previously untreated patients with advanced non-small-cell lung cancer (NSCLC) were treated on a 14 day cycle with cisplatin (60 mg m-2 i.v.) and vindesine (3 mg m-2 i.v.) on day 1, followed by a 3 day continuous infusion of 5-fluorouracil (800 mg m-2 day-1) starting on day 8. An overall response rate of 40.4% was observed in 47 evaluable patients, which included one complete response and 18 partial responses. Responses were achieved in 61.1% of stage 3 patients and 27.6% of stage 4 patients. The median progression-free interval was 19.3 weeks, and median survival time was 41.6 weeks (47.1 weeks for patients with stage 3 disease and 38.7 weeks for those with stage 4 disease). Toxicity was well tolerated. Gastrointestinal and renal toxicities did not exceed WHO grade 2. Grade 3 or 4 leucopenia and anaemia occurred in nine (19%) and four (9%) patients respectively, but only grade 2 thrombocytopenia was observed. Phlebitis at the infusion site was observed in 24 patients (53%). This treatment programme achieved a response rate similar to other active combination regimens for the treatment of advanced NSCLC, and was less toxic. PMID:8624270

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

    PubMed

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

    2015-10-01

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

  1. 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.

  2. 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.

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

    PubMed Central

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

    2015-01-01

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

  4. Infliximab enhances the therapeutic effects of 5-fluorouracil resulting in tumor regression in colon cancer

    PubMed Central

    Liu, Fen; Ai, Feiyan; Tian, Li; Liu, Shaojun; Zhao, Lian; Wang, Xiaoyan

    2016-01-01

    Colon cancer (CC) is among the most common malignant diseases with a dismal survival. Tumor necrosis factor-alpha (TNF-α) has been identified as a therapeutic target in various cancers, and anti-TNF-α treatment has shown promising effects in different cancer models. However, if TNF-α can be targeted in CC, the therapeutic values of anti-TNF-α treatment in CC remain unknown. Our study indicated that TNF-α is highly expressed in CC cell lines and patient tumor samples. High expression of TNF-α is an independent adverse prognosticator of CC. Targeting the TNF-α by its antibody infliximab induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity and enhanced apoptosis leading to cell death. The combination of infliximab with 5-fluorouracil showed better responses in vitro and in vivo than 5-fluorouracil alone. In conclusion, this study identified TNF-α as a target of CC and anti-TNF-α treatment synergized with chemotherapy leading to a better outcome in preclinical models. PMID:27757041

  5. 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.

  6. [Chemotherapy].

    PubMed

    Aiba, Keisuke

    2004-05-01

    Cancer chemotherapy in the treatment of colorectal cancer has been evolving so extensively than ever. 5-fluorouracil (5-FU) has been a pivotal and a single active agent in the treatment of colorectal cancer. Reproducing and consistent better response rate has been shown since the introduction of the concept of biochemical modulation of 5-FU by leucovorin, a reduced folate, to the clinic and a combination chemotherapy of 5-FU and leucovorin (FL) has enable us to obtain a response rate around 20-30% and a median survival time ranging from 10 to 12 months. IFL regimen combing CPT-11 with FL showed a better MST ranging from 14 to 15 months, but now serious toxicity precludes general use outside of clinical trials. In the Europe, de Gramont regimen, an unique dose and schedule of 5-FU using a combination of continuous intravenous infusion of 5-FU with leucovorin over two days and bolus infusion of 5-FU twice over the same period, has been developed and shown improved antitumor activity and toxic profiles. FOLFOX 4, a combination chemotherapy of de Gramont regimen and oxaliplatin which is a third generation of cisplatin and a uniqe toxic profile with neuropathy, has demonstrated improved MST over a year and acceptable toxic profiles. Now FOLFOX 4 is considered to be a standard chemotherapy for the patients with advanced colorectal cancer, since a large phase III randomized study has shown that FOLFOX 4 was the most active and less toxic treatment regimen among active regimens such as IFL and IROX (CPT-11 and oxaliplatin). More recently, a combination of IFL and bevacizumab which is one of the molecular target agents and a antibody agent against vascular endothelial growth factor (VEGF), has demonstrated better MST reaching 20 months. Future large scale trials will attempt to develop more active regimen incorporating so-called molecular target agents.

  7. 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.

  8. RTOG 0529: A Phase II 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

    PubMed Central

    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.

    2012-01-01

    Purpose A multi-institutional phase II trial assessed the utility of dose-painted IMRT (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% as compared to the conventional radiation/5FU/MMC arm from RTOG 9811. Methods and Materials T2-4N0-3M0 anal cancer patients received 5FU and MMC days 1 and 29 of DP-IMRT, prescribed per stage - T2N0: 42Gy elective nodal and 50.4Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3: 45Gy elective nodal, 50.4Gy ≤ 3cm or 54Gy > 3cm metastatic nodal and 54Gy 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, 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=0.032), grade 3+ gastrointestinal, 21% (9811 36%, P=0.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<0.0001) with DP-IMRT. On initial pre-treatment review, 81% required DP-IMRT re-planning, while final review revealed only three 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. While DP-IMRT proved feasible, the high pre-treatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials. PMID:23154075

  9. 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

  10. 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

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

    2016-10-01

    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

  11. 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.

  12. Paclitaxel with mitoxantrone with or without 5-fluorouracil and high-dose leucovorin in the treatment of metastatic breast cancer.

    PubMed

    Greco, F A; Hainsworth, J D

    1997-10-01

    Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. We added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, 5-fluorouracil, and high-dose leucovorin. Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous infusion on day 1; mitoxantrone 10 mg/m2 by intravenous bolus on day 1; 5-fluorouracil 350 mg/m2 by intravenous bolus on days 1, 2, and 3; and leucovorin 300 mg intravenous over 30 to 60 minutes, immediately preceding 5-fluorouracil on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. Of 45 assessable patients, 23 (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. There were four treatment-related deaths, two sepsis, one congestive heart failure, and one sepsis and congestive heart failure, the last two after a large cumulative anthracycline dose. This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although how its activity compares with that of other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than had been anticipated based on previous results with the mitoxantrone/5-fluorouracil/high-dose leucovorin regimen or with single-agent paclitaxel administered at this dose and schedule. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with

  13. 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.

  14. 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

  15. A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer.

    PubMed

    Alonso, M C; Tabernero, J M; Ojeda, B; Llanos, M; Solà, C; Climent, M A; Seguí, M A; López, J J

    1995-04-01

    One hundred patients with metastatic breast cancer were randomly selected to receive combined chemotherapy treatment with adriamycin (50 mg/m2) or mitoxantrone (12 mg/m2) associated with 5-fluorouracil (600 mg/m2) and cyclophosphamide (600 mg/m2) administered intravenously every 21 days with a maximum of ten cycles. All patients included in this study were under 75 years of age and had ECOG performance status of less than 4. They had not been treated previously with chemotherapy for metastatic disease. Patients treated with adjuvant chemotherapy, which could not have included anthracyclines, had to have relapsed at least 12 months after the completion of therapy. There were no statistically significant differences in pretreatment characteristics or metastatic disease location between the two groups. Ninety-four patients were assessable for response. No differences were observed in response rate or in survival between the groups. The response rate (complete response (CR) and partial response (PR)) was 68% (13% CR and 55% PR for CAF; 0% CR and 68% PR for CNF). Median survival for all patients was 19 months (18 months with CAF and 19 months with CNF). All patients were assessable for toxicity. There were no differences in gastrointestinal and cardiac toxicity. More grade I-II hematologic toxicity episodes (p < 0.001) and treatment delays (p = 0.05) due to leucopenia were observed with the CNF group, and more grade III alopecia (p < 0.001) was observed with the CAF group. Patients received further therapeutic manoeuvres after finishing the study with a sequential treatment consisting of hormonal therapy and chemotherapy with mitomycin (M) -vinblastine (Vbl) (M 10 mg/m2 day 1, Vbl 5 mg/m2 days 1, 15 and 29; maximum 5 cycles). This chemotherapy treatment was received by 32 patients, with a response rate of 34% and grade III-IV hematologic toxicity of 37%. Treatment with CNF can be considered a good alternative to CAF for first-line treatment of metastatic breast cancer

  16. 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.

  17. 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.

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

    PubMed

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

    2016-08-01

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

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

    PubMed

    Wen, Feng; Li, Qiu

    2016-06-21

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

  20. 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

  1. GR-891: a novel 5-fluorouracil acyclonucleoside prodrug for differentiation therapy in rhabdomyosarcoma cells

    PubMed Central

    Marchal, J A; Prados, J; Melguizo, C; Gómez, J A; Campos, J; Gallo, M A; Espinosa, A; Arena, N; Aránega, A

    1999-01-01

    Differentiation therapy provides an alternative treatment of cancer that overcomes the undesirable effects of classical chemotherapy, i.e. cytotoxicity and resistance to drugs. This new approach to cancer therapy focuses on the development of specific agents designed to selectively engage the process of terminal differentiation, leading to the elimination of tumorigenic cells and recovery of normal cell homeostasis. A series of new anti-cancer pyrimidine acyclonucleoside-like compounds were designed and synthesized by structural modifications of 5-fluorouracil, a drug which causes considerable cell toxicity and morbidity, and we evaluated their applicability for differentiation therapy in human rhabdomyosarcoma cells. We tested the pyrimidine derivative GR-891, (RS)-1-{[3-(2-hydroxyethoxy)-1-isopropoxy]propyl}-5-fluorouracil, an active drug which shows low toxicity in vivo and releases acrolein which is an aldehyde with anti-tumour activity. Both GR-891 and 5-fluorouracil caused time- and dose-dependent growth inhibition in vitro; however, GR-891 showed no cytotoxicity at low doses (22.5 μmol l−1 and 45 μmol l−1) and induced terminal myogenic differentiation in RD cells (a rhabdomyosarcoma cell line) treated for 6 days. Changes in morphological features and in protein organization indicated re-entry in the pathway of muscular maturation. Moreover, GR-891 increased adhesion capability mediated by the expression of fibronectin, and did not induce overexpression of P-glycoprotein, the mdr1 gene product, implicated in multidrug resistance. New acyclonucleoside-like compounds such as GR-891 have important potential advantages over 5-fluorouracil because of their lower toxicity and their ability to induce myogenic differentiation in rhabdomyosarcoma cells. Our results suggest that this drug may be useful for differentiation therapy in this type of tumour. 1999 Cancer Research Campaign PMID:10070873

  2. 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

  3. 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.

  4. [Biochemical modulation of 5-fluorouracil by high-dose leucovorin].

    PubMed

    Aiba, K

    1988-03-01

    The biochemical modulation of 5-fluorouracil (FU) by using it in combination with leucovorin (LV) is reviewed. One of the mechanisms of action of FU is inhibition of thymidylate synthase (TS), a critical enzyme in the de novo synthesis of thymidylate required for DNA repair and synthesis. In the presence of 5, 10-methylene tetrahydrofolate, 5-fluoro-deoxyuridine monophosphate (FdUMP), which is an active nucleotide of FU, forms a ternary complex with TS, resulting in enzyme inhibition. The rationale for the use of LV with FU is to increase of formation and stability of catalytically inactive ternary complexes. In clinical trials, the dose schedules of 500 mg/m2 iv bolus or 500 mg/m2 continuously iv infusion is frequently used in order to obtain an ideal plasma concentration of active LV metabolites. Preliminary clinical trials using the combination of FU and LV appear to be capable of increasing of the clinical activity of FU for colorectal and breast cancers. Several randomized studies have supported the increase in response rates seen in the uncontrolled trials but additional studies are required to demonstrate a positive impact on the survival of treated patients.

  5. 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.

  6. Continuous infusion cisplatin and 5-fluorouracil with bolus vinorelbine in the treatment of advanced nonsmall cell carcinoma of the lung.

    PubMed

    Beuzeboc, P; Livartowski, A; Dierick, A; Paraiso, D; Pouillart, P

    1995-01-01

    Thirty-three patients, with histologically proven advanced nonsmall cell lung cancer (NSCLC) were treated at Institut Curie with a three-drug combination chemotherapy. The regimen consisted of cisplatin 25 mg/m2 per day continuous infusion (CI) and 5-fluorouracil (5-FU) CI 600 mg/m2 on 5 consecutive days with 30 minutes infusion navelbine 25 mg/m2 on days 1 and 5 only. Cycles were repeated every 28 days. Response was evaluated after three cycles. One patient died of an ischemic cerebrovascular stroke after the third cycle. Thirty-two pts were evaluable. Partial response was achieved in 11/20 patients with stage III disease (55%) and in 7/12 patients with stage IV disease (58%). WHO grade 4 toxicities were leucopenia 31%, thrombocytopenia 4%, and mucositis 4%. The tolerance was acceptable. Median survival was 19 months for stage III and 9.5 months for stage IV. We conclude that the combination of 5-FU, navelbine, and cisplatin is an effective chemotherapy regimen for patients with advanced stage NSCLC.

  7. Continuous-infusion cisplatin and bolus 5-fluorouracil in colorectal carcinoma.

    PubMed

    Posner, M R; Belliveau, J F; Weitberg, A B; Sabbath, K; Wiemann, M C; Cummings, F J; Calabresi, P

    1987-10-01

    Twenty-one evaluable patients with metastatic colorectal carcinoma were treated with a combination of continuous-infusion cisplatin (25 mg/m2/day X 3 days) and bolus 5-fluorouracil (400 mg/m2/day X 3 days). Toxicity was minimal. Seven patients (33%) responded. All responses were observed among the 16 previously untreated patients (44%) and lasted a median of 30 weeks. The results indicate the need for phase III trials of this treatment.

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

    PubMed Central

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

    1996-01-01

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

  9. 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.

  10. tRNA Modifying Enzymes, NSUN2 and METTL1, Determine Sensitivity to 5-Fluorouracil in HeLa Cells

    PubMed Central

    Hori, Masato; Okada, Kaoru; Yazama, Futoshi; Konishi, Hiroaki; Xiao, Yegui; Qi, Guangying; Shimamoto, Fumio; Ota, Takahide; Temme, Achim; Tatsuka, Masaaki

    2014-01-01

    Nonessential tRNA modifications by methyltransferases are evolutionarily conserved and have been reported to stabilize mature tRNA molecules and prevent rapid tRNA decay (RTD). The tRNA modifying enzymes, NSUN2 and METTL1, are mammalian orthologs of yeast Trm4 and Trm8, which are required for protecting tRNA against RTD. A simultaneous overexpression of NSUN2 and METTL1 is widely observed among human cancers suggesting that targeting of both proteins provides a novel powerful strategy for cancer chemotherapy. Here, we show that combined knockdown of NSUN2 and METTL1 in HeLa cells drastically potentiate sensitivity of cells to 5-fluorouracil (5-FU) whereas heat stress of cells revealed no effects. Since NSUN2 and METTL1 are phosphorylated by Aurora-B and Akt, respectively, and their tRNA modifying activities are suppressed by phosphorylation, overexpression of constitutively dephosphorylated forms of both methyltransferases is able to suppress 5-FU sensitivity. Thus, NSUN2 and METTL1 are implicated in 5-FU sensitivity in HeLa cells. Interfering with methylation of tRNAs might provide a promising rationale to improve 5-FU chemotherapy of cancer. PMID:25233213

  11. 5-Fluorouracil derivatives from the sponge Phakellia fusca.

    PubMed

    Xu, Xiao-Hua; Yao, Guang-Min; Li, Yan-Ming; Lu, Jian-Hua; Lin, Chang-Jiang; Wang, Xin; Kong, Chui-Hua

    2003-02-01

    5-Fluorouracil derivatives were isolated from the marine sponge Phakellia fusca collected around the Yongxing Island of the Xisha Islands in the South Sea of China. Their structures were determined on the basis of spectral analysis and X-ray diffraction.

  12. 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

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

    PubMed Central

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

    1995-01-01

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

  14. 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.

  15. 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

  16. In vivo interaction of anti-cancer drugs with misonidazole or metronidazole: methotrexate, 5-fluorouracil and adriamycin.

    PubMed Central

    Tannock, I. F.

    1980-01-01

    I have studied the effects on growth of two tumours in mice and on host toxicity, of combining Misonidazole (MISO) or Metronidazole (METRO) with Methotrexate (MTX)-5-fluorouracil (FU) or Adriamycin (ADR). The nitroimidazoles alone had no effect on the growth of either tumour, but MISO (1 mg/g) led to a small increase in delay to regrowth of the 16/C mammary carcinoma but not the KHT fibrosarcoma, when given after X-irradiation. MTX was active only against the KHT tumour, and growth delay was not increased by the addition of MISO or METRO. FU delayed growth of both tumours, and growth delay was increased slightly by single-dose MISO. ADR was active only against the 16/C tumour, and delay to regrowth was increased by adding MISO. Host toxicity assessed by death and loss of body weight was much greater when MISO or METRO were added to MTX, and a little greater when they were added to FU. ADR plus MISO caused no deaths and no greater loss of body weight than ADR alone. The addition of MISO to treatment with anticancer drugs led to a slightly greater and more prolonged myelosuppression. METRO and MISO increase the anti-tumour effects of some anti-cancer drugs, but may also increase host toxicity. Nitroimidazoles should be used with caution in combination with chemotherapy. PMID:7459220

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

    PubMed Central

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

    2010-01-01

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

  18. 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

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

    PubMed

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

    2013-01-01

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

  20. [A cancer of unknown primary site with diffuse metastasis to the bone marrow treated effectively with FAM combination chemotherapy].

    PubMed

    Yumoto, Y; Okuda, T; Kato, Y; Tashima, M; Sawada, H; Yamagishi, M; Uchino, H

    1988-05-01

    A patient with cancer of unknown primary site suffering from diffuse bone marrow metastasis and DIC, was treated with FAM (5-fluorouracil, adriamycin and mitomycin C) combination chemotherapy. She was a 58-year-old housewife. Bone marrow biopsy revealed that her marrow tissue was completely replaced by cancer cells, and bone scintigraphy showed diffuse bone marrow metastasis in all the vertebrae, sternum, pelvic bones and skull. After 5 months administration of 3 courses of FAM therapy, the cancer cells were completely eradicated in the bone marrow upon biopsy taken at almost the same position as the previous one. The values of CEA, CA 19-9 and CA 125 were normalized, suggesting that this therapy was very effective.

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

    PubMed

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

    2015-01-01

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

  2. Sequence-dependence of cisplatin and 5-fluorouracil in advanced and recurrent gastric cancer.

    PubMed

    Koizumi, Wasaburo; Kurihara, Minoru; Hasegawa, Koichi; Chonan, Akimichi; Kubo, Yasuhiko; Maekawa, Ryuichiro; Iwasaki, Ryozo; Sasai, Tadashi; Fukuyama, Yoshio; Ishikawa, Kunitsugu; Miyoshi, Kazuo; Yasutake, Koichi; Hayakawa, Makoto

    2004-09-01

    This randomized controlled clinical trial was designed to compare the safety and effectiveness of different sequences of treatment with cisplatin (CDDP) and 5-fluorouracil (5-FU) in patients with unresectable advanced and post-operative recurrent gastric cancer. Patients with unresectable advanced or post-operative recurrent gastric cancer were randomly assigned by a registration center to group A or B. Group A received CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 1 and 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 2-5. Group B was given 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 1-4, followed by CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 5. Each course of chemotherapy was repeated every 28 days. A total of 74 patients were enrolled. One patient died accidentally, and 5 could not be evaluated. Response was assessable in 68 patients. The response rate was 31.3% (10/32) in group A as compared with 13.9% (5/36) in group B. Although the response rate was higher in Group A, the difference was not significant (p=0.085). The response rate in patients with diffuse type tumors was significantly lower in group B. There was no difference between the groups in response among patients with intestinal type tumors. The median overall survival was 239 and 174 days and time to progression was 175 and 140 days in group A and group B, respectively. Although there were trends toward longer survival and time to progression in group A, the differences between the groups were not statistically significant. There was also no difference in the type or incidence of adverse reactions. The results of this controlled study indicate that the overall response rate was slightly but not significantly higher in patients who received CDDP before 5-FU. Among patients with diffuse type tumors, the response rate was significantly lower when 5-FU was administered before CDDP. Our results suggest that CDDP should be given

  3. 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

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

    PubMed Central

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

    2016-01-01

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

  5. Improved treatment of a brain-tumor model. Part 2: Sequential therapy with BCNU and 5-fluorouracil.

    PubMed

    Gerosa, M A; Dougherty, D V; Wilson, C B; Rosenblum, M L

    1983-03-01

    A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.

  6. Surviving cells after treatment with gemcitabine or 5-fluorouracil for the study of de novo resistance of pancreatic cancer.

    PubMed

    Liu, Qing-Hua; Zhang, Jing; Zhao, Chen-Yan; Yu, Dang-Hui; Bu, Hai-Ji; Chen, Ying; Ni, Can-Yong; Zhu, Ming-Hua

    2012-01-01

    One of the hallmarks of pancreatic cancer is its inherent insensitivity to chemotherapy. This study was undertaken to develop a cell model for the study of de novo resistance of pancreatic cancer. The surviving pancreatic cancer cells after a 3-day exposure to gemcitabine or 5-fluorouracil followed by another 7-day recovery were potentially drug-resistant. They had similar morphology and comparable growth and tumorigenic potentials to their untreated parental cells. Repeated subculture affected the cell-cycle profile and growth characteristics of the surviving cells. Our data suggest that surviving pancreatic cancer cells after drug treatment are a useful model for exploring intrinsic resistance.

  7. Severe adverse effects of 5-fluorouracil in S-1 were lessened by haemodialysis due to elimination of the drug.

    PubMed

    Inoue, Kazunori; Nagasawa, Yasuyuki; Yamamoto, Ryohei; Omori, Hiroki; Kimura, Tomonori; Tomida, Kodo; Furumatsu, Yoshiyuki; Imai, Enyu; Isaka, Yoshitaka; Rakugi, Hiromi

    2009-04-01

    S-1 and cisplatin are used as one of the first-line chemotherapies for gastric cancer in Japan. The plasma concentration of 5-fluorouracil (5-FU) is increased in patients with renal dysfunction because gimeracil in S-1 inhibits the degradation of 5-FU and about 50% of gimeracil is excreted in the urine. We describe a 35-year-old man with acute kidney injury while taking S-1 and cisplatin for advanced gastric cancer and who presented severe adverse effects of 5-FU. This case report describes the evolution of the plasma concentrations of 5-FU with haemodialysis along with a decrease in the adverse drug effects.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  10. 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

  11. 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.

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

    PubMed

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

    2015-12-01

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

  13. Up-regulation of stem cell markers by P21-activated kinase 1 contributes to 5-fluorouracil resistance of colorectal cancer.

    PubMed

    Huynh, Nhi; Shulkes, Arthur; Baldwin, Graham; He, Hong

    2016-08-01

    Cancer stem cells (CSC) are tumorigenic and resistant to chemotherapy. In colorectal cancer (CRC), CSCs have been identified by the expression of specific markers, including CD44, Bmi1 and Nanog. Although p21-activated kinase 1 (PAK1), acting downstream of Ras, stimulates Wnt/β-catenin signaling and is known to play an important role in CRC development and progression, the role of PAK1 in the expression of CSC markers has not previously been investigated. The effect of PAK1 over-expression, knockdown or inhibition on the expression or alteration (in the case of CD44) of CSC markers in human CRC cell lines was measured by immunofluorescence and Western blotting. The effect of PAK1 modulation on tumorigenesis, and on resistance to treatment with 5-fluorouracil (5-FU), was measured by sphere formation in vitro and by growth of xenografted tumors in vivo. The results show that PAK1 activity correlated with the expression of CSC markers and the CD44 isoform profile, and with tumor growth both in vitro and in vivo. Furthermore PAK overexpression partially overcame the inhibition of CRC growth by 5-FU, and PAK inhibition was synergistic with 5-FU treatment. Our findings lay the foundation for a combination therapy in which PAK1 inhibitors targeting CSCs may be combined with conventional 5-FU-based chemotherapy for the treatment of CRC.

  14. 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

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

    PubMed

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

    2014-11-14

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

  16. Poly(butylcyanoacrylate) nanoparticles for topical delivery of 5-fluorouracil.

    PubMed

    Simeonova, M; Velichkova, R; Ivanova, G; Enchev, V; Abrahams, I

    2003-09-16

    Poly(butylcyanoacrylate) nanoparticles (PBCN) as a drug carrier of 5-fluorouracil (5FU) intended for topical treatment of skin lesia were investigated. The presence of 5FU (as saline solution, pH 10-11) in the polymerization medium affected the polymerization as well as the nanoparticle formation by influencing the initiation of the polymerization reaction. 5FU acted as an initiator in the anionic polymerization of n-butylcyanoacrylate monomer through its nucleophilic nitrogen centers. The results obtained by GPC, 1H NMR, and X-ray diffraction allude to a possible mechanism of cytostatic immobilization in the polymer matrix, with evidence for both free and bound forms of the drug.

  17. Accidental use of low-dose 5-fluorouracil in pregnancy.

    PubMed

    Van Le, L; Pizzuti, D J; Greenberg, M; Reid, R

    1991-12-01

    Five percent 5-fluorouracil (5-FU), an antineoplastic agent, is often applied to the lower genital tract in the treatment of vaginal and vulvar human papillomavirus infections. Little is known regarding possible teratogenic effects from its topical use in pregnancy. Five cases of antenatal lower genital tract 5-FU use were correlated with pregnancy outcome. Topical 5-FU was applied up to 16 weeks' gestation. Intravaginal doses ranged from 1 to 2.5 g; one patient applied 5-FU to the vulva. Antenatal ultrasound performed on four patients did not show any fetal structural abnormalities. One patient underwent antenatal genetic amniocentesis that detected a 47,XXX complement of chromosomes. All the pregnancies continued without complications and with subsequent term delivery of healthy infants. The unwitting vaginal and vulvar use of 5-FU in pregnancy did not result in significant morbidity or mortality; expectant management of such pregnancies should be considered. PMID:1667807

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

    PubMed

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

    2012-07-01

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

  19. Prevention of 5-fluorouracil-related stomatitis by oral cryotherapy: a randomized controlled study.

    PubMed

    Papadeas, E; Naxakis, S; Riga, M; Kalofonos, Ch

    2007-02-01

    Stomatitis is a common adverse effect of intravenously infused 5-fluorouracil (5FU). Although there are encouraging studies about the preventive role of oral cryotherapy in stomatitis induced by intravenous administration of 5FU, this simple and cost-effective method is not part of clinical practice. This prospective randomized study investigates whether oral cryotherapy alleviates 5FU-induced stomatitis. Thirty six patients, included in the cryotherapy group, were instructed to hold ice cubes in their oral cavity, shortly before, during and shortly after the infusion of 5FU. Both mean physician and patient-graded stomatitis of our cryotherapy group were compared with those of a control group (40 patients) and were found significantly reduced for all three chemotherapy cycles. The percentage of patients who were free from oral toxicity was significantly higher in the cryotherapy group in all three chemotherapy cycles, as judged both by patients and physicians. The results of this study encourage the use of cryotherapy in patients receiving 5FU in alleviating stomatitis by using a side-effect-free, easy to perform and inexpensive measure, which does not interfere with the efficacy of antineoplastic agents. PMID:16829196

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2016-10-01

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

  2. Pharmacokinetic characteristics and anticancer effects of 5-Fluorouracil loaded nanoparticles

    PubMed Central

    Li, Su; Wang, Anxun; Jiang, Wenqi; Guan, Zhongzhen

    2008-01-01

    Background It is expected that prolonged circulation of anticancer drugs will increase their anticancer activity while decreasing their toxic side effects. The purpose of this study was to prepare 5-fluorouracil (5-FU) loaded block copolymers, with poly(γ-benzyl-L-glutamate) (PBLG) as the hydrophobic block and poly(ethylene glycol) (PEG) as the hydrophilic block, and then examine the 5-FU release characteristics, pharmacokinetics, and anticancer effects of this novel compound. Methods 5-FU loaded PEG-PBLG (5-FU/PEG-PBLG) nanoparticles were prepared by dialysis and then scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the shape and size of the nanoparticles, and ultraviolet spectrophotometry was used to evaluate the 5-FU in vitro release characteristics. The pharmacokinetic parameters of 5-FU/PEG-PBLG nanoparticles in rabbit plasma were determined by measuring the 5-FUby high-performance liquid chromatography (HPLC). To study in vivo effects, LoVo cells (human colon cancer cell line) or Tca8113 cells (human oral squamous cell carcinoma cell line) were implanted in BALB/c nude mice that were subsequently treated with 5-FU or 5-FU/PEG-PBLG nanospheres. Results 5-FU/PEG-PBLG nanoparticles had a core-shell spherical structure with a diameter of 200 nm and a shell thickness of 30 nm. The drug loading capacity was 27.1% and the drug encapsulation was 61.5%. Compared with 5-FU, 5-FU/PEG-PBLG nanoparticles had a longer elimination half-life (t1/2, 33.3 h vs. 5 min), lower peak concentration (C, 4563.5 μg/L vs. 17047.3 μg/L), and greater distribution volume (VD, 0.114 L vs. 0.069 L). Compared with a blank control, LoVo cell xenografts and Tca8113 cell xenografts treated with 5-FU or 5-FU/PEG-PBLG nanoparticles grew slower and had prolonged tumor doubling times. 5-FU/PEG-PBLG nanoparticles showed greater inhibition of tumor growth than 5-FU (p < 0.01). In the PEG-PBLG nanoparticle control group, there was no tumor

  3. Photocatalytic treatment of wastewater from 5-fluorouracil manufacturing

    SciTech Connect

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

    1996-02-01

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

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

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    1991-02-01

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

  6. 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.

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

    PubMed Central

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

    2016-01-01

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

  8. Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy.

    PubMed

    James, Mark I; Iwuji, Chinenye; Irving, Glen; Karmokar, Ankur; Higgins, Jennifer A; Griffin-Teal, Nicola; Thomas, Anne; Greaves, Peter; Cai, Hong; Patel, Samita R; Morgan, Bruno; Dennison, Ashley; Metcalfe, Matthew; Garcea, Giuseppe; Lloyd, David M; Berry, David P; Steward, William P; Howells, Lynne M; Brown, Karen

    2015-08-10

    In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDH(high)/CD133(-)). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.

  9. Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy

    PubMed Central

    James, Mark I.; Iwuji, Chinenye; Irving, Glen; Karmokar, Ankur; Higgins, Jennifer A.; Griffin-Teal, Nicola; Thomas, Anne; Greaves, Peter; Cai, Hong; Patel, Samita R.; Morgan, Bruno; Dennison, Ashley; Metcalfe, Matthew; Garcea, Giuseppe; Lloyd, David M.; Berry, David P.; Steward, William P.; Howells, Lynne M.; Brown, Karen

    2015-01-01

    In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDHhigh/CD133−). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct. PMID:25979230

  10. Oral supplementation of butyrate reduces mucositis and intestinal permeability associated with 5-Fluorouracil administration.

    PubMed

    Ferreira, Talita Mayra; Leonel, Alda Jusceline; Melo, Marco Antônio; Santos, Rosana R G; Cara, Denise Carmona; Cardoso, Valbert N; Correia, Maria I T D; Alvarez-Leite, Jacqueline I

    2012-07-01

    Mucositis affects about 40 % of patients undergoing chemotherapy. Short chain fatty acids (SCFA), mainly butyrate, are claimed to improve mucosal integrity, reduce intestinal permeability and act as anti-inflammatory agents for the colon mucosa. We evaluated the effects of oral administration of SCFA or butyrate in the 5FU-induced mucositis. Mice received water, SCFA or butyrate during all experiment (10 days) and a single dose of 5FU (200 mg/kg) 3 days before euthanasia. We evaluated inflammatory and histological score by morphometry, and by activity of enzymes specific to neutrophil, eosinophil and macrophage and TLR-4, TNF-alpha and IL6 expressions. Intestinal permeability and tight junction protein ZO-1 expression were evaluated. Mice from the 5FU (5-Fluorouracil) group presented weight loss, ulcerations and inflammatory infiltration of neutrophils and eosinophils, increased expression of IL6 and TNF-alpha and increased intestinal permeability. SCFA minimized intestinal damage, reduced ulcerations without affecting intestinal permeability. Butyrate alone was more efficient at improving those parameters than in SCFA solution and also reduced intestinal permeability. The expression of pro-inflammatory cytokines and ZO-1 tended to be higher in the SCFA supplemented but not in the butyrate supplemented group. We showed the beneficial effects of butyrate on intestinal mucositis and its promising function as an adjuvant in the treatment of diseases not only of the colon, but also of the small intestine.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2014-12-01

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

  14. Effect of Eriobotrya japonica seed extract on 5-fluorouracil-induced mucositis in hamsters.

    PubMed

    Takuma, Daisuke; Guangchen, Sun; Yokota, Junko; Hamada, Atsuhide; Onogawa, Masahide; Yoshioka, Saburo; Kusunose, Masahiko; Miyamura, Mitsuhiko; Kyotani, Syojiro; Nishioka, Yutaka

    2008-02-01

    In this study, we investigated the effects of an Eriobotrya japonica seed extract (ESE) on mucositis using a 5-fluorouracil (5-FU)-induced mucositis hamster model. This model was prepared by intraperitoneally administering 90 mg/kg of 5-FU to hamsters on Day 1, scratching 1 cm(2) of the left cheek pouch of hamsters with a wire brush on Days 2, 3, and 4, and intraperitoneally administering 60 mg/kg of 5-FU on Day 5. Mucositis was evaluated based on the mucositis score at the mucositis site, left cheek pouch thickness, histological findings on HE staining, and plasma lipid peroxide levels. On Day 10, the mucositis score and left cheek pouch thickness in the ESE group were significantly lower than those in the tap water group. Histologically, the two groups showed a defect of the cheek pouch epithelium on Day 6. On Day 10, epithelial injury and bacterial infection were noted in the tap water group. However, in the ESE group, similar findings were not observed. On Day 6, the plasma lipid peroxide level in the tap water group was significantly higher than that in the normal group. In the ESE group, the plasma lipid peroxide level was significantly lower than that in the tap water group. These results suggest that ESE is useful for treating chemotherapy-induced mucositis.

  15. 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.

  16. 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

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

    PubMed

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

    2011-02-01

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

  18. Chemotherapy plus percutaneous radiofrequency ablation in patients with inoperable colorectal liver metastases

    PubMed Central

    Sgouros, Joseph; Cast, James; Garadi, Krishna K; Belechri, Maria; Breen, David J; Monson, John RT; Maraveyas, Anthony

    2011-01-01

    AIM: To access the efficacy of chemotherapy plus radiofrequency ablation (RFA) as one line of treatment in inoperable colorectal liver metastases. METHODS: Eligible patients were included in three Phase II studies. In the first study percutaneous RFA was used first followed by 6 cycles of 5-fluorouracil, leucovorin and irinotecan combination (FOLFIRI) (adjunctive chemotherapy trial). In the other two, chemotherapy (FOLFIRI or 5-fluorouracil, leucovorin and oxaliplatin combination) up to 12 cycles was used first with percutaneous RFA offered to responding patients (primary chemotherapy trials). RESULTS: Thirteen patients were included in the adjunctive chemotherapy trial and 17 in the other two. At inclusion they had 1-4 liver metastases (up to 6.5 cm in size). Two patients died during chemotherapy. All patients in the adjunctive chemotherapy trial and 44% in the primary chemotherapy studies had their metastases ablated. Median PFS and overall survival in the adjunctive study were 13 and 24 mo respectively while in the primary chemotherapy studies they were 10 and 21 mo respectively. Eighty one percent of the patients had tumour relapse in at least one previously ablated lesion. CONCLUSION: Chemotherapy plus RFA in patients with low volume inoperable colorectal liver metastases seems safe and relatively effective. The high local recurrence rate is of concern. PMID:21528091

  19. CHK1 Inhibitors in Combination Chemotherapy

    PubMed Central

    Dent, Paul; Tang, Yong; Yacoub, Adly; Dai, Yun; Fisher, Paul B.; Grant, Steven

    2011-01-01

    Cellular sensing of DNA damage, along with concomitant cell cycle arrest, is mediated by a great many proteins and enzymes. One focus of pharmaceutical development has been the inhibition of DNA damage signaling, and checkpoint kinases (Chks) in particular, as a means to sensitize proliferating tumor cells to chemotherapies that damage DNA. 7-Hydroxystaurosporine, or UCN-01, is a clinically relevant and well-studied kinase activity inhibitor that exerts chemosensitizing effects by inhibition of Chk1, and a multitude of Chk1 inhibitors have entered development. Clinical development of UCN-01 has overcome many initial obstacles, but the drug has nevertheless failed to show a high level of clinical activity when combined with chemotherapeutic agents. One very likely reason for the lack of clinical efficacy of Chk1 inhibitors may be that the inhibition of Chk1 causes the compensatory activation of ATM and ERK1/2 pathways. Indeed, inhibition of many enzyme activities, not necessarily components of cell cycle regulation, may block Chk1 inhibitor–induced ERK1/2 activation and enhance the toxicity of Chk1 inhibitors. This review examines the rationally hypothesized actions of Chk1 inhibitors as cell cycle modulatory drugs as well as the impact of Chk1 inhibition upon other cell survival signaling pathways. An understanding of Chk1 inhibition in multiple signaling contexts will be essential to the therapeutic development of Chk1 inhibitors. PMID:21540473

  20. 5-Fluorouracil-induced bilateral persistent serpentine supravenous hyperpigmented eruption, bilateral mottling of palms and diffuse hyperpigmentation of soles

    PubMed Central

    Suvirya, Swastika; Agrawal, Avinash; Parihar, Anit

    2014-01-01

    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. PMID:25336557

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

    PubMed

    Ranganath, Praveen; Einhorn, Lawrence; Albany, Costantine

    2015-01-01

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

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

    PubMed Central

    Ranganath, Praveen; Einhorn, Lawrence; Albany, Costantine

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  4. 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

  5. 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

  6. Suppression of autophagy by chloroquine sensitizes 5-fluorouracil-mediated cell death in gallbladder carcinoma cells

    PubMed Central

    2014-01-01

    Autophagy1 is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemothery. Here we show that in human gallbladder carcinoma (GBC) cells lines, SGC-996 and GBC-SD, autophagy is induced by the DNA damaging agent 5-fluorouracil (5-FU). While in combination with the pre-treatment of chloroquine (CQ), a inhibitor of autophagy, the inhibition of 5-FU to the proliferation and viability of GBC cells was potentiated. Furthermore, 5-FU treatment resulted in a general increase of the apoptotic rate and G0/G1 arrest of GBC cells, and the effect was potentiated by CQ pre-treatment. Since 5-FU induced autophagy in GBC cells, and CQ inhibited autophagy, our findings suggest a possible mechanism that CQ inhibited 5-FU-induced autophagy, which modified the cytotoxicity of 5-FU. The combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of gallbladder carcinoma. PMID:24581180

  7. Incidence of leukopenia after intraperitoneal vs combined intravenous/intraperitoneal chemotherapy in pseudomyxoma peritonei

    PubMed Central

    Horvath, Philipp; Beckert, Stefan; Struller, Florian; Königsrainer, Alfred; Königsrainer, Ingmar

    2016-01-01

    AIM: To investigate the clinical impact of post-hyperthermic intraperitoneal chemotherapy (HIPEC) leukopenia, intraperitoneal and combined intravenous/intraperitoneal drug administrations were compared. METHODS: Two patient cohorts were retrospectively analyzed regarding the incidence of postoperative leukopenia. The first cohort (n = 32) received Mitomycin C (MMC)-based HIPEC intraperitoneally (35 mg/m² for 90 min) and the second cohort (n = 10) received a bi-directional therapy consisting of oxaliplatin (OX) (300 mg/m2 for 30 min) intraperitoneally and 5-fluorouracil (5-FU) 400 mg/m² plus folinic acid 20 mg/m² intravenously. The following data were collected retrospectively: Age, sex, length of operation, length of hospital stay, amount of resection including extent of peritonectomy, peritoneal cancer index, CC (completeness of cytoreduction)-status and leukocyte-count before cytoreductive surgery (CRS) and HIPEC, on days 3, 7 and 14 after CRS and HIPEC. HIPEC leukopenia was defined as < 4000 cells/m³. RESULTS: Leukopenia occurred statistically more often in the MMC than in the OX/5-FU-group (10/32 vs 0/10; P = 0.042). Leukopenia set-on was on day 7 after CRS and MMC-HIPEC and lasted for two to three days. Three patients (33%) required medical treatment. Patients affected by leukopenia were predominantly female (7/10 patients) and older than 50 years (8/10 patients). The length of hospital stay tended to be higher in the MMC-group without reaching statistical significance (22.5 ± 11 vs 16.5 ± 3.5 d). Length of operation (08:54 ± 01:44 vs 09:48 ± 02:28 h) were comparable between patients with and without postoperative leukopenia. Prior history of systemic chemotherapy did not trigger post-HIPEC leukopenia. Occurrence of leucopenia did not trigger surgical site infections, intraabdominal abscess formations, hospital-acquired pneumonia or anastomotic insufficiencies. CONCLUSION: Surgeons must be aware that there is a higher incidence of postoperative

  8. Spectroscopic and calorimetric studies of formation of the supramolecular complexes of PAMAM G5-NH₂ and G5-OH dendrimers with 5-fluorouracil in aqueous solution.

    PubMed

    Buczkowski, Adam; Olesinski, Tomasz; Zbicinska, Elzbieta; Urbaniak, Pawel; Palecz, Bartlomiej

    2015-07-25

    The results of spectroscopic measurements (increase in solubility, equilibrium dialysis, (1)H NMR titration) and calorimetric measurements (isothermal titration ITC) indicate exothermic (ΔH<0) and spontaneous (ΔG < 0) combination of an antitumor drug, 5-fluorouracil, by both cationic PAMAM G5-NH2 dendrimer and its hydroxyl analog PAMAM G5-OH in aqueous solutions at room temperature. PAMAM G5-NH2 dendrimer combines about 70 molecules of the drug with equilibrium constant K ≅ 300, which is accompanied by an increase in the system order (ΔS < 0). Hydroxyl dendrimer, PAMAM G5-OH, combines about 14 molecules of 5-fluorouracil with equilibrium constant K ≅ 100. This process is accompanied by an increase in the system disorder (ΔS > 0).

  9. [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.

  10. Percutaneous tumor ablation: microencapsulated echo-guided interstitial chemotherapy combined with cryosurgery increases necrosis in prostate cancer.

    PubMed

    Le Pivert, P J; Morrison, D R; Haddad, R S; Renard, M; Aller, A; Titus, K; Doulat, J

    2009-06-01

    This study aimed at confirming the increased growth inhibition (GI) of human prostate tumors produced by a intentionally palliative combination treatment of cryochemotherapy, i.e., partial cryoablation (CA) followed by intratumor partial chemotherapy with injection of microencapsulated 5-fluorouracil (MCC/5FU) at the ice ball (IB) periphery. We report the local effectiveness of cryochemotherapy compared to chemotherapy only with using multiple injections of MCC/5FU spaced out to maximize cumulative effect of sustained release of 5-fluorouracil (5FU) during a 21-day period. Prostate bioluminescent tumor cells - DU145 Luc+ - were implanted sub-cutaneously and bilaterally in each flank of nude mice. Tumors were treated with: (i) cryoablation alone (CA), causing necrosis in approximately 45% of the tumor volume; (ii) cryo-chemotherapy (CA+MCC/5FU), a combined regimen consisting of partial CA followed immediately and on day 14 by ultrasound assisted, intra-tumor injections (40 mul) of MCC/5FU( 0.81 ng/mm3 of tumor) containing Ethiodol (IPO) an imaging contrast agent, on two opposite sides of the unfrozen part of tumor; (iii) intratumor chemotherapy (MCC/5FU), consisting of three successive intra-tumor injections of microencapsulated 5FU on two opposite sides on Day 0, 4, and 11, and (iv) control series (MM), consisting of a single injection of echogenic microcapsules (mucaps) containing IPO but no 5FU. Tumor growth and viability were followed during a 21-day period with using biometric measurements, bioluminescent imaging (BLI) and ultrasonography (US), and then animals were sacrificed. CA, spared 54.4% of the tumor volume and the IB kill ratio was 0.4 +/-0.9. The maximum tumor volume reduction observed by Day 3 was short-lived as re-growth became significant by Day 6. CA+ MCC/5FU spared 55.6% of the tumor volume and the IB kill ratio was 0.54 +/- 0.12. The viable tumor cells, as measured by BLI remained at preoperative levels. After 11 days CA+ MCC/5FU limited the

  11. 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

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

    PubMed

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

    2016-01-01

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

  13. 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

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

    PubMed

    Tolba, Mai F; Abdel-Rahman, Sherif Z

    2015-01-01

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

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

    PubMed

    Tolba, Mai F; Abdel-Rahman, Sherif Z

    2015-01-01

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

  16. An Immune-Modulating Diet in Combination with Chemotherapy Prevents Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice.

    PubMed

    Nakamura, Kentaro; Sasayama, Akina; Takahashi, Takeshi; Yamaji, Taketo

    2015-01-01

    Cancer cachexia is characterized by muscle wasting caused partly by systemic inflammation. We previously demonstrated an immune-modulating diet (IMD), an enteral diet enriched with immunonutrition and whey-hydrolyzed peptides, to have antiinflammatory effects in some experimental models. Here, we investigated whether the IMD in combination with chemotherapy could prevent cancer cachexia in colon 26 tumor-bearing mice. Forty tumor-bearing mice were randomized into 5 groups: tumor-bearing control (TB), low dose 5-fluorouracil (5-FU) and standard diet (LF/ST), low dose 5-FU and IMD (LF/IMD), high dose 5-FU and standard diet (HF/ST) and high dose 5-FU and IMD (HF/IMD). The ST and IMD mice received a standard diet or the IMD ad libitum for 21 days. Muscle mass in the IMD mice was significantly higher than that in the ST mice. The LF/IMD in addition to the HF/ST and HF/IMD mice preserved their body and carcass weights. Plasma prostaglandin E2 levels were significantly lower in the IMD mice than in the ST mice. A combined effect was also observed in plasma interleukin-6, glucose, and vascular endothelial growth factor levels. Tumor weight was not affected by different diets. In conclusion, the IMD in combination with chemotherapy prevented cancer cachexia without suppressing chemotherapeutic efficacy.

  17. 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

  18. [Dilution of the toxic action of 5-fluorouracil on the mucosa of the small intestine in mice using the sap of plantain].

    PubMed

    Borovskaia, T G; Udintsev, S N; Zueva, E P; Fomina, T I; Neĭshtadt, E L

    1987-01-01

    The study was concerned with an attempt at reducing the acute toxic effect of 5-fluorouracil (5-FU) on gut mucosa in mice with Ehrlich ascites tumors. An official preparation of plantain sap was shown to ward off this effect and to contribute to the normalising of certain parameters of epithelial cells. The DNA level of tumor cells showed a more drastic decline after combined treatment with 5-FU and the preparation than after the cytostatic drug alone. PMID:3617613

  19. [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.

  20. 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

  1. MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism

    PubMed Central

    Pereira, Diane M.; Simões, André E. S.; Gomes, Sofia E.; Castro, Rui E.; Carvalho, Tânia; Rodrigues, Cecília M. P.; Borralho, Pedro M.

    2016-01-01

    The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA. In addition, ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU, but failed to sensitize HCT116 p53−/− cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted in hibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment. PMID:27144434

  2. MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism.

    PubMed

    Pereira, Diane M; Simões, André E S; Gomes, Sofia E; Castro, Rui E; Carvalho, Tânia; Rodrigues, Cecília M P; Borralho, Pedro M

    2016-06-01

    The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA. In addition, ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU, but failed to sensitize HCT116 p53-/- cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted inhibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment. PMID:27144434

  3. 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...

  4. 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

  5. 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

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

    PubMed

    Tanriverdi, Ozgur

    2014-07-01

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

  7. 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.

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

    PubMed

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

    2014-01-01

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

  9. 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.

  10. Antimalarial drug resistance and combination chemotherapy.

    PubMed Central

    White, N

    1999-01-01

    Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives. PMID:10365399

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

    PubMed Central

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

    2015-01-01

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

  12. 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.

  13. Phase II study of combined chemotherapy with docetaxel, CDDP and 5-FU for highly advanced esophageal cancer.

    PubMed

    Osaka, Yoshiaki; Shinohara, Motoo; Hoshino, Sumito; Ogata, Takashi; Takagi, Yu; Tsuchida, Akihiko; Aoki, Tatsuya

    2011-02-01

    Advanced esophageal cancer with widespread metastasis to lymph nodes or other organs is difficult to treat and has an extremely poor prognosis. A new combined chemotherapy of docetaxel with cisplatin (CDDP) and 5-fluorouracil (5-FU) (DPF therapy) was performed and its efficacy and safety were examined. Among those hospitalized between May 2003 and October 2009, 30 patients with stage III or stage IV unresectable, untreated advanced esophageal squamous cell carcinoma which had invaded other organs were enrolled in this study. The regimen of DPF therapy was as follows: a set of intravenous drips of 60 mg/m(2) of docetaxel (day 1), 60 mg/m(2) of CDDP (day 1) and 800 mg/m(2) of 5-FU (days 1-5) was administered twice at an interval of 3 to 4 weeks. Antitumor effects, adverse reactions and treatment outcomes were then examined. The patients included 26 men and 4 women aged 40 to 73 years (average age, 58.1 years), and the performance status (PS) was 1 in 18 cases and 2 in 12 cases. The main location of the esophageal cancer was the upper/middle/lower thoracic esophagus in 7/14/9 cases, respectively. Clinical stage was III in 5 cases and IV in 25. The effective rate of DPF therapy was 83.3% for the primary lesion (complete response, CR: 4 cases, partial response, PR: 21 cases), 72.4% for lymph node metastasis (CR: 3 cases, PR: 18 cases) and 72.0% for distant organ metastasis (CR: 3 cases, PR: 15 cases). The observed adverse reactions of grade 2 or higher of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) included anemia (16.7%), leukopenia (73.3%), liver dysfunction (20.0%), anorexia (16.7%), stomatitis (33.3%), esophagitis (16.7%), alopecia (16.7%) and diarrhea (26.7%). The therapy completion rate was 96.7% and the therapy-related death rate was 3.3%. Treatments given after the completion of the DPF therapy were surgery in 6 cases, chemotherapy such as additional DPF in 12, chemoradiation in 4, esophageal stent placement in 1, and no treatment in 7. The

  14. Topical 5-fluorouracil solution in the treatment of warts--clinical experience and percutaneous absorption.

    PubMed

    Senff, H; Reinel, D; Matthies, C; Witts, D

    1988-03-01

    Disseminated warts in six patients were pre-treated with topical 5-fluorouracil solution three times daily for 5 consecutive days. Curettage was then carried out under local anaesthesia. During pre-treatment less than 0.1% of the dose applied was absorbed through the skin. The warts had not reappeared in 5 of the 6 patients at follow-up 1 year later.

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

    PubMed Central

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

    2009-01-01

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

  16. 5-Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells.

    PubMed

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

    2015-03-15

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

  17. In vivo isolated liver perfusion technique in a rat hepatic metastasis model: 5-fluorouracil concentrations in tumor tissue.

    PubMed

    de Brauw, L M; van de Velde, C J; Tjaden, U R; de Bruijn, E A; Bell, A V; Hermans, J; Zwaveling, A

    1988-02-01

    An in vivo method of isolated rat liver perfusion was developed with true vascular isolation and recirculating perfusate. This new surgical technique to temporarily isolate the liver vascularly, and the perfusion procedure are described in depth. Twelve inbred WAG/RIJ rats were subjected to 25 min of normothermic liver perfusion without chemotherapy, and all rats survived the procedure. Hepatic functional and histological integrity were not significantly altered during perfusion. To determine the role of isolated liver perfusion (ILP) as a means of improved targeting of antitumor agents, 5-fluorouracil (5-FU) concentrations were monitored in hepatic tumor and liver tissues and in systemic plasma using high-performance liquid chromatography. Fifty-one rats with hepatic tumors of colonic origin were randomly assigned to one of three dosage groups (20, 40, or 80 mg/kg) receiving 5-FU by ILP, hepatic artery infusion (HAI), or jugular vein infusion (JVI). ILP resulted in significantly increased 5-FU concentrations in liver tissue. However, no significant differences were found in tumor tissue concentrations of 5-FU between the three treatment modalities. 5-FU concentrations in tumor tissue increased as a function of the dose with ILP, HAI, and JVI. ILP was associated with the lowest systemic drug concentrations. The low systemic 5-FU concentrations with ILP suggest a higher maximum tolerable dose. This mode of treatment deserves to be studied further in our model before conclusions can be drawn regarding its therapeutic potential. PMID:3339874

  18. Expression of the breast cancer resistance protein and 5-fluorouracil resistance in clinical breast cancer tissue specimens

    PubMed Central

    WANG, MIN; WANG, XIANMING; YUAN, JIANHUI; GUO, LIANGFENG

    2013-01-01

    The breast cancer resistance protein (BCRP) is a recently characterized xenobiotic half-transporter protein that acts as an energy-dependent efflux pump and may be associated with the multidrug-resistant phenotype. The aim of this study was to determine the association between BCRP expression and 5-fluorouracil (5-FU) resistance in clinical breast cancer tissue specimens. The BCRP expression was investigated using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) by use of the Master SYBR-Green I reagent and immunohistochemistry (IHC) by use of the BXP-21 anti-BCRP monoclonal antibody in clinical breast cancer tissue specimens. Chemosensitivity to 5-FU for BCRP-positive clinical breast cancer tissue specimens was colorimetrically assessed with the cytotoxicity assay through methyl thiazolyl tetrazolium (MTT) reduction. A total of 37 BCRP-positive clinical breast cancer tissue specimens were identified with quantitative RT-PCR and IHC. There was a significant correlation in BCRP expression between the results of quantitative RT-PCR and IHC in the specimens. The fold resistance to 5-FU was 7–12 compared to sensitivity to paclitaxel as determined by the colorimetric assay through MTT reduction in the 37 specimens. Our study results indicated that 5-FU resistance may be mediated by BCRP expression in clinical breast cancer tissue specimens, which may help optimize the design of breast cancer clinical chemotherapy schemes in BCRP-positive specimens. PMID:24649260

  19. Hyperfractionated Radiotherapy with Concurrent Cisplatin/5-Fluorouracil for Locoregional Advanced Head and Neck Cancer: Analysis of 105 Consecutive Patients

    PubMed Central

    Zaboli, David; Tan, Marietta; Gogineni, Hrishikesh; Lake, Spencer; Fan, Katherine; Zahurak, Marianna L.; Messing, Barbara; Ulmer, Karen; Zinreich, Eva S.; Levine, Marshall A.; Tang, Mei; Pai, Sara I.; Blanco, Ray G.; Saunders, John R.; Best, Simon R.; Califano, Joseph A.; Ha, Patrick K.

    2012-01-01

    Objective. We reviewed a cohort of patients with previously untreated locoregional advanced head and neck squamous cell carcinoma (HNSCC) who received a uniform chemoradiotherapy regimen. Methods. Retrospective review was performed of 105 patients with stage III or IV HNSCC treated at Greater Baltimore Medical Center from 2000 to 2007. Radiation included 125 cGy twice daily for a total 70 Gy to the primary site. Chemotherapy consisted of cisplatin (12 mg/m2/h) daily for five days and 5-fluorouracil (600 mg/m2/20 h) daily for five days, given with weeks one and six of radiation. All but seven patients with N2 or greater disease received planned neck dissection after chemoradiotherapy. Primary outcomes were overall survival (OS), locoregional control (LRC), and disease-free survival (DFS). Results. Median followup of surviving patients was 57.6 months. Five-year OS was 60%, LRC was 68%, and DFS was 56%. Predictors of increased mortality included age ≥55, female gender, hypopharyngeal primary, and T3/T4 stage. Twelve patients developed locoregional recurrences, and 16 patients developed distant metastases. Eighteen second primary malignancies were diagnosed in 17 patients. Conclusions. The CRT regimen resulted in favorable outcomes. However, locoregional and distant recurrences cause significant mortality and highlight the need for more effective therapies to prevent and manage these events. PMID:22778748

  20. 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.

  1. 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

  2. Treatment of advanced colorectal cancer with high-dose intensity folinic acid and 5-fluorouracil plus supportive care.

    PubMed

    Petrioli, R; Lorenzi, M; Aquino, A; Marsili, S; Frediani, B; Palazzuoli, V; Marzocca, G; Botta, G; Tani, F; De Martino, A

    1995-11-01

    This randomised clinical trial, involving patients with advanced colorectal cancer, was carried out to compare the effectiveness of accelerated folinic acid (FA) plus 5-fluorouracil (5-FU) with that of the conventional regimen of 5-FU alone. Both regimens were administered with simulataneous supportive care. 185 patients were eligible: 94 were randomly allocated to receive FA 200 mg/m2 i.v. plus 5-FU 400 mg/m2 i.v. on days 1-5 every 3 weeks; and 91 to receive 5-FU 400 mg/m2 i.v. on days 1-5 every 4 weeks. The response rate was 33.3% in the accelerated FA/5-FU and 18.6% in the 5-FU arm (P = 0.045). Median survival was 13.5 months in the FA/5-FU arm and 7.5 months in the 5-FU arm (P = 0.039). Toxicity was mild and slightly more pronounced in the FA/5-FU arm (P = 0.078). This study indicates that, in patients with advanced colorectal cancer, accelerated chemotherapy with FA and 5-FU and simultaneous supportive care is capable of achieving a higher response rate and longer survival than conventional 5-FU alone, without severe toxicity. PMID:8562173

  3. Magnetite/poly(alkylcyanoacrylate) (core/shell) nanoparticles as 5-Fluorouracil delivery systems for active targeting.

    PubMed

    Arias, José L; Gallardo, Visitación; Ruiz, M A Adolfina; Delgado, Angel V

    2008-05-01

    In this article, a reproducible emulsion polymerization process is described to prepare core/shell colloidal nanospheres, loaded with 5-Fluorouracil, and consisting of a magnetic core (magnetite) and a biodegradable polymeric shell [poly(ethyl-2-cyanoacrylate), poly(butylcyanoacrylate), poly(hexylcyanoacrylate), or poly(octylcyanoacrylate)]. The heterogeneous structure of these carriers can confer them both the possibility of being used as drug delivery systems and the responsiveness to external magnetic fields, allowing an active drug targeting without a concurrent systemic distribution. Zeta potential determinations as a function of ionic strength showed that the surface behaviour of the core/shell particles is similar to that of pure cyanoacrylate particles. The first magnetization curve of both magnetite and magnetite/polymer particles demonstrated that the polymer shell reduces the magnetic responsiveness of the particles, but keeps unchanged their ferrimagnetic character. Two drug loading mechanisms were studied: absorption or entrapment in the polymeric network, and surface adsorption. We found that the acidity of the medium had significant effects on the drug absorption per unit mass of polymer, and needs to be controlled to avoid formation of macroaggregates and to reach significant 5-Fluorouracil absorption. The type of polymer and the drug concentration are also main factors determining the drug incorporation to the core/shell particles. 5-Fluorouracil release evaluations showed a biphasic profile affected by the type of polymeric shell, the type of drug incorporation and the amount of drug loaded.

  4. Chemotherapy

    MedlinePlus

    ... getting chemotherapy. Chemotherapy is most often given in cycles. These cycles may last one day, several days, or a ... period when no chemotherapy is given between each cycle. A rest period may last for days, weeks, ...

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

    PubMed Central

    2012-01-01

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

  6. miR-139-5p sensitizes colorectal cancer cells to 5-fluorouracil by targeting NOTCH-1.

    PubMed

    Liu, Heyong; Yin, Yuan; Hu, Yaling; Feng, Yuyang; Bian, Zehua; Yao, Surui; Li, Min; You, Qingjun; Huang, Zhaohui

    2016-07-01

    Multidrug resistance (MDR), a phenomenon that often occurs with drug treatment and is characterized by relapse or attenuation of drug efficacy, is almost unavoidable in colorectal cancer (CRC) patients receiving 5-fluorouracil (5-FU)-based chemotherapy. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression. Our previous study has identified miR-139-5p as a potential tumor suppressor in CRC, but its role in chemoresistance of CRC has not been elucidated. In this study, we demonstrated that miR-139-5p was down-regulated either in CRC tumors receiving chemotherapy or in 5-FU-resistant CRC cell lines (HCT-8/5-FU and HCT-116/5-FU). Ectopic expression of miR-139-5p sensitized CRC cells to 5-FU by increasing 5-FU-induced apoptosis. In addition, miR-139-5p inhibited the expression of the miR-139-5p target gene NOTCH-1 and its downstream molecules MRP-1 and BCL-2, two key MDR-associated genes. Furthermore, silencing NOTCH-1 expression promoted the chemotherapeutic effects of 5-FU, and up-regulation of NOTCH-1 abrogated miR-139-5p-mediated sensitization to 5-FU in LoVo and HCT-116 cells. Taken together, our data indicate a new role of miR-139-5p/NOTCH-1 pathway in the drug resistance of CRC cells to 5-FU, which may be a promising therapeutic target for the anti-MDR treatment of CRC. PMID:27173050

  7. 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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  10. 5-Fluorouracil-induced RNA stress engages a TRAIL-DISC-dependent apoptosis axis facilitated by p53.

    PubMed

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

    2015-12-22

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

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

    PubMed Central

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

    2016-01-01

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

  13. 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

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

    PubMed

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

    2016-05-01

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

  15. 5-Fluorouracil preferentially sensitizes mutant KRAS non-small cell lung carcinoma cells to TRAIL-induced apoptosis.

    PubMed

    Wang, Haizhen; Yang, Tao; Wu, Xiangwei

    2015-11-01

    Mutations in the KRAS gene are very common in non-small cell lung cancer (NSCLC), but effective therapies targeting KRAS have yet to be developed. Interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of cell death, has increased following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and in xenograft models. However, results from clinical trials of TRAIL-based therapy are disappointingly modest at best and many have demonstrated a lack of therapeutic benefit. Current research has focused on selecting a subpopulation of cancer patients who may benefit from TRAIL-based therapy and identifying best drugs to work with TRAIL. In the current study, we found that NSCLC cells with a KRAS mutation were highly sensitive to treatment with TRAIL and 5-fluorouracil (5FU). Compared with other chemotherapeutic agents, 5FU displayed the highest synergy with TRAIL in inducing apoptosis in mutant KRAS NSCLC cells. We also found that, on a mechanistic level, 5FU preferentially repressed survivin expression and induced expression of TRAIL death receptor 5 to sensitize NSCLC cells to TRAIL. The combination of low-dose 5FU and TRAIL strongly inhibited xenograft tumor growth in mice. Our results suggest that the combination of TRAIL and 5FU may be beneficial for patients with mutant KRAS NSCLC.

  16. 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

  17. 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

  18. 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.

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

    SciTech Connect

    Sandborg, R.R.

    1986-01-01

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

  20. Synthesis, in vitro aerobic and hypoxic cytotoxicity and radiosensitizing activity of novel metronidazole tethered 5-fluorouracil

    PubMed Central

    2013-01-01

    Background and the purpose of the study Several 2, 4-dinitrophenyl and 2,4-dinitrophenylamine tethered 5-FU (5-fluorouracil) compared to their components have shown minimal or no cytotoxicity to HT-29 cell line under aerobic conditions but high cytotoxicity and radiosensitizing effects under hypoxic conditions. In the present study the cytotoxicity and radiation potentiation of three novel analogues of these compounds by replacing 2,4-dinitrophenyl moiety with 2-methyl-5-nitroimidazole, a known radiosensitizer and cytotoxic agent was investigated. Methods Tethered compounds 7–9 were prepared by the reaction of 1-(t-butoxycarbonyl)-5-fluorouracil 6 with metronidazole esters 2–4 followed by removal of the t-butoxycarbonyl protecting group. Cytotoxicity of compounds in HT-29 cells with or without radiation were determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), propidium iodide (PI)-digitonin and clonogenic assays. Results Tethered compounds 7–9 induced time-and concentration–dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration- dependent radiosensitization effects under hypoxic conditions. Conclusion Tethered compounds 7–9 compared to 5-FU 5 showed minimal cytotoxicities under aerobic and selective radiosensitizing activities under hypoxic conditions. Also effects of these compounds were higher than those of metronidazole 1 which is a known cytotoxin and radiosensitizer under hypoxic conditions. PMID:24359860

  1. 19F Nuclear Magnetic Resonance Analysis of 5-Fluorouracil Metabolism in Four Differently Pigmented Strains of Nectria haematococca

    PubMed Central

    Parisot, Denise; Malet-Martino, Marie C.; Martino, Robert; Crasnier, Philippe

    1991-01-01

    19F nuclear magnetic resonance spectroscopy was used to study the metabolism of 5-fluorouracil in four strains of Nectria haematococca which displayed similar sensitivities to growth inhibition by this compound but differed in their pigmentation. The major metabolites, 5-fluorouridine and α-fluoro-β-alanine, were excreted into the medium by all four strains. The classical ribofluoronucleotides (5-fluorouridine-5′-monophosphate, -diphosphate, and -triphosphate) and α-fluoro-β-alanine were identified in the acid-soluble fraction of perchloric acid extracts of mycelia. Two hydrolysis products of 5-fluorouracil incorporated into RNA were found in the acid-insoluble pool. They were unambiguously assigned to 5-fluorouridine-2′-monophosphate and 3′-monophosphate with specific hydrolysis reactions on isolated RNA. The lack of fluorodeoxyribonucleotides and the fact that the four strains incorporated similar amounts of fluororibonucleotides into their RNAs strongly suggest an RNA-directed mechanism of cytotoxicity for 5-fluorouracil. The heavily pigmented wild type differed from the three low-pigmented strains in its low uptake of 5-fluorouracil and, consequently, in its reduced biosynthesis of 5-fluorouridine and α-fluoro-β-alanine. At present, it is not clear whether this change in 5-fluorouracil metabolism is a side effect of pigment production or results from another event. PMID:16348609

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

    PubMed

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

    2015-01-01

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

  3. 5-Fluorouracil sensitizes colorectal tumor cells towards double stranded DNA breaks by interfering with homologous recombination repair

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-01-01

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

  6. 5-Fluorouracil-lipid conjugate: potential candidate for drug delivery through encapsulation in hydrophobic polyester-based nanoparticles.

    PubMed

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

    2014-11-01

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

  7. Actikerall™ (5-Fluorouracil 0.5% and Salicylic Acid 10%) Topical Solution for Patient-directed Treatment of Actinic Keratoses.

    PubMed

    Nguyen, H P; Rivers, J K

    2016-05-01

    Actinic keratosis (AK), a common cutaneous lesion with the potential to transform into squamous cell carcinoma, has traditionally been treated with ablative and/or surgical procedures. Recently, a topical formulation combining 0.5% 5-fluorouracil with 10% salicylic acid (5-FU-SA) was introduced in Europe under the trade name Actikerall™ for the treatment of grade I/II AKs. In a single randomized phase III trial, 5-FU-SA was shown to be superior to diclofenac 3% gel in hyaluronic acid, as measured by the histological clearance of one defined lesion (72% vs. 59.1%) and by complete clinical clearance (55.4% vs. 32.0%). 5-FU-SA should be applied once daily to a total area of up to 25 cm(2), which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks. The most common side effects are local inflammation and pruritus at the application site, and no serious adverse effects have been reported to date. Now commercially available in Canada, 5-FU-SA represents a patientapplied therapeutic option for the treatment of both overt and subclinical AKs.

  8. 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

  9. 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. PMID:24200004

  10. 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.

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

    PubMed

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

    2015-11-01

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

  12. 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.

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

    PubMed

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

    2016-01-01

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery. PMID:27010513

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

    PubMed

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

    1978-01-01

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

  15. 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

  16. Regulation of Pyrimidine and Arginine Biosynthesis Investigated by the Use of Phaseolotoxin and 5-Fluorouracil 1

    PubMed Central

    Jacques, Steve; Sung, Zinmay Renee

    1981-01-01

    Purified phaseolotoxin inhibits the growth of carrot cells. Such inhibitions can be reversed completely by citrulline but not by arginine. This toxin inhibits ornithine transcarbamylase activity in vitro, which leads to an accumulation of ornithine and a decrease in arginine levels intracellularly. In carrot cells, 5-fluorouracil (5-FU) toxicity can be reduced by the addition of purified toxin and citrulline, or ornithine. The toxin also decreases the incorporation of [14C]uracil and [14C]5-FU into trichloroacetic acid precipitable material by 50%. Finally, a 5-FU-resistant line, F5 (Sung ZR, Jacques S 1980 Planta 148: 389-396), was found to be more sensitive to the toxin than were 5-FU-sensitive cells. One millimolar 5-FU roughly doubled the ability of F5 to tolerate phaseolotoxin. These results demonstrate a close regulation between the pyrimidine and arginine path-ways in carrots. PMID:16661663

  17. 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

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

    PubMed

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

    1984-05-01

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

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

    PubMed Central

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

    2016-01-01

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

  20. Vitamin D analogs enhance the anticancer activity of 5-fluorouracil in an in vivo mouse colon cancer model

    PubMed Central

    2013-01-01

    Background Active vitamin D analogs that are less toxic than calcitriol can be useful in the combined treatment of patients suffering from colon cancer. In the present study we demonstrate, for the first time in an in vivo model system, the biological effect of combined therapy using 5-fluorouracil (5-FU) along with vitamin D analog PRI-2191 (tacalcitol, 1,24-dihydroxyvitamin D3) or PRI-2205 (5,6-trans-isomer of calcipotriol) on colon cancer. Methods We investigated the influence of vitamin D analogs on the anticancer activity of 5-FU or capecitabine in the treatment of mice bearing MC38 mouse colon tumors implanted subcutaneously or orthotopically. The cell cycle distribution, E-cadherin expression and caspase 3/7 activity in vitro were also evaluated. Results We observed that both PRI-2191 and PRI-2205 significantly enhanced the antitumor activity of 5-FU; but these results depend on the treatment regimen. Applying the optimal schedule of combined therapy we observed a significant decrease in tumor growth, metastasis and also a prolongation of the survival time of mice, in comparison with the administrations of 5-FU given alone. Both combinations indicated a synergistic effect and did not cause toxicity. Moreover, analogs applied after completed course of administration of 5-FU, prolonged the antitumor effect of the drug. Furthermore, when the prodrug of 5-FU, capecitabine, was used, potentiation of its activity was also observed. Conclusions Our data suggest that vitamin D analogs (especially PRI-2191) might be potentially applied to clinical use in order to enhance the anticancer effect of 5-FU and also prolong its activity against colon cancer. The activity of PRI-2191 is realized through stopping the cells in the G0/G1 cell cycle phase and increasing the expression of E-cadherin. PMID:23777514

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

    PubMed Central

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

    1997-01-01

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

  2. Synthesis of FUDP-N-acetylglucosamine and FUDP-glucose in Saccharomyces cerevisiae cells treated with 5-fluorouracil.

    PubMed

    Günther Sillero, María A; Pérez-Zúñiga, Francisco; Gomes, Joana; de Carvalho, Ana Isabel; Martins, Susana; Silles, Eduardo; Sillero, Antonio

    2008-03-01

    Saccharomyces cerevisiae cells (strain W303-1A) treated with 5-fluorouracil and grown in 2% (fermentative conditions) or in 0.1% glucose (oxidative conditions) accumulated two types of 5-fluoro-UDP-sugars (FUDP-sugars): FUDP-N-acetylglucosamine and FUDP-glucose. No difference was observed in both conditions of culture. The viability of yeast cells on treatment with 5-fluorouracil was also followed. Both FUDP-sugars were partially purified by column chromatography (on Hypersil ODS and Mono Q columns) and characterized by: (i) treatment with alkaline phosphatase (EC 3.1.3.1), snake venom phosphodiesterase (EC 3.1.4.1) and UDP-glucose dehydrogenase (EC 1.1.1.22); (ii) UV spectra; and (iii) matrix-assisted laser desorption/ionization-time of flight mass analysis and 1H-nuclear magnetic resonance spectrometry. The syntheses of both FUDP-sugars were inversely related to the concentration of uracil and directly related to the concentration of 5-fluorouracil in the culture medium. The strain W303-1A, requiring uracil for growth, was useful as a tool to analyze the effect of 5-fluorouracil on nucleotide metabolism.

  3. 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 ...

  4. 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.

  5. Effect of consecutive lower-dose cisplatin in enhancement of 5-fluorouracil cytotoxicity in experimental tumor cells in vivo.

    PubMed

    Araki, H; Fukushima, M; Kamiyama, Y; Shirasaka, T

    2000-11-28

    It is known that cisplatin (CDDP) potentiates the cytotoxicity of 5-fluorouracil (5-FU), and that the biochemical mechanism is an increase in the intracellular reduced folate levels in the tumor cells. We investigated the effect of consecutive administration with lower-dose CDDP on intracellular accumulation of reduced folate and the activity of methionine synthase, a key enzyme in intracellular methionine synthesis. When CDDP (1 mg/kg) was administered i.p. to ascitic Yoshida sarcoma-bearing rats for 4 consecutive days, both the reduced folate levels and methionine synthase activity in the cells significantly increased, as the same as a single 5 mg/kg dose of CDDP. Furthermore, when Yoshida sarcoma-bearing rats were pre-treated with 1 mg/kg CDDP for 5 consecutive days, [14C]L-methionine incorporation into the isolated ascitic cells was significantly inhibited as compared to that in non-treated cells, suggesting that consecutive administration of lower-dose CDDP is capable of inducing the intracellular modulation of reduced folate levels and methionine synthase activity via inhibition of cellular uptake of methionine. In addition, 5-day administration of lower-dose (1 mg/kg) CDDP potentiated the antitumor effect of 5 mg/kg S-1, a new oral preparation of tegafur, given for 7 consecutive days, and this combined effect was almost similar to the antitumor effect of a combination of S-1 and a single conventional dose (5 mg/kg) of CDDP. Consecutive lower-dose CDDP also may be concluded to act as an important modulator of the enhancement of 5-FU cytotoxicity in experimental tumors.

  6. 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.

  7. Effective palliative treatment of metastatic carcinoid tumors with intra-arterial chemotherapy/chemoembolization combined with octreotide acetate.

    PubMed

    Hajarizadeh, H; Ivancev, K; Mueller, C R; Fletcher, W S; Woltering, E A

    1992-05-01

    Survival in patients with metastatic carcinoid tumors is dependent on control of tumor growth and adequate palliation of vasoactive amine-induced symptoms of flushing, diarrhea, wheezing, and valvular heart disease. Eight patients with carcinoid tumors metastatic to the liver were treated with long-term octreotide acetate therapy (100 to 500 micrograms three times a day), intra-arterial 5-fluorouracil infusion (2 g/day x 5 days), and hepatic tumor chemoembolization. All eight patients became asymptomatic and have remained so with a mean follow-up duration of 22 months from the time of first infusion. Following institution of subcutaneous octreotide acetate, intra-arterial infusion, and tumor chemoembolization, all patients are alive with a mean survival of 40 months from the time of diagnosis of carcinoid syndrome (range: 2 to 108 months). Four patients had greater than a 50% decrease in tumor size after therapy (mean follow-up duration: 10.6 months), and the other four patients have had stable disease after institution of therapy. It appears that combinations of long-term subcutaneous administration of octreotide acetate, intra-arterial 5-fluorouracil, and tumor chemoembolization effectively control progressive liver metastasis and provide excellent symptomatic palliation in patients with hepatic metastasis from functional carcinoid tumors.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  16. 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

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

    PubMed Central

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

    2014-01-01

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

  18. The effects of 5-fluorouracil on the proteome of colon cancer cells.

    PubMed

    Marin-Vicente, Consuelo; Lyutvinskiy, Yaroslav; Romans Fuertes, Patricia; Zubarev, Roman A; Visa, Neus

    2013-04-01

    The pyrimidine analogue 5-fluorouracil (5FU) is used as a treatment for solid tumors, but its mechanism of action is not fully understood. We have used mass spectrometry to study the mechanism of action of 5FU, and we have measured the effects of this drug on the composition and on the turnover of the proteome of RKO cancer cells. We have identified novel potential targets of 5FU that are affected after very short exposure times. We have also shown that 5FU has a massive effect on the proteins involved in RNA metabolism. After only 1 h of treatment, 5FU causes a post-transcriptional reduction in the abundance of components of the translation machinery (mostly ribosomal proteins), and this reduction is accompanied by a down-regulation of the translational capacity of the cells. Neither rapamycin nor raltitrexed, two drugs that also block cell proliferation, reduce the abundances of ribosomal proteins as 5FU does, which suggests that the down-regulation of ribosomal proteins is coupled to the mechanism of action of 5FU. Some of our observations conflict with previous reports based on RNA quantification. This shows how important it is to complement RNA profiling studies with analyses of drug toxicity at the protein level.

  19. [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.

  20. 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.

  1. 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.

  2. 5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Comprehensive Review of the Literature.

    PubMed

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

    2016-06-01

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

  3. miR-203 enhances chemosensitivity to 5-fluorouracil by targeting thymidylate synthase in colorectal cancer.

    PubMed

    Li, Tao; Gao, Feng; Zhang, Xi-Peng

    2015-02-01

    MicroRNAs (miRNAs) are a conserved class of small non-coding RNAs that play important roles in diverse biological processes, including chemoresistance. However, the molecular mechanism as to how miR-203 modulates the chemosensitivity to 5-fluorouracil (5-FU) in colorectal cancer is poorly known. In the present study, we found that miR-203 was downregulated in the 5-FU-resistant cell line LoVo/5-Fu, and was inversely correlated with the extent of 5-FU chemoresistance. Cytotoxicity assay showed that the inhibition of miR-203 expression enhanced 5-FU chemoresistance in colorectal cancer cells, while miR-203 overexpression increased 5-FU chemosensitivity. We then validated that thymidylate synthase (TYMS) was a direct target of miR-203 and miR-203 suppressed TYMS protein levels. Silencing of TYMS enhanced 5-FU chemosensitivity, similar to the roles of miR-203. Finally, we discovered that miR-203 increased the inhibitory effects of 5-FU on tumor growth in vivo. Overall, our data indicate that miR-203 enhances 5-FU chemosensitivity via the downregulation of TYMS in colorectal cancer and provide important insight into the mechanism of 5-FU resistance in colorectal cancer patients. More important, the present study suggests that miR-203 has the potential as a therapeutic strategy for 5-FU-resistant colorectal cancer.

  4. 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.

  5. 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

  6. Supercritical CO2 foamed polycaprolactone scaffolds for controlled delivery of 5-fluorouracil, nicotinamide and triflusal.

    PubMed

    Salerno, Aurelio; Saurina, Javier; Domingo, Concepción

    2015-12-30

    The manufacture of porous polycaprolactone (PCL) scaffolds containing three different drugs, namely 5-fluorouracil, nicotinamide and triflusal, was investigated in this work with the aim of obtaining bioactive systems with controlled drug delivery capabilities. The scaffolds were prepared by means of a supercritical CO2 (scCO2) foaming technique by optimizing the drug loading process. This was achieved by dissolving the drugs in organic solvents miscible with scCO2 and by mixing these drug/solvent solutions with PCL powder. The as prepared mixtures were further compressed to eliminate air bubbles and finally processed by the scCO2 foaming technique. ScCO2 saturation and foaming conditions were optimized to create the porosity within the samples and to allow for the concomitant removal of the organic solvents. Physical and chemical properties of porous scaffolds, as well as drug content and delivery profiles, were studied by HPLC. The results of this study demonstrated that the composition of the starting PCL/drug/solvent mixtures affected polymer crystallization, scaffold morphology and pore structure features. Furthermore, it was found that drug loading efficiency depended on both initial solution composition and drug solubility in scCO2. Nevertheless, in the case of highly scCO2-soluble drugs, such as triflusal, loading efficiency was improved by adding a proper amount of free drug inside of the pressure vessel. The drug delivery study indicated that release profiles depended mainly upon scaffolds composition and pore structure features. PMID:26570986

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2014-08-01

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

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

    PubMed

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

    2016-09-20

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed

    Jin, Qiao; Mitschang, Fabian; Agarwal, Seema

    2011-10-10

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

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

    PubMed

    Wu, Jing; Hu, Dong; Zhang, Rongbo

    2012-10-01

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

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

    PubMed

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

    2011-08-15

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

  15. 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.

  16. Clinical, biochemical and histological study of the effect of antimicrobial photodynamic therapy on oral mucositis induced by 5-fluorouracil in hamsters.

    PubMed

    Cruz, Érika de Paula da; Campos, Luana; Pereira, Filipi da Silva; Magliano, Gabriela Campos; Benites, Bernar Monteiro; Arana-Chavez, Victor Elias; Ballester, Rafael Yagüe; Simões, Alyne

    2015-06-01

    Oral mucositis (OM) is a debilitating side effect of chemotherapy, which can be relieved by phototherapy. Antimicrobial photodynamic therapy (aPDT) may be used for the treatment of OM, when infection is present. However, there are no studies showing that aPDT affects tissue repair process when used in the treatment of lesions caused by OM. This work aims to evaluate the effect of aPDT in healing OM induced by 5-Fluorouracil (5-FU). Two hundred forty-five hamsters were divided into two groups, control (C) and experimental, which were subdivided into 4 subgroups (Ch, ChP, ChL, aPDT). C group received only the vehicle of chemotherapy and anesthesia, whereas all animals of the experimental groups received anesthesia and chemotherapy agent 5-FU to induce OM. Ch group received no OM treatment; ChP group received an application of methylene blue (MB) 0.01%; ChL received irradiation with low-power-laser (LPL-660 nm/120 J /cm(2)/40 mW/4.4 J per point); and aPDT received MB and LPL irradiation. OM Clinical severity were daily assessed by a blinded examiner. The animals were sacrificed after 5, 7 and 10 days of experiment and their oral mucosa were removed for biochemical (enzymatic activity of SOD and catalase) and histological analyzes (light microscopy). After statistical analysis was performed, results showed that aPDT reduced the severity of OM on the tenth day of the experiment, when compared to the initial OM score (p < 0.05), as well as increased keratinization with organized collagen deposition in the lamina propria. In conclusion, aPDT can be safely used in animals with infected OM because it does not affect lesion-repairing processes. PMID:25612464

  17. 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.

  18. 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.

  19. Design, synthesis and biological evaluation of 5-fluorouracil-derived benzimidazoles as novel type of potential antimicrobial agents.

    PubMed

    Fang, Xue-Jie; Jeyakkumar, Ponmani; Avula, Srinivasa Rao; Zhou, Qian; Zhou, Cheng-He

    2016-06-01

    A series of 5-fluorouracil benzimidazoles as novel type of potential antimicrobial agents were designed and synthesized for the first time. Bioactive assay manifested that some of the prepared compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains in comparison with reference drugs norfloxacin, chloromycin and fluconazole. Noticeably, 3-fluorobenzyl benzimidazole derivative 5c gave remarkable antimicrobial activities against Saccharomyces cerevisiae, MRSA and Bacillus proteus with MIC values of 1, 2 and 4μg/mL, respectively. Experimental research revealed that compound 5c could effectively intercalate into calf thymus DNA to form compound 5c-DNA complex which might block DNA replication and thus exert antimicrobial activities. Molecular docking indicated that compound 5c should bind with DNA topoisomerase IA through three hydrogen bonds by the use of fluorine atom and oxygen atoms in 5-fluorouracil with the residue Lys 423. PMID:27117429

  20. 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.

  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. 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.

  3. 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.

  4. A 5-fluorouracil-loaded polydioxanone weft-knitted stent for the treatment of colorectal cancer.

    PubMed

    Li, Gang; Chen, Yufeng; Hu, Jun; Wu, Xiaojian; Hu, Junyan; He, Xiaowen; Li, Jiashen; Zhao, Zheng; Chen, Zexian; Li, Yuling; Hu, Hong; Li, Yi; Lan, Ping

    2013-12-01

    In-stents restenosis caused by tumour ingrowth is a major problem for patients undergoing stent displacement because the conventional stents often lack a sustained anti-tumour capability. The aim of this paper was to develop a weft-knitted polydioxanone stent which can slow release 5-fluorouracil (5-FU). In order to determine the most suitable drug concentration, the 5-FU safe concentration in vivo and appropriate loading percentage in the membranes were investigated, and then 5-FU-loaded poly-l-lactide membranes at concentration of 3.2%, 6.4% and 12.8% were coated onto the stent using electro-spinning method, respectively. The morphology, chemical structure and in vitro drug release property of the coating membranes were subsequently examined. Their anti-tumour activity and mechanism were assessed in vitro and in vivo using a human colorectal cancer cell line HCT-116 and tumour-bearing BALB/c nude mice. The half maximal inhibitory concentration (IC50) and the median lethal dose (LD50) demonstrated that the 6.4% and 12.8% membranes had better anti-tumour effects than pure 5-FU due to the sustainable drug releasing property of the coated membranes on the stent. The membranes possessing appropriate drug loading doses, such as 6.4% or 12.8% also provided better anti-in-stents restenosis effects than other groups tested. Therefore, it is concluded that the drug-loaded stents have great potential for the use in the treatment of intestinal cancers in the future.

  5. 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

  6. 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

  7. Incidence of delayed onset infection after trabeculectomy with adjunctive mitomycin C or 5-fluorouracil treatment

    PubMed Central

    Mochizuki, K.; Jikihara, S.; Ando, Y.; Hori, N.; Yamamoto, T.; Kitazawa, Y.

    1997-01-01

    AIMS/BACKGROUND—The introduction of the adjunctive use of antiproliferatives to trabeculectomy has greatly improved the success rate of this operation. Trabeculectomy with antiproliferative treatment, however, is usually associated with a cystic and thin walled filtering bleb, which may be more susceptible to infection. The objective of this study was to evaluate the incidence, clinical findings, and risk factors of delayed onset, bleb related infection after trabeculectomy with adjunctive mitomycin C (MMC) or 5-fluorouracil (5-FU) treatment.
METHODS—The records of 632 glaucoma patients who underwent 966 trabeculectomies, with and without the use of adjunctive MMC or 5-FU treatment, between January 1985 and February 1995 were analysed. The mean follow up period was 3.5 (2.4) years (range 0.1 to 11.2 years). The mean patient age was 54.8 (18.8) years (range 0 to 88 years).
RESULTS—Bleb related infection occurred in one of 76 trabeculectomies that did not receive antiproliferatives (1.3%), three of 228 treated with 5-FU (1.3%) trabeculectomies, and seven of 662 treated with MMC (1.1%). Five eyes developed blebitis; six eyes developed endophthalmitis. Bleb related infection developed an average of 3.1 (1.6) (range 0.4 to 6.0) years after trabeculectomy. All eyes had avascular or hypovascular blebs that were cystic in shape before infection and all eyes had reduced intraocular pressure. Early wound leaks and chronic, intermittent bleb leaks were identified to be risk factors for the bleb related infection.
CONCLUSION—The incidence of delayed onset, bleb related infection after trabeculectomy with antiproliferative treatment is similar to that after trabeculectomy without antiproliferatives.

 PMID:9486030

  8. Development of implants for sustained release of 5-fluorouracil using low molecular weight biodegradable polymers.

    PubMed

    Hanafy, A Fh; El-Egaky, A M; Mortada, S A; Molokhia, A M

    2009-12-01

    Anticancer drugs have poor efficacy especially against solid tumors that hinder drug penetration into the tumor. Thus, the dose has to be increased, but toxicity is a limiting factor. Local administration of a polymeric biodegradable poly-L-lactic acid (PLA) and poly(L-lactic acid-co-glycolic acid) copolymer (PLGA) implant containing an anticancer drug may be an acceptable method of concentrating the drug near the tumor site. This work sought to synthesize low molecular weight PLA and PLGA by polycondensation to yield polymers with good physical properties to make them suitable for use in implantable therapy. The synthesized polymers were characterized by determining their molecular weight, melting point, and percentage crystallinity using DSC. Fourier transformationinfra red spectrum (FT-IR), nuclear magnetic resonance (NMR) and specific optical rotation measurement were also used to characterize the synthesized polymers. Morphological characteristics were assessed using scanning electron microscopy (SEM). Implants were manufactured using compression (C) and injection molding (IM) and were loaded with 12 mg 5-fluorouracil (5-FU) per 120 mg implant. In vitro release patterns of all implants were assessed in phosphate buffered saline pH 7.4 (PBS 7.4) at 37°C. Factors affecting the release of 5-FU from implants were the polymer species, manufacturing technique, drug particle size, drug concentration, implant dimensions, and coating of the implant. Implants prepared with PLGA had significantly faster release of 5-FU than those prepared with PLA. Those manufactured using compression had significantly faster drug release than those prepared by injection molding. A PLA implant that contained 12 mg 5-FU/120 mg with a diameter of 0.3 cm and that was loaded with a drug particle size smaller than 150 μm and prepared by injection molding and then subsequently coated with PLA had the longest release period of 45 days.

  9. 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

  10. 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

  11. 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.

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

    PubMed

    Eftekhar, Ebrahim; Jaberie, Hajar; Naghibalhossaini, Fakhraddin

    2016-01-01

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

  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. 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.

  15. Molecular insights on the cyclic peptide nanotube-mediated transportation of antitumor drug 5-fluorouracil.

    PubMed

    Liu, Huifang; Chen, Jian; Shen, Qing; Fu, Wei; Wu, Wei

    2010-12-01

    Self-assembled cyclic peptide nanotubes (CPNs) show a potential use in drug delivery. In this study, the CPN composed of (Trp-D-Leu)(4)-Gln-D-Leu was synthesized and tested for the transport of the antitumor drug 5-fluorouracil (5-FU). CPN-mediated release of 5-FU from liposomes experimentally tested the transportation function of the synthetic CPNs. To explore the transportation mechanism of CPNs, computational studies have been performed on the CPN models stacked by 8 subunits, including conventional molecular dynamics (CMD) simulations, and steered molecular dynamics (SMD) simulations in the environment of hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer. Our CMD simulations demonstrated that the ortho-CPN is the most stable nanotube, in which the Gln residue is in the ortho-position relative to other residues. The calculated diffusion coefficient value for inner water molecules was 1.068 × 10(-5) cm(2)·s(-1), almost half that of the bulky water and 24 times faster than that of the typical gramicidin A channel. The CPN conserved its hollow structure along the 10 ns CMD simulations, with a tile angle of 50° relative to the normal of DMPC membrane. Results from SMD simulations showed that the 5-FU molecule was transported by hopping through different potential energy minima distributed along subunits, and finally exited the nanotube by escaping from the kink region at the last two subunits. The hopping of 5-FU was driven by switching from hydrophobic interactions between 5-FU and the interior wall of the nanotube to hydrogen bonding interactions of 5-FU with the backbone carbonyl group and amide group of ortho-CPN. The calculated binding free energy profile of 5-FU interacting with the CPN indicated that there was an energy well near the outer end of the nanotube.

  16. Novel 5-fluorouracil-resistant human esophageal squamous cell carcinoma cells with dihydropyrimidine dehydrogenase overexpression

    PubMed Central

    Kikuchi, Osamu; Ohashi, Shinya; Nakai, Yukie; Nakagawa, Shunsaku; Matsuoka, Kazuaki; Kobunai, Takashi; Takechi, Teiji; Amanuma, Yusuke; Yoshioka, Masahiro; Ida, Tomomi; Yamamoto, Yoshihiro; Okuno, Yasushi; Miyamoto, Shin’ichi; Nakagawa, Hiroshi; Matsubara, Kazuo; Chiba, Tsutomu; Muto, Manabu

    2015-01-01

    5-Fluorouracil (5-FU) is a key drug for the treatment of esophageal squamous cell carcinoma (ESCC); however, resistance to it remains a critical limitation to its clinical use. To clarify the mechanisms of 5-FU resistance of ESCC, we originally established 5-FU-resistant ESCC cells, TE-5R, by step-wise treatment with continuously increasing concentrations of 5-FU. The half maximal inhibitory concentration of 5-FU showed that TE-5R cells were 15.6-fold more resistant to 5-FU in comparison with parental TE-5 cells. TE-5R cells showed regional copy number amplification of chromosome 1p including the DPYD gene, as well as high mRNA and protein expressions of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU degradation. 5-FU treatment resulted in a significant decrease of the intracellular 5-FU concentration and increase of the concentration of α-fluoro-ureidopropionic acid (FUPA), a metabolite of 5-FU, in TE-5R compared with TE-5 cells in vitro. Conversely, gimeracil, a DPD inhibitor, markedly increased the intracellular 5-FU concentration, decreased the intracellular FUPA concentration, and attenuated 5-FU resistance of TE-5R cells. These results indicate that 5-FU resistance of TE-5R cells is due to the rapid degradation of 5-FU by DPD overexpression. The investigation of 5-FU-resistant ESCC with DPYD gene copy number amplification and consequent DPD overexpression may generate novel biological evidence to explore strategies against ESCC with 5-FU resistance. PMID:26396918

  17. 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.

  18. 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.

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

    PubMed Central

    2016-01-01

    Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination. PMID:27087736

  20. N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture

    PubMed Central

    Weiss, Jason T.; Fraser, Craig; Rubio-Ruiz, Belén; Myers, Samuel H.; Crispin, Richard; Dawson, John C.; Brunton, Valerie G.; Patton, E. Elizabeth; Carragher, Neil O.; Unciti-Broceta, Asier

    2014-01-01

    Palladium-activated prodrug therapy is an experimental therapeutic approach that relies on the unique chemical properties and biocompatibility of heterogeneous palladium catalysis to enable the spatially-controlled in vivo conversion of a biochemically-stable prodrug into its active form. This strategy, which would allow inducing local activation of systemically administered drug precursors by mediation of an implantable activating device made of Pd0, has been proposed by our group as a way to reach therapeutic levels of the active drug in the affected tissue/organ while reducing its systemic toxicity. In the seminal study of such an approach, we reported that propargylation of the N1 position of 5-fluorouracil suppressed the drug's cytotoxic properties, showed high stability in cell culture and facilitated the bioorthogonal restoration of the drug's pharmacological activity in the presence of extracellular Pd0-functionalized resins. To provide additional insight on the properties of this system, we have investigated different N1-alkynyl derivatives of 5-fluorouracil and shown that the presence of substituents near the triple bond influence negatively on its sensitivity to palladium catalysis under biocompatible conditions. Comparative studies of the N1- vs. the N3-propargyl derivatives of 5-fluorouracil revealed that masking each or both positions equally led to inactive derivatives (>200-fold reduction of cytotoxicity relative to the unmodified drug), whereas the depropargylation process occurred faster at the N1 position than at the N3, thus resulting in greater toxigenic properties in cancer cell culture. PMID:25121087

  1. 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

  2. Clinical evolution of cystic teratoma during treatment with combination chemotherapy.

    PubMed

    Taylor, H G; Tell, D T; Skoog, S J; McLeod, D G

    1986-09-01

    Progressive, cystic tumor enlargement in the abdomen developed in a patient with teratocarcinoma during treatment with systemic chemotherapy. Tumor markers were elevated in the cyst fluid and negative in serum. Further, the patient underwent a successful surgical debulking of large amounts of cystic teratoma.

  3. 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.

  4. High pathologic complete remission rate from induction docetaxel, platinum and fluorouracil (DCF) combination chemotherapy for locally advanced esophageal and junctional cancer.

    PubMed

    Noronha, Vanita; Joshi, Amit; Jandyal, Sunny; Jambhekar, Nirmala; Prabhash, Kumar

    2014-09-01

    Adding docetaxel to the cisplatin/5-fluorouracil induction regimen for locally advanced esophageal and GEJ cancer may increase the pathologic complete remission (pCR) rate, leading to an improved outcome. Institutional ethics committee approved the protocol of retrospective analysis of patients with locally advanced esophageal and GEJ carcinoma, who received 2-3 cycles of docetaxel, cisplatin and 5-fluorouracil (DCF) induction chemotherapy with primary growth factors and prophylactic antibiotics. Following chemotherapy, a restaging scan was performed. If disease was deemed resectable, surgery was performed. Between February 2010 and October 2013, 31 patients received induction DCF. Ninety-four percent patients had squamous histology. Response rate was 81 %: complete remission (CR)-23 % and partial remission-58 %. Eighty-seven percent patients underwent surgery; R0 resection rate was 67 %. pCR occurred in 26 %. Common grade 3/4 toxicities included anemia-23 %, neutropenia-42 %, febrile neutropenia-39 %, diarrhea-39 %, hyponatremia-55 % and hypokalemia-39 %. There were no toxic deaths. At a median follow-up of 34 months (95 % CI 31.3-36.6), estimated median progression-free survival (PFS) was 27 months (95 % CI 11-39) and the overall survival (OS) at 1 year, 2 years and 3 years was 80, 68 and 55 %, respectively. Patients who attained pCR had a significant longer PFS and OS; median PFS and OS were not reached in patients with pCR and were 15 months (95 %CI 8.4-21.5 months), P = 0.012 and 25 months (95 %CI 10.3-39.7), P = 0.023, respectively, in patients who did not attain a pCR. DCF induction chemotherapy leads to pCR of 26 %, which rivals that obtained from chemoradiotherapy. Toxicity is substantial but manageable with adequate supportive care.

  5. [Complete resection for giant thymic carcinoma after simultaneous combination chemotherapy].

    PubMed

    Ueki, Tomoyuki; Ueshima, Y; Kurioka, H; Enoki, Y; Hosokawa, Y

    2005-04-01

    A 19-year-old man visited our hospital complaining of dyspnea. Chest X-ray and computed tomography (CT) showed a huge mass in the right anterior mediastinum. We diagnosed this as invasive thymoma by microscopic examination of specimens obtained by echo-guided needle biopsy. The patient underwent 6 courses chemotherapy [1st course : carboplatin (CBDCA) + doxorubicin hydrochloride (DXR) + vincristine sulfate (VCR) + cyclophosphamide (CPA), 2nd, 3rd-6th course : cisplatin (CDDP) + ADM + VCR + CPA]. At achievement of partial response (the reduction rate of the tumor size : 91.4%), the tumor was completely resected. The pathological examination of the resected specimens yielded a diagnosis of large cell carcinoma. Preoperative chemotherapy with ADOC regimen may be effective in advanced thymic carcinoma.

  6. 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

  7. 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

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

    PubMed

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

    2015-06-01

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

  9. 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

  10. 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.

  11. [Chemotherapy of yolk sac tumor heterotransplanted to nude mice (author's transl)].

    PubMed

    Sawada, M; Hayakawa, K; Matsui, Y; Nishiura, H; Okudaira, Y

    1980-10-01

    Chemotherapy of yolk sac tumor heterotransplanted to nude mice was studied. 1. Yolk sac tumor of the ovary taken from a 38-year -old woman was transplanted to BALB/c female nude mice. The transplantable tumor cells produce a solid tumor, designated as YST-1 tumor. The YST-1 tumor cells preserve the histological appearance of a human yolk sac tumor and produce x-fetoprotein. The tumors on passage 8 were used for experimental chemotherapy. 2. Anticancer drugs clinically known to be effective for ovarian cancer, such as Adriamycin, Carbazilquinone, 5-Fluorouracil, Cyclophosphamide, Mitomycin C, Chromomycin A3, Vinblastine and Bleomycin were administered intraperitoneally to tumor-bearing nude mice. Tumor size was measured two or three times a week during the course of experiments. Therapeutic effects were evaluated by tumor size and relative tumor size before and after experiments. Among these drugs, Vinblastine and Bleomycin combination showed the significant effect arresting the growth of YST-1 tumor.

  12. Conversion Chemotherapy for Technically Unresectable Colorectal Liver Metastases: A Retrospective, STROBE-Compliant, Single-Center Study Comparing Chemotherapy Alone and Combination Chemotherapy With Cetuximab or Bevacizumab.

    PubMed

    Basso, Michele; Dadduzio, Vincenzo; Ardito, Francesco; Lombardi, Pasquale; Strippoli, Antonia; Vellone, Maria; Orlandi, Armando; Rossi, Sabrina; Cerchiaro, Eleonora; Cassano, Alessandra; Giuliante, Felice; Barone, Carlo

    2016-05-01

    The response rate of patients with unresectable liver-limited metastases of colorectal cancer can be improved by converting inoperable disease to operable disease. However, the benefits of conversion chemotherapy for survival are still controversial.Patients considered to have technically inoperable disease by a multidisciplinary team were retrospectively analyzed. Patients were stratified based on the treatment they received, into the chemotherapy only (G1), chemotherapy plus bevacizumab (G2), or chemotherapy plus cetuximab (G3) groups. The primary endpoint was the resection rate. The secondary endpoint was the overall survival (OS), according to both the treatment received and liver surgery status.In total, 104 patients were included: 30 in the G1, 39 in the G2, and 35 in the G3 groups. All G3 patients had the wild-type KRAS exon 2. The surgical resection rates for patients in the G1, G2, and G3 groups were 43.3% (13/30), 30.7% (12/39), and 51.4% (18/35), respectively. Disease-free survival did not show significant differences among the 3 groups. The median OS was 35.2 months in the G1, 28.8 months in the G2, and 42.1 months in the G3 (P = 0.25) groups. The OS was significantly higher in patients who underwent surgical resection than those who did not. The median OS was 28.4 months in patients who did not undergo resection, whereas it had not been reached after a median follow-up period of 37.5 months for patients who underwent surgical resection (events: 21/43).Our data confirmed that the conversion of initially inoperable disease to operable disease conferred a survival benefit, even in patients who relapsed after surgery. The addition of cetuximab to chemotherapy improved the objective response and resection rates, conferring a potential survival benefit even in patients whose diseases were not converted to operable disease, compared to chemotherapy alone or in combination with bevacizumab. PMID:27196492

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

    PubMed Central

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

    2014-01-01

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

  14. A new optimization based approach to experimental combination chemotherapy.

    PubMed

    Pereira, F L; Pedreira, C E; de Sousa, J B

    1995-01-01

    A new approach towards the design of optimal multiple drug experimental cancer chemotherapy is presented. Once an adequate model is specified, an optimization procedure is used in order to achieve an optimal compromise between after treatment tumor size and toxic effects on healthy tissues. In our approach we consider a model including cancer cell population growth and pharmacokinetic dynamics. These elements of the model are essential in order to allow less empirical relationships between multiple drug delivery policies, and their effects on cancer and normal cells. The desired multiple drug dosage schedule is computed by minimizing a customizable cost function subject to dynamic constraints expressed by the model. However, this additional dynamic wealth increases the complexity of the problem which, in general, cannot be solved in a closed form. Therefore, we propose an iterative optimization algorithm of the projected gradient type where the Maximum Principle of Pontryagin is used to select the optimal control policy.

  15. 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.

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

    PubMed Central

    Spencer, Drew A; Young, Jacob S; Kanojia, Deepak; Kim, Julius W; Polster, Sean P; Murphy, Jason P; Lesniak, Maciej S

    2015-01-01

    Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future. PMID:25996044

  17. 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

  18. Prognostic significance of p16 in locoregionally advanced head and neck cancer treated with concurrent 5-fluorouracil, hydroxyurea, cetuximab and intensity-modulated radiation therapy.

    PubMed

    Tong, Charles C L; Lau, K H Vincent; Rivera, Michael; Cannan, David; Aguirre-Ghiso, Julio; Sikora, Andrew G; Gupta, Vishal; Forsythe, Kevin; Ko, Eric C; Misiukiewicz, Krzysztof; Gurudutt, Vivek; Teng, Marita S; Packer, Stuart H; Genden, Eric M; Kao, Johnny

    2012-05-01

    A phase II trial was conducted to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) into a well-described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen. Patients with stage IVa-IVb or high-risk stage III squamous cell carcinomas were enrolled. Prior organ-conserving surgery or induction chemotherapy was allowed. IMRT was administered in 1.5 Gy fractions twice daily on days 1-5 of weeks 1, 3, 5, 7±9 for a total dose of 60-73.5 Gy. Concurrent systemic therapy consisted of 5-FU (600 mg/m2), HU (500 mg BID) and cetuximab (250 mg/m2). p16INK4A expression was assessed by immunohistochemistry. From January 2007 to January 2010, 65 patients (61 with stage IV disease; 31 with oropharyngeal primaries) were enrolled. At a median follow-up of 28 months, 2-year locoregional control, distant control, progression-free survival, event-free survival and overall survival were 79, 83, 72, 63 and 80%, respectively. In 48 patients with available pre-treatment tissue, p16 overexpression was associated with significantly increased distant control (p=0.03), progression-free survival (p=0.02), event-free survival (p=0.007) and overall survival (p=0.03). The most common grade 3-4 toxicities were mucositis (46%), leukopenia (18%), anemia (18%) and dermatitis (17%). Concurrent 5-FU, HU, cetuximab and SIB-IMRT is a highly active regimen, particularly in patients with p16-positive disease. PMID:22322320

  19. 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 Central

    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. PMID:23646193

  20. 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.

  1. 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

  2. Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha

    PubMed Central

    Braybrooke, J P; Propper, D J; O’Byrne, K J; Koukourakis, M I; Patterson, A V; Houlbrook, S; Love, S D; Varcoe, S; Taylor, M; Ganesan, T S; Talbot, D C; Harris, A L

    2000-01-01

    Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNα), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m–2, 9 MIU m–2and 18 MIUm–2. IFNα was administered on day 0 cycle two, day –1 and day 0 cycle three and day –2, day –1 and day 0 cycle four. A fourth cohort was treated with IFNα 9 MIU m–2three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNα. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNα led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P = 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNα. A single dose of IFNα as low as 3 MIU m–2can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNα for biomodulation of 5-FU. © 2000 Cancer Research Campaign PMID:10901374

  3. The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil

    PubMed Central

    2011-01-01

    Background Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (β-F1-ATPase). The bioenergetic signature is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the bioenergetic signature of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti-metabolite, 5-fluorouracil (5-FU). Methods The bioenergetic signature of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the bioenergetic signature and the cell death response. In vivo tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells. Results We demonstrate that the bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable. Conclusions Overall, we suggest that the determination of the bioenergetic

  4. 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.

  5. The Effect of Analogues of 1α,25-Dihydroxyvitamin D2 on the Regrowth and Gene Expression of Human Colon Cancer Cells Refractory to 5-Fluorouracil

    PubMed Central

    Neska, Jacek; Swoboda, Paweł; Przybyszewska, Małgorzata; Kotlarz, Agnieszka; Bolla, Narasimha Rao; Miłoszewska, Joanna; Grygorowicz, Monika Anna; Kutner, Andrzej; Markowicz, Sergiusz

    2016-01-01

    This study aimed to evaluate the capacity of hypocalcemic analogues of 1α,25-dihydroxyvitamin D2 (1,25D2) and 1α,25-dihydroxyvitamin D3 (1,25D3) to inhibit regrowth and regulate the stemness-related gene expression in colon cancer cells undergoing renewal after exposure to 5-fluorouracil (5-FU). All of the tested analogues of 1,25D2 equally potently decreased the clonogenicity and the proliferative activity of HT-29 cells which survived the exposure to 5-FU, but differently regulated gene expression of these cells during their renewal. 1,25D2 and analogues (PRI-1907 and PRI-1917), as well as 1,25D3 and analogue PRI-2191, decreased the relative expression level of several stemness-related genes, such as NANOG, OCT3/4, PROM1, SOX2, ALDHA1, CXCR4, in HT-29/5-FU cells during their renewal, in comparison to untreated HT-29/5-FU cells. The other 1,25D2 analogues (PRI-1906 and PRI-1916) were not capable of downregulating the expression of these stemness-related genes as the analogues PRI-1907 and PRI-1917 did. All of the tested vitamin D analogues upregulated CDH1, the gene encoding E-cadherin associated with epithelial phenotype. Out of the series of analogues studied, side-chain branched analogues of 1,25D2 (PRI-1907, PRI-1917) and the analogue of 1,25D3 (PRI-2191) might be used to target cancer cells with stem-like phenotypes that survive conventional chemotherapy. PMID:27314328

  6. Nobiletin induces apoptosis and potentiates the effects of the anticancer drug 5-fluorouracil in p53-mutated SNU-16 human gastric cancer cells.

    PubMed

    Moon, Jeong Yong; Cho, Moonjae; Ahn, Kwang Seok; Cho, Somi Kim

    2013-01-01

    Nobiletin is a typical polymethoxyl flavone from citrus fruits that has anticancer properties, but the molecular mechanism of its inhibitory effects on the growth of p53-mutated SNU-16 human gastric cancer cells has not been explored. In this study, nobiletin was found to be effective at inhibiting the proliferation of SNU-16 cells than other flavonoids. Nobiletin induced the death of SNU-16 cells through apoptosis, as evidenced by the increased cell population in the sub-G1 phase, the appearance of fragmented nuclei, an increase in the Bax/Bcl-2 ratio, the proteolytic activation of caspase-9, an increase in caspase-3 activity, and the degradation of poly(ADP-ribose) polymerase (PARP) protein. We found that the combination of nobiletin plus the anticancer drug 5-fluorouracil (5-FU) reduced the viability of SNU-16 cells in a concentration-dependent manner and exhibited a synergistic anticancer effect (combination index = 0.38) when 5-FU was used at relatively low concentrations. The expression of p53 protein increased after treatment with 5-FU, but not nobiletin, whereas the expression of p21 (WAF1/CIP1) protein increased after treatment with nobiletin, but not 5-FU. The cellular responses to nobiletin and 5-FU occurred through different pathways. The results of this study suggest the potential application of nobiletin to the enhancement of 5-FU efficiency in p53 mutant tumors.

  7. Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil

    PubMed Central

    Dobritzsch, Doreen; Schneider, Gunter; Schnackerz, Klaus D.; Lindqvist, Ylva

    2001-01-01

    Dihydropyrimidine dehydrogenase catalyzes the first step in pyrimidine degradation: the NADPH-dependent reduction of uracil and thymine to the corresponding 5,6-dihydropyrimidines. Its controlled inhibition has become an adjunct target for cancer therapy, since the enzyme is also responsible for the rapid breakdown of the chemotherapeutic drug 5-fluorouracil. The crystal structure of the homodimeric pig liver enzyme (2× 111 kDa) determined at 1.9 Å resolution reveals a highly modular subunit organization, consisting of five domains with different folds. Dihydropyrimidine dehydrogenase contains two FAD, two FMN and eight [4Fe–4S] clusters, arranged in two electron transfer chains that pass the dimer interface twice. Two of the Fe–S clusters show a hitherto unobserved coordination involving a glutamine residue. The ternary complex of an inactive mutant of the enzyme with bound NADPH and 5-fluorouracil reveals the architecture of the substrate-binding sites and residues responsible for recognition and binding of the drug. PMID:11179210

  8. 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

  9. 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

    2013-06-01

    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.

  10. 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.

  11. 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

  12. Combination chemotherapy of Echinococcus granulosus--in vitro studies.

    PubMed

    Taylor, D H; Morris, D L; Richards, K S

    1988-01-01

    Both benzimidazole carbamates and isoquinoline compounds have activity against protoscoleces of Echinococcus granulosus in culture in vitro; combinations of albendazole sulphoxide and praziquantel are more effective than either agent alone. PMID:3188154

  13. Development of a 5-fluorouracil-loaded PLGA microsphere delivery system by a solid-in-oil-in-hydrophilic oil (S/O/hO) novel method for the treatment of tumors.

    PubMed

    Lin, Qing; Cai, Yunpeng; Yuan, Minglu; Ma, Lin; Qiu, Mingfeng; Su, Jing

    2014-12-01

    Tumor treatment requires a long-term regimen of chemotherapy, and both surgical tumor resection and radiation therapy are also used. The present study aimed to develop a novel method for 5-fluorouracil (5-FU)-loaded microspheres which enhance the therapeutic effects of chemotherapy, the quality of life of patients and reduce chemotherapy systemic side-effects. The preparation of a 5-FU microsphere delivery system by a solid-in-oil-in-hydrophilic oil (S/O/hO) novel method was carried out and then in vitro and in vivo evaluation of the 5-FU-microsphere delivery system was conducted. The 5-FU microsphere delivery system prepared had sustained-release function and achieved local treatment efficacy for tumors. The encapsulation efficiency of the 5-FU microsphere delivery system was >90% [better than the fabrication method using water-in-oil-in-water (W/O/W)]. The drug release profile from the 5-FU-loaded sustained-release microsphere delivery system matched the pseudo zero-order equation for 30 days in vitro. The plasma concentration of 5-FU was higher than the water solution by subcutaneous injection. The tumor growth rate of rabbits using the 5-FU microsphere delivery system was much lower than the rate in rabbit using a subcutaneous injection of 5-FU water solution. The 5-FU-loaded sustained-release microspheres using the novel method (S/O/hO) is a potential and effective method with which to inhibit tumor growth.

  14. 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.

  15. Treatment of advanced pancreatic cancer with 5-fluorouracil, folinic acid and interferon alpha-2A: results of a phase II trial.

    PubMed Central

    Bernhard, H.; Jäger-Arand, E.; Bernhard, G.; Heike, M.; Klein, O.; Riemann, J. F.; Meyer zum Büschenfelde, K. H.; Dippold, W.; Knuth, A.

    1995-01-01

    Interferon alpha-2a (IFN-alpha) and folinic acid (FA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. A phase II study was initiated to evaluate the effect of a combination of 5-FU/FA/IFN-alpha in patients with advanced pancreatic cancer. Sixty previously untreated patients with advanced adenocarcinoma of the pancreas were treated with 500 mg m-2 FU via an intravenous bolus 1 h after the initiation of a 2 h infusion of 500 mg m-2 FA. Before starting the FA infusion, 6 million units (MU) of IFN-alpha was administered subcutaneously. The treatment was repeated once a week. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR) and 28 (49%) no change of disease (NC). Thirteen patients (23%) had progressive disease (PD). The median survival time was 10 months for all patients, 22 months for patients with partial remission and 5 months for patients with progressive disease. Many patients with tumour-related pain whose tumours were affected in terms of PR, MR, NC were free of pain during treatment with this regimen (22/36 patients). The common toxicities observed were fever (56%), nausea (37%) and diarrhoea (33%). These data suggest that biochemical modulation of 5-FU with FA and IFN-alpha has some positive effects in the treatment of pancreatic cancer of moderate toxicity. PMID:7819023

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

    PubMed

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

    1991-07-01

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

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

    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.

  18. A Phase II Trial of Induction nab-Paclitaxel and Cetuximab Given With Cisplatin and 5-Fluorouracil Followed by Concurrent Cisplatin and Radiation for Locally Advanced Squamous Cell Carcinoma of the Head and Neck

    PubMed Central

    Adkins, Douglas; Ley, Jessica; Trinkaus, Kathryn; Thorstad, Wade; Lewis, James; Wildes, Tanya; Siegel, Barry A.; Dehdashti, Farrokh; Gay, Hiram; Mehan, Paul; Nussenbaum, Brian

    2013-01-01

    Background Complete Response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with cisPlatin and 5-Fluorouracil (5-FU)[PF] is a favorable predictive factor for overall survival and disease-control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20–30%. We evaluated the efficacy and feasibility of induction nAb-paclitaxel and Cetuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase II trial. Methods Patients with HNSCC were treated with ACPF (nab-paclitaxel 100 mg/m2/week; cetuximab 250 mg/m2/week; cisplatin 75 mg/m2 Day 1; 5-fluorouracil 750 mg/m2/day Days 1–3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m2 on days 1,22 and 43 of RT). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint. Results Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty-nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive radiation therapy (RT) per protocol and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2-year overall and progression-free survivals were 84% and 65%, respectively. Conclusion Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted. PMID:22991252

  19. 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,

  20. Combinational strategies of metformin and chemotherapy in cancers.

    PubMed

    Zhang, Hui-Hui; Guo, Xiu-Li

    2016-07-01

    Chemotherapeutic regimens are the most common treatment to inhibit tumor growth, but there is great variability in clinical responses of cancer patients; cancer cells often develop resistance to chemotherapeutics which results in tumor recurrence and further progression. Metformin, an extensively prescribed and well-tolerated first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer adjuvant drug combined with chemotherapeutic drugs to improve treatment efficacy and lower doses. In this review, we summarized the molecular mechanisms underlying anticancer effects of metformin, which included insulin- and AMPK-dependent effects, selectively targeting cancer stem cells, reversing multidrug resistance, inhibition of the tumor metastasis and described the antineoplastic effects of metformin combined with chemotherapeutic agents in digestive system cancers (colorectal, gastric, hepatic and pancreatic cancer), reproductive system cancers (ovarian and endometrial cancer), prostate cancer, breast cancer, lung cancer, etc. Moreover, the clinical trials regarding metformin in combination of chemotherapeutic drugs were presented and the clinical obstacle or limitation related to the potential role of metformin in cancer treatment was also discussed in this review. PMID:27118574

  1. 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.

  2. 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.

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

    PubMed Central

    Rashad, Mohammad A

    2013-01-01

    Purpose To evaluate the success rate of a modified bleb needling technique in eyes with previous glaucoma surgery that had elevated intraocular pressure. Methods A retrospective study of 24 eyes of 24 patients that underwent repeated bleb needling performed for failing and failed blebs on slit lamp with 5-fluorouracil (5-FU) injections on demand. This was performed after gonioscopic examination to define levels of filtration block. Results There was significant reduction of mean IOP from 36.91 mmHg to 14.73 mmHg at the final follow-up (P < 0.001). The overall success rate was 92%. Conclusion Repeated needling with adjunctive 5-FU proved a highly effective, safe alternative to revive filtration surgery rather than another medication or surgery. PMID:23293510

  4. Study on the role of 5-fluorouracil in the polymerization of butylcyanoacrylate during the formation of nanoparticles.

    PubMed

    Simeonova, M; Velichkova, R; Ivanova, G; Enchev, V; Abrahams, I

    2004-01-01

    The possible involvement of 5-fluorouracil (5FU) in the initiation process of the polymerization of n-butylcyanoacrylate monomer during nanoparticle formation was investigated. 5FU in acidic solution (pH 2-3) may interfere in the initiation process through its amino groups via the formation of zwitterions. The proposed zwitterionic mechanism of initiation was supported by the molecular weight profiles of the polymer, determined by gel permeation chromatography, and the covalent linkage of the cytostatic to the main polymer chain. H NMR analyses clearly demonstrated that a significant fraction of 5FU was covalently bonded to the poly(butylcyanoacrylate) chains through its amino groups preferentially through one of the two nitrogen atoms. In vitro release study performed shows that the investigated 5FU-loaded PBCN are suitable for sustaining delivery of 5FU.

  5. Colon Cancer Cells Gene Expression Signature As Response to 5- Fluorouracil, Oxaliplatin, and Folinic Acid Treatment.

    PubMed

    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:27445811

  6. 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

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

    PubMed Central

    Aitini, Enrico; Rossi, Anna; Morselli, Patrizia; Vivorio, Beatrice; Bruschi, Alessandra; Bottura, Chiara; Colombo, Giorgio L

    2012-01-01

    Background Colorectal cancer is one of the most frequent and lethal cancers. The aim of this study was to analyze the costs relating to treatment of colorectal cancer between Xelox and Folfox-4 at a regional level according to the clinical experience at an Italian hospital in Lombardy. Methods A cost analysis was carried out regarding resource consumption by patients suffering from colorectal cancer based on data collected over a 12-month period between 2010 and 2011. The analysis involved 40 patients who attended the Department of Medical Oncology and Hematology at Carlo Poma Hospital to undergo adjuvant therapy for colorectal cancer. A chart was created for each patient containing their medical history, their pharmacological therapy indicating the number and duration of chemotherapy cycles, dose in mg administered for each cycle, number of day hospital visits for each cycle, number of days spent in hospital to position the central vein catheter, type of infusion pump used, any subsequent supportive therapy, and any side effects and outpatient visits connected with side effects. Results The cost analysis shows the savings involved in using Xelox for a single cycle of treatment, ie, approximately €1414.00 per patient (53% compared with Folfox-4). For each single cycle of treatment, the savings generated by using capecitabine compared with 5-FU can be attributed mostly to the fact that oral administration of chemotherapy requires fewer resources and does not require use of a central vein catheter (approximately 70% of overall cost) which amply compensates for the higher cost of capecitabine compared with 5-FU-LV. Sensibility analysis confirms the results of the base-case scenario. Conclusion The results of our study indicate that infusion via a central vein catheter represents a significant cost, and that substitution with an oral therapy, even when associated with drugs administered intravenously, represents a consistent saving of hospital resources. PMID

  8. 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

  9. Outcome of Neoadjuvant Chemotherapy on Local Recurrence and Distant Metastasis of Oral Squamous Cell Carcinoma: A Retrospective Study

    PubMed Central

    Tabrizi, Reza; Garajei, Ata; Shafie, Ehsan; Jamshidi, Samira

    2016-01-01

    Statement of the Problem Neoadjuvant chemotherapy (NCH) is controversial in the treatment of oral squamous cell carcinoma (OSCC). Purpose The aim of this study was to evaluate the efficacy of NCH on OSCC prognosis. Materials and Method In this retrospective cohort study, 94 patients were studied in two groups. The patients in group 1 received NCH before the surgery, and those in group 2 underwent resection without any chemotherapy prior to surgery. The employed NCH agents consisted of cisplatin in combination with 5-fluorouracil in two treatment courses. Tumor size, lymph node involvement, age, and follow-up time were considered as variable factors of the study. Local recurrence (LR) and distant metastasis (DM) were outcomes of the study. Results Comparison of LR and DM in various tumor sizes demonstrated no significant difference between the two groups (p> 0.05). Analysis of the data did not show any statistically significant difference between the groups for LR in subjects with N0, N1 and N2. Each one-year increase in age was associated with 10% increase in the hazard ratio (HR) (HR distance metastasis Y/N = 1.10, p= 0.05). In the same analysis, when considering LR as a dependent factor, LR risk in N2 was 3 times more than in N1 (p= 0.02). LR risk in N3 was 5 times more than in N1 [HR local recurrence (p= 0.006). Conclusion Based on our results, neoadjuvant chemotherapy with combination of cisplatin and 5-fluorouracil may not improve prognosis of OSCC. However, further studies are suggested to assess other neoadjuvant chemotherapy protocols in OSCC patients.

  10. Outcome of Neoadjuvant Chemotherapy on Local Recurrence and Distant Metastasis of Oral Squamous Cell Carcinoma: A Retrospective Study

    PubMed Central

    Tabrizi, Reza; Garajei, Ata; Shafie, Ehsan; Jamshidi, Samira

    2016-01-01

    Statement of the Problem Neoadjuvant chemotherapy (NCH) is controversial in the treatment of oral squamous cell carcinoma (OSCC). Purpose The aim of this study was to evaluate the efficacy of NCH on OSCC prognosis. Materials and Method In this retrospective cohort study, 94 patients were studied in two groups. The patients in group 1 received NCH before the surgery, and those in group 2 underwent resection without any chemotherapy prior to surgery. The employed NCH agents consisted of cisplatin in combination with 5-fluorouracil in two treatment courses. Tumor size, lymph node involvement, age, and follow-up time were considered as variable factors of the study. Local recurrence (LR) and distant metastasis (DM) were outcomes of the study. Results Comparison of LR and DM in various tumor sizes demonstrated no significant difference between the two groups (p> 0.05). Analysis of the data did not show any statistically significant difference between the groups for LR in subjects with N0, N1 and N2. Each one-year increase in age was associated with 10% increase in the hazard ratio (HR) (HR distance metastasis Y/N = 1.10, p= 0.05). In the same analysis, when considering LR as a dependent factor, LR risk in N2 was 3 times more than in N1 (p= 0.02). LR risk in N3 was 5 times more than in N1 [HR local recurrence (p= 0.006). Conclusion Based on our results, neoadjuvant chemotherapy with combination of cisplatin and 5-fluorouracil may not improve prognosis of OSCC. However, further studies are suggested to assess other neoadjuvant chemotherapy protocols in OSCC patients. PMID:27602396

  11. Synergistic chemotherapy by combined moderate hyperthermia and photochemical internalization.

    PubMed

    Christie, Catherine; Molina, Stephanie; Gonzales, Jonathan; Berg, Kristian; Nair, Rohit Kumar; Huynh, Khoi; Madsen, Steen J; Hirschberg, Henry

    2016-04-01

    Combination therapies of photochemical internalization (PCI) and moderate hyperthermia (MHT) were investigated in an in vitro system consisting of human and rat glioma spheroids. PCI using the amphiphilic photosensitizer, AlPcS2a and two anti cancer agents BLM or 5-FU were used. Spheroids were irradiated with λ = 670 nm laser light in an incubator at temperatures ranging from 37 to 44°C. For each temperature investigated, spheroids were divided into 4 groups: control, drug-only, photodynamic therapy (PDT), and PCI. PDT and PCI spheroids were exposed to radiant exposures ranging from 0.3 to 2.5 J cm(-2) using an irradiance of 5 mW cm(-2). Toxicity was evaluated from spheroid growth kinetics. The combination of PCI and MHT resulted in significant increases in BLM efficacy at 44°C for both cell line derived spheroids compared to controls at 37°C over the range of radiant exposures examined. 5-FU PCI was ineffective for the human cell line at both 37 and 44°C. PMID:27446650

  12. Synergistic chemotherapy by combined moderate hyperthermia and photochemical internalization

    PubMed Central

    Christie, Catherine; Molina, Stephanie; Gonzales, Jonathan; Berg, Kristian; Nair, Rohit Kumar; Huynh, Khoi; Madsen, Steen J.; Hirschberg, Henry

    2016-01-01

    Combination therapies of photochemical internalization (PCI) and moderate hyperthermia (MHT) were investigated in an in vitro system consisting of human and rat glioma spheroids. PCI using the amphiphilic photosensitizer, AlPcS2a and two anti cancer agents BLM or 5-FU were used. Spheroids were irradiated with λ = 670 nm laser light in an incubator at temperatures ranging from 37 to 44°C. For each temperature investigated, spheroids were divided into 4 groups: control, drug-only, photodynamic therapy (PDT), and PCI. PDT and PCI spheroids were exposed to radiant exposures ranging from 0.3 to 2.5 J cm−2 using an irradiance of 5 mW cm−2. Toxicity was evaluated from spheroid growth kinetics. The combination of PCI and MHT resulted in significant increases in BLM efficacy at 44°C for both cell line derived spheroids compared to controls at 37°C over the range of radiant exposures examined. 5-FU PCI was ineffective for the human cell line at both 37 and 44°C. PMID:27446650

  13. 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.

  14. 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

  15. 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%.

  16. Comprehensive Assessment of Host Responses to 5-Fluorouracil-Induced Oral Mucositis through Transcriptomic Analysis

    PubMed Central

    Ho, Tin-Yun; Wu, Ching-Zong; Hong, Hsiang-Hsi; Huang, Yi-Fang

    2015-01-01

    Background Chemotherapy plays an important role in current cancer therapy; however, several problems remain unsolved on the issue of host-therapeutics interaction. The purpose of this study was to investigate the host responses after 5-flurouracil (5-FU) administration and to find the target genes and their relationship with other cytokines in the 5-FU-induced oral mucositis (OM) mouse model through transcriptomic analysis. Materials and Methods Thirty-six 6 to 8 week-old male BALB/c mice were randomly divided into the control group and 5-FU-treated group. In the 5-FU group, mice received 5-FU (100 mg/kg, intraperitoneally) on day 1, day 8, day 15, day 22, and day 29, respectively. We evaluated the oral mucosal change under macroanalysis and histological examination at indicated periods, and then applied transcriptomic analysis of gene expression profile and Immunohistochemical stain to identify the target molecules related to 5-FU-induced OM. Results The most prominent histological change in this model was observed in the fifth week. The gene expression of Bone gamma-carboxyglutamate protein, related sequence 1 (Bglap-rs1) (–12.69-fold) and Chitinase 3-like 4 (Chi3l4) (–6.35-fold) were significantly down-regulated in this phase. The quantitative real-time PCR results also revealed the expression levels were 0.62-fold in Bglap-rs1 and 0.13-fold in Chi3l4 compared with the control group. Immunohistochemical stain showed significant expression of cluster of differentiation 11b (p<0.01), interleukin-1β (p<0.001) and tumor necrosis factor-α (p<0.05), and down-regulation of Bglap-rs1 (p<0.01) compared with the control group. By Kyoto Encyclopedia of Genes and Genomes pathway analysis, there were twenty-three pathways significantly participated in this study (p<0.05). Conclusions Through comprehensively transcriptomic analysis and IHC stain, we discovered several valuable pathways, verified the main pro-inflammatory cytokines, and revealed two significantly down

  17. 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

    PubMed Central

    Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

    2015-01-01

    Background Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Methods Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Results Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. Conclusion While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. PMID:26109878

  18. [A Case of HER2-Positive Stage IV Advanced Gastric Cancer Treated with Chemotherapy Combined with Trastuzumab].

    PubMed

    Takaya, Kai; Takahashi, Ryosuke; Honma, Satoru; Horii, Shinichiro; Takahashi, Hirokazu; Hagiwara, Motohisa; Chin, Masahiro; Hashizume, Eiji

    2016-09-01

    We report a case of human epidermal growth factor receptor(HER)2 positive stage IV advanced gastric cancer successfully treated with chemotherapy combined with trastuzumab. A 50-year-old man was diagnosed with type 3 gastric cancer complicated by liver and lymph node metastases. Owing to a HER2 immunohistochemistry tumor score of 3+, we initiated capecitabine plus CDDP plus trastuzumab chemotherapy. After 6 chemotherapy courses, computed tomography showed the liver metastasis had disappeared and the paraaortic lymph nodes had shrunk. We continued the capecitabine plus trastuzumab chemotherapy, which resulted in a progression free survival of 31 months. After 38 chemotherapy courses, the primary tumor progressed; therefore, the patient underwent surgery. Chemotherapy combined with trastuzumab can allow for resec- tion of the primary tumor. PMID:27628555

  19. Low-dose total body irradiation versus combination chemotherapy for lymphomas with follicular growth pattern.

    PubMed

    Meerwaldt, J H; Carde, P; Burgers, J M; Monconduit, M; Thomas, J; Somers, R; Sizoo, W; Glabbeke, M V; Duez, N; de Wolf-Peeters, C

    1991-10-01

    The treatment of Non-Hodgkin's lymphomas with follicular growth pattern and advanced stage of disease remains controversial. Treatments varying from no initial treatment up to aggressive combination chemotherapy have been advocated. The EORTC Lymphoma Cooperative Group has performed a randomized prospective trial comparing short duration low dose total body irradiation (TBI) vs combination chemotherapy (CHVmP) + consolidation radiotherapy. Ninety-three patients were entered; of 84 evaluable patients, 44 received TBI and 40 CHVmP. Complete remission (CR) rates were 36%--TBI and 55%--CHVmP, but overall response rates were identical, 76 versus 69%. No significant difference in freedom from progression or survival was observed. No unexpected toxicity was seen. Although numbers are small, we cannot conclude that aggressive combination chemo-radiotherapy resulted in a better survival. Our analysis confirms that there is a constant risk of relapse. Other approaches should be explored if survival benefit is the ultimate goal in treatment of this patient population.

  20. Chondroitin sulphate decorated nanoparticulate carriers of 5-fluorouracil: development and in vitro characterization.

    PubMed

    Yadav, Awesh K; Agarwal, Abhinav; Jain, Sanyog; Mishra, Anil K; Bid, Hemant; Rai, Gopal; Agrawal, Hirnanshu; Agrawal, Govind P

    2010-08-01

    The present study investigates prospective of tailored nanoparticles as vectors to provide improved therapeutic efficacy of encapsulated anti-cancer drug 5-FU. Condritin Sulphate (CS) conjugated PLGA nanoparticles were prepared using PEG-bis-amine and adipic dihydrazide as spacers and loaded with an anti-cancer drug 5-FU (CS-PEG-PLGA-FU and CS-ADH-PLGA-FU). The formulations were then compared with non CS-anchored monomethoxy(polyethylene glycol) (MPEG-PLGA-FU) nanoparticles. Nanoparticlulate systems were further characterized by FTIR, NMR, TEM studies and particle size/polydispersity index (PDI) analysis. DSC and XRD were also performed to assess the nature of 5-FU inside the nanoparticles. The nanoparticles prepared using amphiphilic block copolymer CS-PEG-PLGA were able to sustain the release of 5-FU up to 48 h whereas those of CS-ADH-PLGA and MPEG-PLGA released the drug up to 24 h. The CS-PEG-PLGA-FU nanoparticles were found to be least haemolytic when compared to free drug, CS-ADH-PLGA-FU and MPEG-PLGA-FU nanoparticles. Cytotoxicity studies were performed on MCF-7/MDA-MD 231 breast cancer cells. PLGA nanoparticles exhibited more potent cytotoxic effect on MCF-7/MDA-MD 231 cells than free doxorubicin. Further, enhanced cytotoxicity and lower hemolytic potential of CS-PEG-PLGA-FU nanoparticles suggest a potential application in cancer chemotherapy. PMID:21323107

  1. Chemotherapy response as a prognosticator for survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy

    SciTech Connect

    Eagan, R.T.; Fleming, T.R.; Lee, R.E.; Ingle, J.N.; Frytak, S.; Creagan, E.T.

    1980-07-01

    Twenty-two patients with limited unresectable squamous cell lung cancer were treated with 6 courses of combination chemotherapy consisting of cyclophosphamide, adriamycin, cisplatin, and bleomycin (CAP-Bleo) and short-course thoracic irradiation started after the first 4 weeks of chemotherapy. Of 20 patients with visible tumor who were treated with 4 weeks of chemotherapy alone, 10 (50%) had a tumor regression in that 4 week period and 10 did not. Those patients with tumor regression had significantly better progression free and overall survivals than did patients with no chemotherapy regressions (medians of 258 days vs. 136 days and 356 days vs. 150 days respectively). The original bleomycin dose had to be reduced by 50% primarily because of excessive radiation esophagitis that has not been reported with use of either the CAP regimen or bleomycin along in conjunction with thoracic irradiation. An initial chemotherapy regression seems to be a good prognosticator for progression-free and overall survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy.

  2. Antiproliferative activity, cell-cycle dysregulation, and cellular differentiation: salicyl- and catechol-derived acyclic 5-fluorouracil O,N-acetals against breast cancer cells.

    PubMed

    Marchal, Juan A; Rodríguez-Serrano, Fernando; Caba, Octavio; Aránega, Antonia; Gallo, Miguel A; Espinosa, Antonio; Campos, Joaquín M

    2007-12-01

    Herein we report the preparation and biological activity of three compounds with the general formula 1-[2-(5-substituted-2-hydroxybenzyloxy)-1-methoxyethyl]-5-fluorouracil. 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-methoxybut-3-enyl]-5-fluorouracil [(Z)-11] 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)-11: IC(50)=9.40+/-0.64 microM. Differentiated breast cancer cells generate fat deposits in the cytoplasm. MCF-7 cells treated with (Z)-11 underwent an increase in lipid content relative to control cells after three 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.

  3. Deletion of the Uracil Permease Gene Confers Cross-Resistance to 5-Fluorouracil and Azoles in Candida lusitaniae and Highlights Antagonistic Interaction between Fluorinated Nucleotides and Fluconazole

    PubMed Central

    Gabriel, Frédéric; Sabra, Ayman; El-Kirat-Chatel, Sofiane; Pujol, Sophie; Fitton-Ouhabi, Valérie; Brèthes, Daniel; Dementhon, Karine; Accoceberry, Isabelle

    2014-01-01

    We characterized two additional membrane transporters (Fur4p and Dal4p) of the nucleobase cation symporter 1 (NCS1) family involved in the uptake transport of pyrimidines and related molecules in the opportunistic pathogenic yeast Candida lusitaniae. Simple and multiple null mutants were constructed by gene deletion and genetic crosses. The function of each transporter was characterized by supplementation experiments, and the kinetic parameters of the uptake transport of uracil were measured using radiolabeled substrate. Fur4p specifically transports uracil and 5-fluorouracil. Dal4p is very close to Fur4p and transports allantoin (glyoxyldiureide). Deletion of the FUR4 gene confers resistance to 5-fluorouracil as well as cross-resistance to triazoles and imidazole antifungals when they are used simultaneously with 5-fluorouracil. However, the nucleobase transporters are not involved in azole uptake. Only fluorinated pyrimidines, not pyrimidines themselves, are able to promote cross-resistance to azoles by both the salvage and the de novo pathway of pyrimidine synthesis. A reinterpretation of the data previously obtained led us to show that subinhibitory doses of 5-fluorocytosine, 5-fluorouracil, and 5-fluorouridine also were able to trigger resistance to fluconazole in susceptible wild-type strains of C. lusitaniae and of different Candida species. Our results suggest that intracellular fluorinated nucleotides play a key role in azole resistance, either by preventing azoles from targeting the lanosterol 14-alpha-demethylase or its catalytic site or by acting as a molecular switch for the triggering of efflux transport. PMID:24867971

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

    PubMed

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

    2015-07-01

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

  5. Modified irinotecan and infusional 5-fluorouracil (mFOLFIRI) in patients with refractory advanced pancreas cancer (APC): a single-institution experience

    PubMed Central

    Bupathi, M.; Ahn, D. H.; Wu, C.; Ciombor, K. K.; Stephens, J. A.; Reardon, J.; Goldstein, D. A.; Bekaii-Saab, T.

    2016-01-01

    Pancreatic adenocarcinoma is the fourth leading cause of cancer death. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in outcome measures with acceptable toxicities when combined with 5-fluorouracil (5-FU)/leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in advanced pancreas cancer (APC). We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs), and Kaplan–Meier methods were used to calculate the median progression-free survival (PFS) and overall survival (OS). Forty patients were included in this analysis. Patients received 1–5 lines of prior therapy (25 % with more than 3 lines of prior therapy). The mean age at diagnosis was 60, and 98 % had ECOG of 1. The mean CA 19-9 at the start of therapy was 33,169 U/ml. The median PFS was 2.59 months [95 % confidence interval (CI) (1.90, 3.54)], and OS was 4.75 months [95 % CI (3.14, 8.98)]. The most common AEs included fatigue (98 %), neuropathy (83 %), anorexia (68 %), nausea (60 %) and constipation (55 %). Grade 3 toxicities included fatigue (13 %) and rash (3 %). There were no observed grade 4 toxicities. In this single-institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in a heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC. PMID:26995224

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

    PubMed

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

    2016-06-01

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

  7. Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecologic cancers as compared to cisplatin alone.

    PubMed

    Merouani, A; Davidson, S A; Schrier, R W

    1997-01-01

    To investigate the increased nephrotoxicity of taxol and cisplatin combination chemotherapy in gynecologic cancers as compared to cisplatin alone, the medical records of 25 patients with gynecological cancers were reviewed for evaluation of nephrotoxicity after chemotherapy treatment. The data included age, serum creatinine, calculated creatinine clearance, initial and cumulative dose of cisplatin and taxol, primary site of the cancer, renal ultrasound and hydration protocols. Renal function was evaluated before, during and 6 months after chemotherapy. Renal dysfunction was defined as a greater than 25% decrease in creatinine clearance. Comparing 11 patients treated with taxol and cisplatin versus 14 treated with cisplatin alone, there was a significant difference in effect on renal function. Nine of 11 patients (81%) treated with the combination chemotherapy had a greater than 25% decrease in creatinine clearance while only 4 of the 14 patients (29%) treated with cisplatin alone had such a decrease in creatinine clearance (p < 0.004). The patients treated with the combination chemotherapy, however, received a higher dose of cisplatin (80.4 vs. 66.4 mg/m2, p < 0.02) and were treated longer (6.7 vs. 4.3 months, p < 0.002). Nevertheless, when the patients were matched for age, initial dose and cumulative dose of cisplatin, a higher frequency of nephrotoxicity persisted in patients treated with taxol and cisplatin as compared to cisplatin alone (72 as compared to 20%, p < 0.02). The patients in both groups were comparably hydrated; prerenal failure and urinary tract obstruction were excluded in all patients. Six months after completion of chemotherapy, a significantly lower creatinine clearance was still observed in patients treated with taxol and cisplatin combination therapy (46 vs. 76 ml/min, p < 0.01). In summary, a retrospective analysis of renal function in patients with gynecological cancers showed an increased nephrotoxicity in patients treated with taxol and

  8. 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.

  9. Concurrent Chemoradiotherapy With 5-Fluorouracil and Mitomycin C for Invasive Anal Carcinoma in Human Immunodeficiency Virus-Positive Patients Receiving Highly Active Antiretroviral Therapy

    SciTech Connect

    Fraunholz, Ingeborg

    2010-04-15

    Purpose: To report the clinical outcomes of chemoradiotherapy (CRT) for anal carcinoma in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy. Patients and Methods: Between 1997 and 2008, 21 HIV-positive patients who were receiving highly active antiretroviral therapy were treated with CRT (50.4 Gy at 1.8 Gy/fraction plus a 5.4-10.8-Gy external boost; 5-fluorouracil, 1,000 mg/m{sup 2}, Days 1-4 and 29-32; and mitomycin C, 10 mg/m{sup 2}, Days 1 and 29). A retrospective analysis was performed with respect to the tumor response, local control, cancer-specific and overall survival, and toxicity. The immunologic parameters, including pre- and post-treatment CD4 count, viral load, and acquired immunodeficiency syndrome-specific morbidity was recorded during follow-up (median, 53 months; range, 10-99). Results: CRT could be completed in all 21 patients with a reduction in the chemotherapy dose and/or interruption of radiotherapy in 5 and 5 cases, respectively. Acute Grade 3 toxicity occurred in 8 (38%) of the 21 patients. A complete response was achieved in 17 patients (81%), and tumor persistence or early progression was noted in 4 (19%). Six patients (29%) died, 5 of cancer progression and 1 of treatment-related toxicity. The 5-year local control, cancer-specific, and overall survival rate was 59%, 75%, and 67%, respectively. The median CD4 count significantly decreased from 347.5 cells/muL before CRT to 125 cells/muL 3-7 weeks after CRT completion (p <.001). In 6 (32%) of 19 patients, an increase of the HIV viral load was noted. Both parameters returned to the pretreatment values with additional follow-up. Conclusion: Our data have confirmed that in the highly active antiretroviral therapy era, HIV-related anal cancer can be treated with standard CRT without dose reductions. Close surveillance of the immunologic parameters is necessary.

  10. 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

  11. Aggressive TAFRO syndrome with reversible cardiomyopathy successfully treated with combination chemotherapy.

    PubMed

    Yasuda, Shunichiro; Tanaka, Keisuke; Ichikawa, Ayako; Watanabe, Ken; Uchida, Emi; Yamamoto, Masahide; Yamamoto, Kouhei; Mizuchi, Daisuke; Miura, Osamu; Fukuda, Tetsuya

    2016-10-01

    TAFRO (thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly) syndrome is an atypical manifestation of Castleman's disease. However, the mechanism underlying this very rare syndrome remains unknown, and there is no established standard treatment. Here we report cases of two young females with TAFRO syndrome who showed similar clinical courses. Both cases showed severe anasarca, ascites, and thrombocytopenia. Although high-dose steroids were ineffective, combination chemotherapy showed remarkable effects. However, both patients developed severe but reversible heart failure after CHOP therapy owing to diffuse cardiomyopathy, which was presumably associated with TAFRO syndrome. Therefore, although combination chemotherapy may be very effective in the treatment of TAFRO syndrome, careful observation for cardiomyopathy development is needed, particularly when using adriamycin-containing regimens.

  12. Repertaxin, an inhibitor of the chemokine receptors CXCR1 and CXCR2, inhibits malignant behavior of human gastric cancer MKN45 cells in vitro and in vivo and enhances efficacy of 5-fluorouracil

    PubMed Central

    WANG, JUNPU; HU, WANMING; WANG, KUANSONG; YU, JUN; LUO, BAIHUA; LUO, GENGQIU; WANG, WEIYUAN; WANG, HUILING; LI, JINGHE; WEN, JIFANG

    2016-01-01

    Chemokine-mediated activation of G protein-coupled receptors CXCR1/2 promotes tumor growth, invasion, inflammation and metastasis. Repertaxin, a CXCR1/2 small-molecule inhibitor, has been shown to attenuate many of these tumor-associated processes. The present study aimed to investigate the effects of repertaxin alone and in combination with 5-fluorouracil (5-FU) on the malignant behavior of gastric cancer and the potential mechanisms. Gastric cancer MKN45 cells were treated in vitro with repertaxin and 5-FU, either alone or in combination. MTT and colony formation assay were performed to assess proliferation. Cell cycle progression and apoptosis was completed by flow cytometry. Migration and invasion were also assessed by Transwell and wound-healing assay. Western blot analysis and quantitative RT-PCR were performed to determine expression of signaling molecules. MKN45 cells were also grown as xenografts in nude mice. Mice were treated with repertaxin and 5-FU, and tumor volume and weight, angiogenesis, proliferation and apoptosis were monitored. Combination of repertaxin and 5-FU inhibited MKN45 cell proliferation and increased apoptosis better than either agent alone. Similarly, enhanced effect of the combination was also observed in migration and invasion assays. The improved effect of repertaxin and 5-FU was also observed in vivo, as xenograft models treated with both compounds exhibited significantly decreased tumor volume and increased apoptosis. In conclusion, repertaxin inhibited malignant behavior of human gastric cancer MKN45 cells in vitro and in vivo and enhances efficacy of 5-fluorouracil. These data provide rationale that targeting CXCR1/2 with small molecule inhibitors may enhance chemotherapeutic efficacy for the treatment of gastric cancer. PMID:26847910

  13. [A case of metastatic esophageal cancer responding remarkably to combination chemotherapy of TS-1 and cisplatin].

    PubMed

    Iwase, Hiroaki; Okeya, Masayuki; Shimada, Masaaki; Tsuzuki, Tomoyuki; Nakarai, Keiko; Kaida, Shogo; Doi, Reiko

    2004-05-01

    A 51-year-old male patient with esophageal cancer and cervical, thoracic and celiac artery lymph node metastases was treated by combination chemotherapy of TS-1 and cisplatin. TS-1 (80 mg/m2/day) was administered for 14 days followed by 14 days rest as 1 course. Cisplatin (70 mg/m2/day) was administered in 24-hour continuous intravenous infusion at day 8 after the start of TS-1. Before treatment, the tumor marker, CEA showed 27,060 ng/ml. After 5 courses of chemotherapy, endoscopy revealed that the primary tumor had disappeared and no cancer cells were detected by endoscopic biopsy. Chest and abdominal CT scan also showed almost total disappearance of the lymph nodes metastases. CEA decreased to 710 ng/ml. No high-grade toxicities (WHO grade 3 or 4) were seen during the chemotherapy. He is now very well. This TS-1/cisplatin chemotherapy regimen might be a useful treatment for metastatic esophageal cancer.

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

    PubMed Central

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

    2016-01-01

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

  15. Application of 5-Fluorouracil-Polycaprolactone Sustained-Release Film in Ahmed Glaucoma Valve Implantation Inhibits Postoperative Bleb Scarring in Rabbit Eyes.

    PubMed

    Bi, Xiu-Zeng; Pan, Wei-Hua; Yu, Xin-Ping; Song, Zong-Ming; Ren, Zeng-Jin; Sun, Min; Li, Cong-Hui; Nan, Kai-Hui

    2015-01-01

    This study was designed to investigate whether 5-fluorouracil (5-Fu)-polycaprolactone sustained-release film in Ahmed glaucoma valve implantation inhibits postoperative bleb scarring in rabbit eyes. Eighteen New Zealand white rabbits were randomly divided into three groups (A, B and C; n = 6 per group). Group A received combined 5-Fu-polycaprolactone sustained-release film application and Ahmed glaucoma valve implantation, group B received local infiltration of 5-Fu and Ahmed glaucoma valve implantation, and group C received Ahmed glaucoma valve implantation. Postoperative observations were made of the anterior segment, intraocular pressure, central anterior chamber depth, blebs, drainage tube, and accompanying ciliary body detachment. The pathology of the blebs and surrounding tissues were observed at month 3 postoperatively. We revealed that the 5-Fu-polycaprolactone sustained-release film maintained a release concentration range of 13.7 ± 0.12 to 37.41 ± 0.47 μg/ml over three months in vitro. Postoperatively, diffuse blebs with ridges were found in all eyes in group A, two blebs were observed in group B, and no bleb formation was present in group C. The postoperative central anterior chamber depth in group A was significantly less than that of the other two groups. The postoperative intraocular pressure of group A stabilized at 6.33-8.67 mmHg, whereas that of group C gradually remained at 7.55-10.02 mmHg. The histopathology showed that the fibrous tissue thickness of the blebs in group A was significantly thinner than that of the other groups. We conclude that the 5-Fu-polycaprolactone sustained-release film had a sustained drug release effect, which promoted the inhibition of bleb scarring after Ahmed glaucoma valve implantation.

  16. Application of 5-Fluorouracil-Polycaprolactone Sustained-Release Film in Ahmed Glaucoma Valve Implantation Inhibits Postoperative Bleb Scarring in Rabbit Eyes

    PubMed Central

    Bi, Xiu-Zeng; Pan, Wei-Hua; Yu, Xin-Ping; Song, Zong-Ming; Ren, Zeng-Jin; Sun, Min; Li, Cong-Hui; Nan, Kai-Hui

    2015-01-01

    This study was designed to investigate whether 5-fluorouracil (5-Fu)-polycaprolactone sustained-release film in Ahmed glaucoma valve implantation inhibits postoperative bleb scarring in rabbit eyes. Eighteen New Zealand white rabbits were randomly divided into three groups (A, B and C; n = 6 per group). Group A received combined 5-Fu-polycaprolactone sustained-release film application and Ahmed glaucoma valve implantation, group B received local infiltration of 5-Fu and Ahmed glaucoma valve implantation, and group C received Ahmed glaucoma valve implantation. Postoperative observations were made of the anterior segment, intraocular pressure, central anterior chamber depth, blebs, drainage tube, and accompanying ciliary body detachment. The pathology of the blebs and surrounding tissues were observed at month 3 postoperatively. We revealed that the 5-Fu-polycaprolactone sustained-release film maintained a release concentration range of 13.7 ± 0.12 to 37.41 ± 0.47 μg/ml over three months in vitro. Postoperatively, diffuse blebs with ridges were found in all eyes in group A, two blebs were observed in group B, and no bleb formation was present in group C. The postoperative central anterior chamber depth in group A was significantly less than that of the other two groups. The postoperative intraocular pressure of group A stabilized at 6.33–8.67 mmHg, whereas that of group C gradually remained at 7.55–10.02 mmHg. The histopathology showed that the fibrous tissue thickness of the blebs in group A was significantly thinner than that of the other groups. We conclude that the 5-Fu-polycaprolactone sustained-release film had a sustained drug release effect, which promoted the inhibition of bleb scarring after Ahmed glaucoma valve implantation. PMID:26579716

  17. Synergistic therapeutic effects of Schiff's base cross-linked injectable hydrogels for local co-delivery of metformin and 5-fluorouracil in a mouse colon carcinoma model.

    PubMed

    Wu, Xilong; He, Chaoliang; Wu, Yundi; Chen, Xuesi

    2016-01-01

    In situ formed hydrogels based on Schiff base reaction were formulated for the co-delivery of metformin (ME) and 5-fluorouracil (5FU). The reactive aldehyde-functionalized four-arm polyethylene glycol (PFA) was synthesized by end-capping of 4-arm PEG with 4-formylbenzoic acid (FA) and used as a cross-linking agent. The injectable hydrogels are designed through the quick gelation induced by the formation of covalent bonds via Schiff-base reaction of PFA with 4-arm poly (ethylene glycol)-b-poly (L-lysine) (PPLL). This formulation eliminated the need for metal catalysts and complicated processes in the preparation of in situ-forming hydrogels. In vitro degradation and drug release studies demonstrated that both ME and 5FU were released through PFA/PPLL hydrogels in a controlled and pH-dependent manner. When incubated with mouse colon adenocarcinoma cells (C26), the ME/5FU-incorporated PFA/PPLL hydrogels had synergistic inhibitory effects on the cell cycle progression and cell proliferation in colon cancer cells. After a single subcutaneous injection of the hydrogel containing ME/5FU beside the tumors of BALB/c mice inoculated with C26 cells, the dual-drug-loaded hydrogels displayed superior therapeutic activity resulted from a combination of p53-mediated G1 arrest and apoptosis in C26 cells. Hence, the Schiff's base cross-linked hydrogels containing ME and 5FU may have potential therapeutic applications in the treatments of colon cancer. PMID:26497429

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

    PubMed

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

    2012-12-01

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

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

    PubMed Central

    2013-01-01

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

  20. 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

  1. Target hepatic artery regional chemotherapy and bevacizumab perfusion in liver metastatic colorectal cancer after failure of first-line or second-line systemic chemotherapy.

    PubMed

    Chen, Hui; Zhang, Ji; Cao, Guang; Liu, Peng; Xu, Haifeng; Wang, Xiaodong; Zhu, Xu; Gao, Song; Guo, Jianhai; Zhu, Linzhong; Zhang, Pengjun

    2016-02-01

    Colorectal cancer liver metastasis (CRLM) is a refractory disease after failure of first-line or second-line chemotherapy. Bevacizumab is recommended as first-line therapy for advanced colorectal cancer, but is unproven in CRLM through the hepatic artery. We report favorable outcomes with targeted vessel regional chemotherapy (TVRC) for liver metastatic gastric cancer. TVRC with FOLFOX and bevacizumab perfusion through the hepatic artery was attempted for CRLM for efficacy and safety evaluation. In a single-institution retrospective observational study, 246 patients with CRLM after at least first-line or second-line failure of systemic chemotherapy received TVRC with FOLFOX (i.e. oxaliplatin, leucovorin, and 5-fluorouracil). Of 246 patients, 63 were enrolled into two groups: group 1 (n=30) received bevacizumab and TVRC following tumor progression during previous TVRC treatments; group 2 (n=33) received TVRC plus bevacizumab for CRLM on initiating TVRC. There were no significant differences in the median survival time (14.7 vs. 13.2 months, P=0.367), although the median time to progression was significant (3.3 vs. 5.5 months, P=0.026) between groups. No severe adverse events related to TVRC plus bevacizumab perfusion occurred. Target vessel regional chemotherapy with FOLFOX plus bevacizumab perfusion through the hepatic artery was effective and safe in CRLM. The optimal combination of TVRC and bevacizumab needs further confirmation in future phase II-III clinical trials.

  2. Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Oxaliplatin on Human Colorectal and Gastric Cancer Xenografts.

    PubMed

    Nukatsuka, Mamoru; Nakagawa, Fumio; Takechi, Teiji

    2015-09-01

    TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride (at a molar ratio of 1:0.5) that was approved in Japan in 2014 for the treatment of unresectable advanced or recurrent colorectal cancer. In the present study, the enhancement of therapeutic efficacy using a combination of TAS-102 and oxaliplatin was evaluated in a xenograft-bearing nude mouse model of colorectal and gastric cancer. TAS-102 was orally administered twice-a-day from day 1 to 14, and oxaliplatin was administered intravenously on days 1 and 8. The in vivo growth-inhibitory activity was evaluated based on the tumor volume and the growth-delay period, was estimated based on the period required to reach a tumor volume five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and RTV5 in mice administered TAS-102 with oxaliplatin were significantly superior to those associated with either monotherapy in mice with colorectal (HCT 116, SW-48; p<0.001) and gastric cancer (SC-2, MKN74; p<0.001). MKN74/5FU, a 5-fluorouracil-resistant MKN74 sub-line, was sensitive to both FTD and oxaliplatin in vitro. In vivo, TAS-102 alone was effective in MKN74/5FU, and its anti-tumor activity was significantly enhanced in combination with oxaliplatin (p<0.001). No significant decrease in body weight or toxicity was observed compared to either monotherapy. The present pre-clinical findings indicate that combination of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, and can be utilized in both chemo-naïve tumors and recurrent tumors after 5-fluorouracil treatment.

  3. Advanced epithelial ovarian cancer: toxicity of whole abdominal irradiation after operation, combination chemotherapy, and reoperation

    SciTech Connect

    Schray, M.F.; Martinez, A.; Howes, A.E.; Ballon, S.C.; Podratz, K.C.; Sikic, B.I.; Malkasian, G.D.

    1986-05-01

    Thirty-five patients with advanced ovarian cancer have received, as salvage therapy, irradiation consisting of 30 Gy to the entire abdominal contents with partial liver/kidney shielding and boosts to 42 and 51 Gy for the paraaortic/diaphragmatic and pelvic regions, respectively. These patients had received 6 to 25 cycles (median, 11 cycles) of prior combination chemotherapy (included cisplatin in 30), with second-look laparotomy performed in 33; 24 (68%) had three or more laparotomies. Acute gastrointestinal toxicity was generally mild. Significant hematologic toxicity (leukocytes less than 2000/mm3; or platelets less than 100,000/mm3) was seen in 19 (54%); platelet suppression occurred in 18 of these 19. Nine patients failed to complete the prescribed course of therapy; in seven, this was secondary to hematologic toxicity. Amount of prior chemotherapy and advanced age correlated with degree of hematologic toxicity. Five patients without evidence of disease (laparotomy confirmed) have developed treatment-related bowel obstruction. No other chronic toxicity of clinical significance has been observed. Seven patients have developed bowel obstruction associated with progressive neoplasm. Irradiation was well tolerated symptomatically, but hematologic toxicity associated with prior chemotherapy prevented its completion in 20% of patients. Clinical manifestations of radiation bowel toxicity have been moderate to date and should be interpreted in the context of the aggressive combined modality program.

  4. Malignant Esophagogastric Junction Obstruction: Efficacy of Balloon Dilation Combined with Chemotherapy and/or Radiation Therapy

    SciTech Connect

    Ko, Gi-Young; Song, Ho-Young Hong, Heuk-Jin; Sung, Kyu-Bo; Seo, Tae-Seok; Yoon, Hyun-Ki

    2003-04-15

    Purpose: To assess the efficacy of balloon dilation combined with chemotherapy and/or radiation therapy for palliation of dysphagia due to malignant esophagogastric junction strictures. Methods: Fluoroscopically guided balloon dilation was attempted in 20 patients. The causes of strictures were gastric adenocarcinoma (n = 10) and esophageal squamous cell carcinoma (n = 10). Scheduled chemotherapy and/or radiation therapy followed balloon dilation in all patients. Results: There were no technical failures or major complications. After balloon dilation, 15 (75%) patients showed improvement of dysphagia. No patient complained of reflux esophagitis during the follow-up period. Among the 15 patients, seven needed no further treatment for palliation of dysphagia until their deaths. The remaining eight patients underwent repeat balloon dilation(n = 4) or stent placement (n = 4)3-43 weeks (mean 15 weeks) after the initial balloon dilation because of recurrent dysphagia. Conclusion: Balloon dilation combined with chemotherapy and/or radiation therapy seems to be an easy and reasonably effective palliative treatment for malignant esophagogastric strictures.

  5. Phellinus linteus extract induces autophagy and synergizes with 5-fluorouracil to inhibit breast cancer cell growth.

    PubMed

    Lee, Wen-Ying; Hsu, Keng-Fu; Chiang, Tai-An; Chen, Chee-Jen

    2015-01-01

    Phellinus linteus (PL) is a medicinal mushroom due to its several biological properties, including anticancer activity. However, the mechanisms of its anticancer effect remain to be elucidated. We evaluated the inhibitory effects of the ethanolic extract from the PL combined with 5-FU on MDA-MB-231 breast cancer cell line and to determine the mechanism of cell death. Individually, PL extract and 5-FU significantly inhibited the proliferation of MDA-MB-231 cells in a dose-dependent manner. PL extract (30 mg/mL) in combination with 5-FU (10 μg/mL) synergistically inhibited MDA-MB-231 cells by 1.8-fold. PL did not induce apoptosis, as demonstrated by the DNA fragmentation assay, the sub-G1 population, and staining with annexin V-FITC and propidium iodide. The exposure of MDA-MB-231 cells to PL extracts resulted in several confirmed characteristics of autophagy, including the appearance of autophagic vacuoles revealed by monodansylcadaverine staining, the formation of acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3) characterized by cleavage of LC3 and its punctuate redistribution, and ultrastructural observation of autophagic vacuoles by transmission electron microscopy. We concluded that PL extracts synergized with low doses of 5-FU to inhibit triple-negative breast cancer cell growth and demonstrated that PL extract can induce autophagy-related cell death. PMID:25622112

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2014-12-19

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

  9. 5-Fluorouracil catabolism to 5-fluoro-5,6-dihydrouracil is reduced by acute liver impairment in mice

    SciTech Connect

    Innocenti, Federico; Danesi, Romano; Bocci, Guido; Natale, Gianfranco . E-mail: gianfranco.natale@anist.med.unipi.it; Del Tacca, Mario

    2005-03-01

    This study investigated the effect of acute liver damage on the inactivation of 5-fluorouracil (5-FU) to its main catabolite 5-fluoro-5,6-dihydrouracil (5-FUH{sub 2}) in mice. Plasma pharmacokinetics of 5-FU and 5-FUH{sub 2} in mice receiving 5-FU (10, 30, and 90 mg/kg) were compared to those in mice pretreated with carbon tetrachloride and receiving the same 5-FU doses. Carbon tetrachloride-induced hepatic damage was histopathologically examined under light microscopy and serum transaminases and dihydropyrimidine dehydrogenase activities were also measured. Liver histopathology and elevated aminotransferase activity levels confirmed the presence of liver damage. 5-FU C{sub max} and AUC both increased up to 71% in mice with liver damage. This was reflected by decreased 5-FUH{sub 2} production, since 5-FUH{sub 2} C{sub max} and AUC levels decreased up to 47% and 61%, respectively. Metabolic ratios between 5-FUH{sub 2} and 5-FU AUCs were considerably decreased as well, further suggesting that liver damage caused a reduction in 5-FU catabolism. DPD activity was not altered in damaged livers. The present results indicate that 5-FU disposition in mice could be profoundly altered in the presence of severe liver impairment, potentially leading to enhanced anabolic activation of 5-FU. This effect seems to be ascribed to a reduction of viable hepatocytes, rather than to an inactivation of DPD activity.

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

    NASA Astrophysics Data System (ADS)

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

    1997-05-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    SciTech Connect

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

    2015-12-15

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

  13. Dynamical Interactions of 5-Fluorouracil Drug with Dendritic Peptide Vectors: The Impact of Dendrimer Generation, Charge, Counterions, and Structured Water.

    PubMed

    De Luca, Sergio; Seal, Prasenjit; Ouyang, Defang; Parekh, Harendra S; Kannam, Sridhar Kumar; Smith, Sean C

    2016-06-30

    Molecular dynamics simulations are utilized to investigate the interactions between the skin cancer drug 5-fluorouracil (5FU) and peptide-based dendritic carrier systems. We find that these drug-carrier interactions do not conform to the traditional picture of long-time retention of the drug within a hydrophobic core of the dendrimer carrier. Rather, 5FU, which is moderately soluble in its own right, experiences weak, transient chattering interactions all over the dendrimer, mediated through multiple short-lived hydrogen bonding and close contact events. We find that charge on the periphery of the dendrimer actually has a negative effect on the frequency of drug-carrier interactions due to a counterion screening effect that has not previously been observed. However, charge is nevertheless an important feature since neutral dendrimers are shown to have a significant mutual attraction that can lead to clustering or agglomeration. This clustering is prevented due to charge repulsion for the titrated dendrimers, such that they remain independent in solution.

  14. In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer

    PubMed Central

    Wang, Lu-Lu; Huang, Shuai; Guo, Hui-Hui; Han, Yan-Xing; Zheng, Wen-Sheng; Jiang, Jian-Dong

    2016-01-01

    In situ administration of 5-fluorouracil (5FU) “thermosensitive” gel effectively reduced systemic side effects in treating colon rectal cancer; however, the penetration efficacy of the formulation was considerably low due to the poor lipid solubility of 5FU. The aim of this study was to develop thermosensitive gel-mediated 5FU water-in-oil microemulsion (TG-5FU-ME) for improving the infiltration of 5FU. An in vitro release test showed that TG-5FU-ME sustained the drug’s release up to 10 hours. TG-5FU-ME exhibited good stability, and the microemulsion entrapped did not show any change in morphology and 5FU content during the 4-month storage. Transportation test in the Caco-2 cell monolayer showed that TG-5FU-ME had a permeability 6.3 times higher than that of 5FU thermosensitive gel, and the intracellular uptake of 5FU increased by 5.4-fold compared to that of 5FU thermosensitive gel. In vivo tissue distribution analysis exhibited that the TG-5FU-ME group had drug levels in rectal tissue and mesenteric lymph nodes, which were significantly higher than those of 5FU thermosensitive gel group, with very low blood levels of 5FU in both groups. Furthermore, TG-5FU-ME was not associated with detectable morphological damage to the rectal tissue. Conclusively, TG-5FU-ME might be an efficient rectal delivery system to treat colorectal cancer.

  15. In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer

    PubMed Central

    Wang, Lu-Lu; Huang, Shuai; Guo, Hui-Hui; Han, Yan-Xing; Zheng, Wen-Sheng; Jiang, Jian-Dong

    2016-01-01

    In situ administration of 5-fluorouracil (5FU) “thermosensitive” gel effectively reduced systemic side effects in treating colon rectal cancer; however, the penetration efficacy of the formulation was considerably low due to the poor lipid solubility of 5FU. The aim of this study was to develop thermosensitive gel-mediated 5FU water-in-oil microemulsion (TG-5FU-ME) for improving the infiltration of 5FU. An in vitro release test showed that TG-5FU-ME sustained the drug’s release up to 10 hours. TG-5FU-ME exhibited good stability, and the microemulsion entrapped did not show any change in morphology and 5FU content during the 4-month storage. Transportation test in the Caco-2 cell monolayer showed that TG-5FU-ME had a permeability 6.3 times higher than that of 5FU thermosensitive gel, and the intracellular uptake of 5FU increased by 5.4-fold compared to that of 5FU thermosensitive gel. In vivo tissue distribution analysis exhibited that the TG-5FU-ME group had drug levels in rectal tissue and mesenteric lymph nodes, which were significantly higher than those of 5FU thermosensitive gel group, with very low blood levels of 5FU in both groups. Furthermore, TG-5FU-ME was not associated with detectable morphological damage to the rectal tissue. Conclusively, TG-5FU-ME might be an efficient rectal delivery system to treat colorectal cancer. PMID:27660416

  16. Ajoene and 5-fluorouracil in the topical treatment of Cladophialophora carrionii chromoblastomycosis in humans: a comparative open study.

    PubMed

    Pérez-Blanco, M; Valles, R Hernández; Zeppenfeldt, G Fernández; Apitz-Castro, R

    2003-12-01

    Ajoene and 5-fluorouracil (5-FU) are compounds that have shown in-vitro activity against Cladophialophora carrionii, an important etiologic agent of chromoblastomycosis. An open comparative trial was conducted to assess safety and effectiveness of topical ajoene and 5-FU in the treatment of localized chromoblastomycosis. Thirty-seven patients with a clinically and mycologically confirmed diagnosis were randomly distributed into two groups allocated to ajoene (0.5% gel; n = 19) or 5-FU (1% cream; n = 18). Topical treatment was applied to localized lesions (< or = 2.5-cm diameter) once a day, with occlusion, for 12-16 weeks. Complete clinical and mycological remission was achieved in 14/19 patients (74%) treated with ajoene and 14/18 patients (78%) treated with 5-FU. All 5-FU-treated patients developed a post-treatment scar at the site of the lesion, while ajoene-treated patients showed only a slight depigmentation of the skin. The differences observed in cure rate between ajoene and 5-FU are not statistically significant. Follow-up of all patients for 4 years revealed no relapses in the ajoene-treated group, while one patient in the 5-FU-treated group had a relapse 6 months after the end of therapy. This trial represents the first clinical use of ajoene in the control of a deep mycosis.

  17. The Analysis of Gene Expression on Fertility Decline in Caenorhabditis elegans after the Treatment with 5-Fluorouracil

    PubMed Central

    ZHANG, Si; LU, Zhaolian; LIANG, Hongmei; FU, Ximei; ZHANG, Yan; LIU, Xin; BAO, Genshu; JING, Tao; WANG, Xuan; WANG, Meng; WU, Julong; CHEN, Gen

    2015-01-01

    Background: 5-Fluorouracil could lead to a decline in fertility in Caenorhabditis elegans. The aim of this study was to describe the mechanisms underlying such an altered fertility phenotype and to illustrate the specific genes and pathways that are involved in the related phenotypic changes in C. elegans. Methods: We isolated total RNA from the samples and used a new method called Digital Gene Expression (DGE), which can rapidly identify genes with altered transcript levels. The random genes were confirmed by real-time RT-PCR. Results: We analyzed the results of two methods to draw conclusions based on a comparison between C. elegans and other harmful parasites. Compared with controls, 1147 genes were up-regulated, and 1067 were down-regulated. Overall, 101 up-regulated genes had a log2 ratio higher than 8, whereas the log2 ratio of 141 down-regulated genes was higher than 8. After mapping to the reference database, 4 pathways were confirmed to be involved in this phenomenon, with statistically significant participation from 19 genes. Conclusion: For the first time, the transcript sequence of 5-Fu-treated worms and controls was detected. We found that 4 possible pathways, i.e., ECM-receptor interaction pathway, TGF-beta signaling pathway, Focal adhesion and Hypertrophic cardiomyopathy, may be involved in the number decline in the embryos of C. elegans. Specifically, the ECM-receptor interaction pathway and Focal adhesion may be very important pathways that alter the reproduction of C. elegans. PMID:26587470

  18. Assam Bora rice starch based biocompatible mucoadhesive microsphere for targeted delivery of 5-fluorouracil in colorectal cancer.

    PubMed

    Ahmad, Mohammad Zaki; Akhter, Sohail; Anwar, Mohammed; Ahmad, Farhan Jalees

    2012-11-01

    The aim of this study was to develop novel colon targeted mucoadhesive microspheres (MAMs) for site specific delivery of 5-fluorouracil (5-FU) to colon without the drug being released in the stomach or small intestine. MAMs were prepared using Assam Bora rice starch, a natural mucoadhesive polymer, by a double emulsion solvent evaporation method. The microspheres were characterized for their shape, size, surface morphology, size distribution, incorporation efficiency, and in vitro and in vivo drug release studies. The release study confirmed the insignificant release of 5-FU in physiological condition of stomach and small intestine and major drug release in the cecal content. In vivo release study of the optimized MAMs was compared with immediate release (IR) 5-FU. 5-FU was distributed predominantly in the upper GI tract from the IR, whereas 5-FU was distributed primarily to the lower part of the GI tract from the MAM formulation. Enhanced levels of liver enzymes were found in animals given IR 5-FU as well as augmented levels of serum albumin, creatinine, leucocytopenia and thrombocytopenia was also observed. Thus to sum up, it can be appropriately established that the 5-FU release pattern from MAMs exhibits slow and extended release over longer periods of time with reduced systemic side effects. PMID:22994847

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

    PubMed Central

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

    2016-01-01

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

  20. Development of hydrocortisone succinic acid/and 5-fluorouracil/chitosan microcapsules for oral and topical drug deliveries.

    PubMed

    Lam, Pik-Ling; Lee, Kenneth Ka-Ho; Wong, Raymond Siu-Ming; Cheng, Gregory Yin Ming; Cheng, Shuk Yan; Yuen, Marcus Chun-Wah; Lam, Kim-Hung; Gambari, Roberto; Kok, Stanton Hon-Lung; Chui, Chung-Hin

    2012-05-01

    Recently, we demonstrated the safety use of calendula oil/chitosan microcapsules as a carrier for both oral and topical deliveries. We also reported the improved biological activity towards skin cells and Staphylococcus aureus of phyllanthin containing chitosan microcapsules. However, the possibility of both oral and topical applications was still necessary to be further studied. Here we investigated that both oral and topical applications of chitosan-based microcapsules were tested using hydrocortisone succinic acid (HSA) and 5-fluorouracil (5-FU), respectively. The drug loading efficiency, particle size, surface morphology and chemical compositions of both drug loaded microcapsules were confirmed by UV-vis spectrophotometer, particle size analyzer, scanning electron microscope and Fourier transform infrared spectroscopy. The in vitro release studies revealed that both HSA and 5-FU could be released form chitosan microcapsules. The mean adrenocorticotropic hormone concentration in HSA loaded microcapsule mice plasma was detected to be lower than that of water control. One hundred micrograms per milliliter of 5-FU containing microcapsules exhibited a stronger growth inhibition towards skin keratinocytes than that of free 5-FU. In vitro drug delivery model demonstrated the delivery of 5-FU from microcapsule treated textiles into nude mice skin. Further uses of the drug loaded microcapsules may provide an efficiency deliverable tool for both oral and topical applications.

  1. Dynamical Interactions of 5-Fluorouracil Drug with Dendritic Peptide Vectors: The Impact of Dendrimer Generation, Charge, Counterions, and Structured Water.

    PubMed

    De Luca, Sergio; Seal, Prasenjit; Ouyang, Defang; Parekh, Harendra S; Kannam, Sridhar Kumar; Smith, Sean C

    2016-06-30

    Molecular dynamics simulations are utilized to investigate the interactions between the skin cancer drug 5-fluorouracil (5FU) and peptide-based dendritic carrier systems. We find that these drug-carrier interactions do not conform to the traditional picture of long-time retention of the drug within a hydrophobic core of the dendrimer carrier. Rather, 5FU, which is moderately soluble in its own right, experiences weak, transient chattering interactions all over the dendrimer, mediated through multiple short-lived hydrogen bonding and close contact events. We find that charge on the periphery of the dendrimer actually has a negative effect on the frequency of drug-carrier interactions due to a counterion screening effect that has not previously been observed. However, charge is nevertheless an important feature since neutral dendrimers are shown to have a significant mutual attraction that can lead to clustering or agglomeration. This clustering is prevented due to charge repulsion for the titrated dendrimers, such that they remain independent in solution. PMID:27267604

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

    PubMed

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

    2014-05-01

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

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

    PubMed Central

    YAMASHITA, TOMOMI; KATO, KEIZO; LONG, NGUYEN KHANH; MAKITA, HIROKI; YONEMOTO, KAZUHIRO; IIDA, KAZUKI; TAMAOKI, NARITAKA; HATAKEYAMA, DAIJIRO; SHIBATA, TOSHIYUKI

    2014-01-01

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

  4. Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro.

    PubMed

    Qiao, Jinping; Gu, Chenxin; Shang, Weihu; Du, Jinglei; Yin, Wei; Zhu, Meilin; Wang, Wei; Han, Mei; Lu, Weidong

    2011-06-01

    Tea drinking is widely practiced in the world and has recently increased among cancer patients. However, the effects of concurrent consumption of tea on the bioavailability and the net therapeutic potential of co-administered chemical drugs are not clear. In this study, the effects of green tea on the pharmacokinetics of 5-fluorouracil (5-FU) in rats and the pharmacodynamics in human cell lines in vitro were studied. The pharmacokinetic experiment indicated that there was an approximately 151% increase in the maximum plasma concentration (C(max)) and an approximately 425% increase in the area under the plasma concentration curve (AUC) of 5-FU in the green tea-treated group compared with the control group. Green tea consumption increased the plasma concentration of 5-FU. In addition, the pharmacodynamics experiment showed that at the moderate dose level (equivalent to <6 cups daily in human), neither fresh green tea extract nor (-)-epigallocatechin-3-gallate (EGCG) showed significant additive effects on the cytotoxicity of 5-FU in human cell lines. The results showed that it is crucial to perform therapeutic drug monitoring (TDM) when the cancer patients have a habit of drinking green tea. PMID:21440026

  5. Docetaxel combined with intraperitoneal hyperthermic perfusion chemotherapy and hyperthermia in the treatment of advanced ovarian cancer

    PubMed Central

    ZHANG, TING; PAN, QIONG; XIAO, SONGSHU; LI, LIJIE; XUE, MIN

    2016-01-01

    Ovarian cancer is a clinical type of gynecological malignant tumor with poor prognosis and a high mortality rate. At present, the primary treatment method used is surgery, with chemotherapy as an ajdunctive therapy. Thus, new short-term treatments should be identified. The aim of the present study was to investigate the short-term curative effects and safety of docetaxel combined with intraperitoneal cisplatin chemotherapy and hyperthermia treatment of advanced ovarian cancer. A total of 112 cases of advanced (stage III–IV) ovarian cancer patients confirmed by clinical diagnosis between October 2014 and December 2015 were included in the study. The patients were randomly divided into the study and control groups (n=56 cases). The control group was treated with docetaxel and intraperitoneal cisplatin hyperthermic perfusion chemotherapy, while the study group was treated with docetaxel venous chemotherapy and intraperitoneal cisplatin cyclical hyperthermic perfusion chemotherapy with BR-TRG-1 body cavity hyperthermic perfusion treatment system. Clinical treatment results for short-term curative effects and adverse reactions were compared and analyzed 8 weeks after treatment. The total effective rate of the study and control groups were 87.5 and 62.5%, respectively, and the difference was statistically significant (P<0.05). The controlled rate of ascites, remission rate of tumor and descent rate of CA125 of patients in the study group were better than patients in the control group (P<0.05). The rate of adverse reactions of patients in the study group was 39.3%, and the grade of toxicity was from I to II, while the rate of adverse reactions of patients in the control group was 55.4%, and the grade of toxicity was from II to III. The difference between the two groups was statistically significant (P<0.05). In conclusion, applying the combination of docetaxel, intraperitoneal cisplatin hyperthermic perfusion chemotherapy and hyperthermia to treat advanced ovarian

  6. An observation on combined use of chemotherapy and traditional Chinese medicine to relieve cancer pain.

    PubMed

    Lin, C; Lin, X; Yang, J

    1996-12-01

    We have treated 50 patients with stage III, VI malignant tumors confirmed by pathology. The patients were divided into two groups. One group was treated by combination of chemotherapy and traditional Chinese medicine (treatment group); the other only by chemotherapy (control group). The effect of cancer treatment was evaluated according to the criteria of WHO. The results showed that the effective rate was 80% in treatment group and 52% in control group. The pain relieving rate was 68% in treatment group and 40% in control group (P < 0.01). This fact demonstrates that the application of traditional Chinese medicine can invigorate blood circulation, eliminate blood stasis, soften hardness and dissolve the mass, nourish blood and increase vigor. This kind of application can not only enhance the effect of cancer treatment but also increase the cancer pain relieving rate. PMID:9389100

  7. Immune Effects of Chemotherapy, Radiation, and Targeted Therapy and Opportunities for Combination With Immunotherapy

    PubMed Central

    Wargo, Jennifer A.; Reuben, Alexandre; Cooper, Zachary A.; Oh, Kevin S.; Sullivan, Ryan J.

    2016-01-01

    There have been significant advances in cancer treatment over the past several years through the use of chemotherapy, radiation therapy, molecularly targeted therapy, and immunotherapy. Despite these advances, treatments such as monotherapy or monomodality have significant limitations. There is increasing interest in using these strategies in combination; however, it is not completely clear how best to incorporate molecularly targeted and immune-targeted therapies into combination regimens. This is particularly pertinent when considering combinations with immunotherapy, as other types of therapy may have significant impact on host immunity, the tumor microenvironment, or both. Thus, the influence of chemotherapy, radiation therapy, and molecularly targeted therapy on the host anti-tumor immune response and the host anti-host response (ie, autoimmune toxicity) must be taken into consideration when designing immunotherapy-based combination regimens. We present data related to many of these combination approaches in the context of investigations in patients with melanoma and discuss their potential relationship to management of patients with other tumor types. Importantly, we also highlight challenges of these approaches and emphasize the need for continued translational research. PMID:26320064

  8. Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin–paclitaxel doublet chemotherapy

    PubMed Central

    Roulstone, V; Twigger, K; Zaidi, S; Pencavel, T; Kyula, JN; White, C; McLaughlin, M; Seth, R; Karapanagiotou, EM; Mansfield, D; Coffey, M; Nuovo, G; Vile, RG; Pandha, HS; Melcher, AA; Harrington, KJ

    2016-01-01

    Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin—taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin—paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin—taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication. PMID:22895509

  9. Rationale for treatment design: biochemical modulation of 5-fluorouracil by leucovorin.

    PubMed

    Rustum, Y M; Cao, S; Zhang, Z

    1998-01-01

    Preclinical in vitro and in vivo results have demonstrated the conditions required for optimal modulation of 5-FU activity by LV. The ability to increase intracellular concentrations of higher chain length polyglutamates was a function of duration of longer exposure to LV rather than the dose. In rats bearing advanced colorectal tumors, the role of LV dosage was more clearly evident with the weekly 5-FU treatment schedule than with the daily schedule. Phase III clinical trials in patients with advanced colorectal cancer demonstrated that low-dose and high-dose LV (daily x 5) and weekly high-dose LV schedules yielded similar response rates with different toxicity profiles. A phase III trial demonstrated significant therapeutic advantages for a bimonthly schedule of high-dose LV over a monthly schedule of low-dose LV. Taken together, these results provide insight into LV biomodulation, but the optimal conditions for these regimens for individual patients remain undetermined. To date it has not been possible to identify the optimal conditions for modulation of 5-FU by LV in individual patients with advanced colorectal cancer, and response rates are comparable. A regimen that offers the opportunity to manage treatment-induced toxicity is recommended. With diarrhea being the primary dose-limiting toxicity with the weekly 5-FU and high-dose LV (manifested during the 2-3 weeks of treatment), management of toxicity can be achieved by delaying treatment, by dose reduction, and/or by treatment with octreotide47 without compromising efficacy. In contrast, with the daily x 5 schedule, multiple toxicities (mucositis [stomatitis], diarrhea, neutropenia, and hand and foot syndrome) are manifested regardless of the dose of LV administered. An additional advantage to the weekly schedule is that it provides the opportunity to use 5-FU/LV treatment in sequence or combination with other drugs, such as topoisomerase I inhibitors (CPT-11), antifolates (methotrexate, trimetrexate), and

  10. The rationale of combined radiotherapy and chemotherapy - Joint action of Castor and Pollux.

    PubMed

    Brunner, Thomas B

    2016-08-01

    This article aims to review the rationale behind the combination of radiotherapy and chemotherapy. Theoretical concepts describing the principles of the joint effects of chemoradiotherapy are reviewed. Preclinical and clinical evidence are collected and summarised demonstrating the co-operation between the two modalities which form the mainstay of the treatment of most solid tumours. Initially, the evolution of chemoradiotherapy was mostly empirically driven which is true for both, the early studies and the experimental investigations, rather than relying on scientific rationale. To date, the revised Steel's model proposes five mechanisms, spatial cooperation, cytotoxic enhancement, biological co-operation, temporary modulation and normal tissue protection to describe the interaction between radiotherapy and chemotherapy. Chemoradiotherapy has become the standard modality for most patients with locally advanced solid tumours due to better control of loco-regional disease and prolonged survival. Gradually, molecular prediction of efficacy is integrated such as MGMT status for combining temozolomide with radiotherapy in glioblastoma. As molecular targeted drugs are ready to be taken into triple combinations with chemoradiotherapy it is crucial to have a good understanding of the mechanisms of chemoradiotherapy for the rational development of future combinations. PMID:27644901

  11. Therapeutic and scintigraphic applications of polymeric micelles: combination of chemotherapy and radiotherapy in hepatocellular carcinoma.

    PubMed

    Shih, Ying-Hsia; Peng, Cheng-Liang; Chiang, Ping-Fang; Lin, Wuu-Jyh; Luo, Tsai-Yueh; Shieh, Ming-Jium

    2015-01-01

    This study evaluated a multifunctional micelle simultaneously loaded with doxorubicin (Dox) and labeled with radionuclide rhenium-188 ((188)Re) as a combined radiotherapy and chemotherapy treatment for hepatocellular carcinoma. We investigated the single photon emission computed tomography, biodistribution, antitumor efficacy, and pathology of (188)Re-Dox micelles in a murine orthotopic luciferase-transfected BNL tumor cells hepatocellular carcinoma model. The single photon emission computed tomography and computed tomography images showed high radioactivity in the liver and tumor, which was in agreement with the biodistribution measured by γ-counting. In vivo bioluminescence images showed the smallest size tumor (P<0.05) in mice treated with the combined micelles throughout the experimental period. In addition, the combined (188)Re-Dox micelles group had significantly longer survival compared with the control, (188)ReO4 alone (P<0.005), and Dox micelles alone (P<0.01) groups. Pathohistological analysis revealed that tumors treated with (188)Re-Dox micelles had more necrotic features and decreased cell proliferation. Therefore, (188)Re-Dox micelles may enable combined radiotherapy and chemotherapy to maximize the effectiveness of treatment for hepatocellular carcinoma. PMID:26719687

  12. Hematopoietic toxicity of regional radiation therapy. Correlations for combined modality therapy with systemic chemotherapy

    SciTech Connect

    Abrams, R.A.; Lichter, A.S.; Bromer, R.H.; Minna, J.D.; Cohen, M.H.; Deisseroth, A.B.

    1985-04-01

    Using circulating granulocyte-monocyte precursor colony-forming units in culture (CFUc) numbers as a probe along with standard blood count (CBC), the authors have quantitatively examined the hematopoietic toxicity of conventionally fractionated radiation therapy (RT) when combined with concurrent systemic chemotherapy or when used alone. Among 20 patients with limited stage small cell lung cancer receiving systemic chemotherapy with cyclophosphamide, CCNU, and methotrexate, the addition of involved field chest RT resulted in increased hematopoietic toxicity as judged by increased need for platelet transfusion (P less than 0.05) and decreased frequency of measurable CFUc (P less than 0.04). Among 22 patients receiving regional radiotherapy alone consistent hematopoietic toxicity was also observed. This toxicity, although generally of only mild to moderate clinical significance, was detected earlier and to a greater degree in patients who required radiation to larger treatment volumes, who had significant amounts of bone marrow in the port, and who had a high percentage of cardiac output flowing through the port. These data suggest that the hematopoietic toxicity of regional radiotherapy may be additive to that of concurrent systemic chemotherapy and may occur more promptly and to a greater degree when treatment volumes are larger or incorporate increased amounts of marrow volume or cardiac output.

  13. [Prophylactic effect of UFT in combination with intravesical chemotherapy on the recurrence of superficial bladder tumor].

    PubMed

    Yoshida, O; Kakehi, Y; Nishio, Y; Tomoyoshi, T; Konami, T; Usui, T; Igawa, M; Takenaka, I; Fujita, K

    1992-12-01

    The influence of N1-(2-tetrahydrofuryl)-5-fluorouracil plus uracil (UFT) on the recurrence of superficial bladder tumors was evaluated in a randomized clinical study. Group A (n = 196) underwent transurethral resection (TUR) and the intravesical chemoprophylaxis, while group B (n = 193) received 400 mg per a day of UFT orally for 6 months in addition to the instillation therapy. These adjuvant therapy was started one week after TUR. Consequently, 30 patients in group B showed UFT-related toxicity and administration of UFT was discontinued in 10 of them. In addition, 87 patients in group B did not complete the 6-month course of UFT administration. Comparison of 2-year actuarial non-recurrence curves revealed no significant difference between groups A and B. However, UFT seemed to have a favorable prophylactic effect when recurrence rates were compared among those patients with recurrent tumors (generalized Wilcoxon: p = 0.1277), and those with recurrent multiple tumors (p = 0.0847).

  14. Multifunctional superparamagnetic iron oxide nanoparticles for combined chemotherapy and hyperthermia cancer treatment

    NASA Astrophysics Data System (ADS)

    Quinto, Christopher A.; Mohindra, Priya; Tong, Sheng; Bao, Gang

    2015-07-01

    Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could generate sufficient heat to raise the local temperature to 43 °C, sufficient to trigger apoptosis in cancer cells. Further, we found that DOX-loaded SPIOs resulted in cell death comparable to free DOX, and that the combined effect of DOX and SPIO-induced hyperthermia enhanced cancer cell death in vitro. This study demonstrates the potential of using phospholipid-PEG coated SPIOs for chemotherapy-hyperthermia combinatorial cancer treatment with increased efficacy.Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could

  15. Outcome following incomplete surgical cytoreduction combined with intraperitoneal chemotherapy for colorectal peritoneal metastases

    PubMed Central

    Heaney, Roisin Mary; Shields, Conor; Mulsow, Jurgen

    2015-01-01

    Cytoreductive surgery combined with intraperitoneal chemotherapy can improve survival in appropriately selected patients with colorectal peritoneal metastases. Outcomes are best in those patients in whom a complete cytoreduction can be achieved. Unresectable disease is however encountered in approximately one-quarter of patients at laparotomy. The merits, or otherwise, of proceeding with an incomplete cytoreduction in this setting are unclear. We performed a review of published outcomes following incomplete cytoreduction for colorectal peritoneal metastases. Using the electronic databases, PubMed and MEDLINE, a systematic search of available literature published during the period January 1997 to September 2014 was conducted. Following application of exclusion criteria, 19 papers were identified and included in this review. These comprised fifteen case series, 3 case control studies and one randomised control trial. In the nineteen studies included in this review, 2790 patients underwent cytoreductive surgery with or without intraperitoneal chemotherapy for peritoneal metastases of colorectal origin. Of these, 1732 (62%) underwent a complete cytoreduction while 986 (35%) patients underwent an incomplete cytoreduction. Median survival in the complete cytoreduction group ranged from 11 to 62 mo while survival in the latter group ranged from 2.4 to 32 mo. Of the 986 patients with an incomplete cytoreduction, 331 patients received intraperitoneal chemotherapy and survival in this cohort ranged from 4.5 to 32 mo. An incomplete cytoreduction, with or without intraperitoneal chemotherapy, does not appear to confer a survival benefit. The limited available data points to a palliative benefit in a subset of patients. In the absence of high quality data, the decision as to whether or not to proceed with surgery should be made on an individual patient basis. PMID:26688707

  16. Population pharmacokinetics of oxaliplatin (85 mg/m2) in combination with 5-fluorouracil in patients with advanced colorectal cancer.

    PubMed

    Kho, Yuhan; Jansman, Frank G A; Prins, Nicolaas H; Neef, Cees; Brouwers, Jacobus R B J

    2006-04-01

    Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85 mg/m, are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to construct a population PK model to describe platinum (Pt) concentrations in plasma in 33 patients with colorectal cancer. The secondary objective was to determine the relationship between the amount of Pt in 24-hour urine and the amount of Pt in fractionated urine collection periods. Plasma and urine samples were collected from patients during their first oxaliplatin treatment course. Population PK analysis was performed with WinNonMix. The model that best described the Pt concentrations in plasma was a two-compartment PK model. The elimination clearance (CL) and the elimination clearance of the peripheral compartment (CL2) (median +/- SE) were 25.2 +/- 6.3 L/hr and 68 +/- 24.8 L/hr, respectively. The median volume of distribution (V1) was determined to be 41.6 +/- 9.4 L and the median volume of distribution of the peripheral compartment (V2) was 452.5 +/- 96.4 L. The relationship between the cumulative amount of Pt in urine in the first 12 hours compared with the amount of Pt in 24 hours urine was reflected by a correlation coefficient (r2) of 0.95. The cumulative Pt concentration in urine in the first 10 hours and the first 8 hours compared with 24 hours was reflected by correlation coefficients r2 = 0.93 and r2 = 0.897, respectively. This PK model could be useful in identifying predictors for PK and pharmacodynamic variability to individualize dosing. The results of this study suggest that fractionated urine samples can replace 24-hour urine collection. PMID:16628132

  17. Molecular-targeted therapy for chemotherapy-refractory gastric cancer: a case report and literature review.

    PubMed

    Kuo, Hung-Yang; Yeh, Kun-Huei

    2014-07-01

    The prognosis of advanced gastric cancer (AGC) remains poor despite therapeutic advances in recent decades. Several recent positive phase III trials established the efficacy of second-line chemotherapy for metastatic gastric cancer in prolonging overall survival. However, malnutrition and poor performance of AGC in late stages usually preclude such patients from intensive treatment. Many targeted-therapies failed to show a significant survival benefit in AGC, but have regained attention after the positive result of ramucirumab was announced last year. Among all targeted agents, only trastuzumab, a monoclonal antibody against Human epidermal growth factor receptor-2 (HER2) protein, has been proven as having survival benefit by addition to first-line chemotherapy. Herein we reported a patient who benefited from adding trastuzumab to the same second-line combination chemotherapy (paclitaxel, 5-fluorouracil, and leucovorin) upon progression of bulky liver metastases. At least five months of progression-free survival were achieved without any additional toxicity. We also reviewed literature of molecularly-targeted therapy for chemotherapy-refractory gastric cancer, including several large phase III trials (REGARD, GRANITE-1, EXPAND, and REAL-3) published in 2013-2014. PMID:24982389

  18. Molecular-targeted therapy for chemotherapy-refractory gastric cancer: a case report and literature review.

    PubMed

    Kuo, Hung-Yang; Yeh, Kun-Huei

    2014-07-01

    The prognosis of advanced gastric cancer (AGC) remains poor despite therapeutic advances in recent decades. Several recent positive phase III trials established the efficacy of second-line chemotherapy for metastatic gastric cancer in prolonging overall survival. However, malnutrition and poor performance of AGC in late stages usually preclude such patients from intensive treatment. Many targeted-therapies failed to show a significant survival benefit in AGC, but have regained attention after the positive result of ramucirumab was announced last year. Among all targeted agents, only trastuzumab, a monoclonal antibody against Human epidermal growth factor receptor-2 (HER2) protein, has been proven as having survival benefit by addition to first-line chemotherapy. Herein we reported a patient who benefited from adding trastuzumab to the same second-line combination chemotherapy (paclitaxel, 5-fluorouracil, and leucovorin) upon progression of bulky liver metastases. At least five months of progression-free survival were achieved without any additional toxicity. We also reviewed literature of molecularly-targeted therapy for chemotherapy-refractory gastric cancer, including several large phase III trials (REGARD, GRANITE-1, EXPAND, and REAL-3) published in 2013-2014.

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  1. The role of temperature increase rate in combinational hyperthermia chemotherapy treatment

    NASA Astrophysics Data System (ADS)

    Tang, Yuan; McGoron, Anthony J.

    2010-02-01

    Hyperthermia in combination with chemotherapy has been widely used in cancer treatment. Our previous study has shown that rapid rate hyperthermia in combination with chemotherapy can synergistically kill cancer cells whereas a sub-additive effect was found when a slow rate hyperthermia was applied. In this study, we explored the basis of this difference. For this purpose, in vitro cell culture experiments with a uterine cancer cell line (MES-SA) and its multidrug resistant (MDR) variant MES-SA/Dx5 were conducted. P-glycoprotein (P-gp) expression, Caspase 3 activity, and heat shock protein 70 (HSP 70) expression following the two different modes of heating were measured. Doxorubicin (DOX) was used as the chemotherapy drug. Indocyanine green (ICG), which absorbs near infrared light at 808nm (ideal for tissue penetration), was chosen for achieving rapid rate hyperthermia. Slow rate hyperthermia was provided by a cell culture incubator. Two sets of thermal doses were delivered by either slow rate or rapid rate hyperthermia. HSP70 expression was highly elevated under low dose slow rate incubator hyperthermia while maintained at the baseline level under the other three treatments. Caspase3 level slightly increased after low dose slow rate incubator hyperthermia while necrotic cell death was found in the other three types of heat treatment. In conclusion, when given at the same thermal dose, slow rate hyperthermia is more likely to induce thermotolerance. Meanwhile, hyperthermia showed a dose dependent capability in reversing P-gp mediated MDR; when MDR is reversed, the combinational treatment induced extensive necrotic cell death. During this process, the rate of heating also played a very important role; necrosis was more dramatic in rapid rate hyperthermia than in slow rate hyperthermia even though they were given at the same dose.

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

    PubMed

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

    2016-01-01

    The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5-fluorouracil and is catabolized by the same enzymatic pathway. Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and ß-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non-compartmental model. Thymine peaked quickly (30-45min) in plasma to a maximum concentration of 170±185μg/L (mean±SD). Clearance was high (mean 57.9L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (<1%). Apparent formation rate-limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma ß-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs.

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

    SciTech Connect

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

    2012-02-24

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

  4. Stimuli-free programmable drug release for combination chemo-therapy

    NASA Astrophysics Data System (ADS)

    Fan, Li; Jin, Boquan; Zhang, Silu; Song, Chaojun; Li, Quan

    2016-06-01

    Combinational chemotherapy capable of targeted delivery and programmable multi-drug release leads to enhanced drug efficacy, and is highly desired for cancer treatment. However, effective approaches for achieving both features in a single treatment are limited. In the present work, we demonstrated programmed delivery of both chemotherapeutic and immunotherapeutic agents with tumor cell targeting capability by using SiO2 based self-decomposable nanoparticulate systems. The programmable drug delivery is realized by manipulating drug loading configurations instead of relying on external stimuli. Both in vitro and in vivo results showed specific drug binding to FAT1-expressing colon cancer cells. The loaded dual drugs were demonstrated to be delivered in a sequential manner with specific time intervals between their peak releases, which maximize the synergistic effect of the chemotherapeutics. These features led to significantly enhanced drug efficacy and reduced system toxicity. The tumor weight decreased by 1/350, together with a moderate increase in rats' body weight, which were observed when adopting the dual drug loaded nanoparticles, as compared to those of the control groups. The present system provides a simple and feasible method for the design of targeting and combination chemotherapy with programmed drug release.Combinational chemotherapy capable of targeted delivery and programmable multi-drug release leads to enhanced drug efficacy, and is highly desired for cancer treatment. However, effective approaches for achieving both features in a single treatment are limited. In the present work, we demonstrated programmed delivery of both chemotherapeutic and immunotherapeutic agents with tumor cell targeting capability by using SiO2 based self-decomposable nanoparticulate systems. The programmable drug delivery is realized by manipulating drug loading configurations instead of relying on external stimuli. Both in vitro and in vivo results showed specific drug

  5. Use of Adjuvant 5-Fluorouracil and Radiation Therapy After Gastric Cancer Resection Among the Elderly and Impact on Survival

    SciTech Connect

    Strauss, Joshua; Hershman, Dawn L.; Buono, Donna; McBride, Russell; Clark-Garvey, Sean; Woodhouse, Shermian A.; Abrams, Julian A.

    2010-04-15

    Purpose: In randomized trials patients with resected nonmetastatic gastric cancer who received adjuvant chemotherapy and radiotherapy (chemoRT) had better survival than those who did not. We investigated the effectiveness of adjuvant chemoRT after gastric cancer resection in an elderly general population and its effects by stage. Methods and Materials: We identified individuals in the Surveillance, Epidemiology, and End Results-Medicare database aged 65 years or older with Stage IB through Stage IV (M0) gastric cancer, from 1991 to 2002, who underwent gastric resection, using multivariate modeling to analyze predictors of chemoRT use and survival. Results: Among 1,993 patients who received combined chemoRT or no adjuvant therapy after resection, having a later year of diagnosis, having a more advanced stage, being younger, being white, being married, and having fewer comorbidities were associated with combined treatment. Among 1,476 patients aged less than 85 years who survived more than 4 months, the 313 who received combined treatment had a lower mortality rate (hazard ratio, 0.83; 95% confidence interval, 0.71-0.98) than the 1,163 who received surgery alone. Adjuvant therapy significantly reduced the mortality rate for Stages III and IV (M0), trended toward improved survival for Stage II, and showed no benefit for Stage IB. We observed trends toward improved survival in all age categories except 80 to 85 years. Conclusions: The association of combined adjuvant chemoRT with improved survival in an overall analysis of Stage IB through Stage IV (M0) resected gastric cancer is consistent with clinical trial results and suggests that, in an elderly population, adjuvant chemoradiotherapy is effective. However, our observational data suggest that adjuvant treatment may not be effective for Stage IB cancer, is possibly appropriate for Stage II, and shows significant survival benefits for Stages III and IV (M0) for those aged less than 80 years.

  6. Neuroprotective effects of intravenous transplantation of bone marrow mononuclear cells from 5-fluorouracil pre-treated rats on ischemic stroke.

    PubMed

    Li, Y; Mao, W W; Zhang, C G; Wan, L; Jing, C H; Hua, X M; Li, S T; Cheng, J

    2016-03-15

    Our previous findings showed bone marrow mononuclear cells (BMMNCs) from 5- fluorouracil (5-FU) pre-treated rats (named BMRMNCs) had a better therapeutic efficacy in ischemia/reperfusion rats as compared to BMMNCs from untreated rats. This study was undertaken to explore the potential mechanisms underlying the neuroprotective effects of BMRMNCs in middle cerebral artery occlusion (MCAO) rat model. Rats were intravenously pre-treated with 5-FU and BMRMNCs were collected at different time points. The contents of growth factors in the supernatant and CXCR4 expression were detected by ELISA and flow cytometry, respectively. MCAO was introduced to rats, and BMMNCs and BMRMNCs collected at 7 days after 5-FU pre-treatment were independently transplanted via the tail vein 24h later. The neurological function was evaluated before cell transplantation and at 24h, 7d and 14d after cell transplantation. Rats were sacrificed at 14d after cell transplantation, the brains were collected for TTC staining, infarct volume detection, NISSL staining, counting of viable cells in the CA1 region, and observation of transplanted cells. BMRMNCs had elevated expressions of growth factors as well as CXCR4 expression. Our results confirmed the better therapeutic effects of BMRMNCs in MCAO rats, demonstrated by reduction in infarct volume, improvement of neurological function and more viable cells in the hippocampus. In addition, more transplanted cells were found after BMRMNCs transplantation at 7 days and 14 days although there was no marked difference at 14 days. These findings indicate that BMRMNCs transplantation may protect ischemic stroke, at least partially, via increasing the secretion of growth factors and migration to the injured site.

  7. A novel drug delivery of 5-fluorouracil device based on TiO2/ZnS nanotubes.

    PubMed

    Faria, Henrique Antonio Mendonça; de Queiroz, Alvaro Antonio Alencar

    2015-11-01

    The structural and electronic properties of titanium oxide nanotubes (TiO2) have attracted considerable attention for the development of therapeutic devices and imaging probes for nanomedicine. However, the fluorescence response of TiO2 has typically been within ultraviolet spectrum. In this study, the surface modification of TiO2 nanotubes with ZnS quantum dots was found to produce a red shift in the ultra violet emission band. The TiO2 nanotubes used in this work were obtained by sol-gel template synthesis. The ZnS quantum dots were deposited onto TiO2 nanotube surface by a micelle-template inducing reaction. The structure and morphology of the resulting hybrid TiO2/ZnS nanotubes were investigated by scanning electron microscopy, transmission electron microscopy and X-ray diffraction techniques. According to the results of fluorescence spectroscopy, pure TiO2 nanotubes exhibited a high emission at 380nm (3.26eV), whereas TiO2/ZnS exhibited an emission at 410nm (3.02eV). The TiO2/ZnS nanotubes demonstrated good bio-imaging ability on sycamore cultured plant cells. The biocompatibility against mammalian cells (Chinese Hamster Ovarian Cells-CHO) suggesting that TiO2/ZnS may also have suitable optical properties for use as biological markers in diagnostic medicine. The drug release characteristic of TiO2/ZnS nanotubes was explored using 5-fluorouracil (5-FU), an anticancer drug used in photodynamic therapy. The results show that the TiO2/ZnS nanotubes are a promising candidate for anticancer drug delivery systems. PMID:26249588

  8. The relationship of bleb morphology and the outcome of needle revision with 5-fluorouracil in failing filtering bleb

    PubMed Central

    Lee, Yung-Sung; Wu, Shiu-Chen; Tseng, Hsiao-Jung; Wu, Wei-Chi; Chang, Shirley H.L.

    2016-01-01

    Abstract To investigate the risk factors for failure of needling revision with 5-fluorouracil (5-FU) and to identify the correlation of outcomes of needling revision and the morphological features of dysfunctional filtration blebs using Moorfields bleb grading system. This retrospective, nonrandomized, comparative case–control study included 41 consecutive patients (41 eyes) who underwent 5-FU needling revision for failed or failing filtration blebs between July 2012 and August 2014 in Chang Gung Memorial Hospital, a referral center in Taiwan. The main outcome measures were the bleb survival and the correlation factors of bleb morphology before revision. The secondary outcome measure was the identification of any study factor associated with bleb failure. Forty-one eyes of 41 patients were included in this study. The most frequent glaucoma diagnoses were 10 cases (24%) of neovascular glaucoma and 8 cases (19%) of chronic open-angle glaucoma. Survival of bleb at 6, 12, and 24 months was 42%, 39%, and 23%. Fourteen cases (34%) maintained overall success at the last follow-up, with an average follow-up of 22.7 ± 9.4 months (range: 12–48 months). The central bleb area and height were significantly different between the successful needling group and the failed needling group (P = 0.03 and 0.04, respectively). Further trend test confirmed that smaller central bleb extension and flatter height were associated with a higher chance of failure (P = 0.02 and 0.02, respectively). Time from initial trabeculectomy to needling of less than 4 months and higher intraocular pressure (IOP) in the first postoperative week also led to significantly higher risk for failure (P = 0.01 and 0.03, respectively). A small central area and the flat height of dysfunctional blebs were more likely to fail after the needle revision. Cautious case selections, taking account of the time from the initial filtering surgery and postoperative IOP, may improve the surgical outcome. PMID:27603345

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

    PubMed Central

    Liu, Wei; Wang, Jianrong; Zhang, Miaomiao; Tao, Yuan; Sun, Yan

    2016-01-01

    Background. To compare the efficacy of needle revision with 5-fluorouracil (5-FU) and mitomycin C (MMC) on dysfunctional filtration blebs shortly after trabeculectomy. Methods. It is a prospective randomized study comparing needle revision augmented with MMC or 5-FU for failed trabeculectomy blebs. Results. To date 71 patients (75 eyes) have been enrolled, 40 eyes in the MMC group and 35 in the 5-FU group. 68 patients (72 eyes) have completed 12-month follow-up, 38 eyes in the MMC group and 34 in the 5-FU group. The mean IOP before and that after needle revision in the MMC group were 26.5 ± 4.3 mmHg and 11.3 ± 3.4 mmHg, respectively (P < 0.05), and in the 5-FU group were 27.1 ± 3.8 mmHg and 10.9 ± 3.4 mmHg, respectively (P < 0.05). At 12-month follow-up, complete success rates were 57.5% for MMC group and 34.3% for 5-FU group (P = 0.042; log-rank test) and 75% and 60% (P = 0.145; log-rank test), respectively, for the qualified success. Complication rates between the two groups were not statistically different (P > 0.05). Conclusions. Needle revision and subconjunctival MMC injection were more effective than needling and subconjunctival 5-FU injection for early dysfunctional filtration blebs after trabeculectomies. PMID:26989499

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

    PubMed

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

    2015-07-01

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

  11. SM5-1-conjugated PLA nanoparticles loaded with 5-fluorouracil for targeted hepatocellular carcinoma imaging and therapy.

    PubMed

    Ma, Xibo; Cheng, Zhen; Jin, Yushen; Liang, Xiaolong; Yang, Xin; Dai, Zhifei; Tian, Jie

    2014-03-01

    SM5-1 is a humanized mouse antibody which has a high binding specificity for a membrane protein of about 230 kDa overexpressed in hepatocellular carcinoma (HCC), melanoma and breast cancer. In this study, SM5-1-conjugated poly D, L (lactide-coglycolide) (PLA) PLA containing Cy7 (PLA-Cy7-SM5-1) was prepared to study the targeting specificity of the bioconjugate to HCC-LM3-fLuc cell. Then, SM5-1-conjugated PLA containing 5-fluorouracil (5-FU) (PLA-5FU-SM5-1) and PLA containing 5-FU (PLA-5FU) were prepared for treatment of subcutaneous HCC-LM3-fLuc tumor mice. The results showed that PLA-5FU-SM5-1, PLA-5FU and 5-FU induced a 45.07%, 23.56% and 19.05% tumor growth inhibition rate, respectively, on day 31 post-treatment as determined by bioluminescent intensity. In addition, in order to evaluate the antitumor efficacy of PLA-5FU-SM5-1, HCC-LM3-fLuc cells were injected into the liver to establish the experimental orthotopic liver tumor models. The experiments showed that PLA-5FU-SM5-1, PLA-5FU and 5-FU induced a 53.24%, 31.00%, and 18.11% tumor growth inhibition rate, respectively, on day 31 post-treatment determined by the bioluminescent intensity of the abdomen in tumor-bearing mice. Furthermore, we have calculated the three-dimensional location of the liver cancer in mice using a multilevel adaptive finite element algorithm based on bioluminescent intensity decay calibration. The reconstruction results demonstrated that PLA-5FU-SM5-1 inhibited the tumor rapid progression, which were consistent with the results of subcutaneous tumor mice experiments and in vitro cell experiment results.

  12. A novel drug delivery of 5-fluorouracil device based on TiO2/ZnS nanotubes.

    PubMed

    Faria, Henrique Antonio Mendonça; de Queiroz, Alvaro Antonio Alencar

    2015-11-01

    The structural and electronic properties of titanium oxide nanotubes (TiO2) have attracted considerable attention for the development of therapeutic devices and imaging probes for nanomedicine. However, the fluorescence response of TiO2 has typically been within ultraviolet spectrum. In this study, the surface modification of TiO2 nanotubes with ZnS quantum dots was found to produce a red shift in the ultra violet emission band. The TiO2 nanotubes used in this work were obtained by sol-gel template synthesis. The ZnS quantum dots were deposited onto TiO2 nanotube surface by a micelle-template inducing reaction. The structure and morphology of the resulting hybrid TiO2/ZnS nanotubes were investigated by scanning electron microscopy, transmission electron microscopy and X-ray diffraction techniques. According to the results of fluorescence spectroscopy, pure TiO2 nanotubes exhibited a high emission at 380nm (3.26eV), whereas TiO2/ZnS exhibited an emission at 410nm (3.02eV). The TiO2/ZnS nanotubes demonstrated good bio-imaging ability on sycamore cultured plant cells. The biocompatibility against mammalian cells (Chinese Hamster Ovarian Cells-CHO) suggesting that TiO2/ZnS may also have suitable optical properties for use as biological markers in diagnostic medicine. The drug release characteristic of TiO2/ZnS nanotubes was explored using 5-fluorouracil (5-FU), an anticancer drug used in photodynamic therapy. The results show that the TiO2/ZnS nanotubes are a promising candidate for anticancer drug delivery systems.

  13. A nanomedicine-promising approach to provide an appropriate colon-targeted drug delivery system for 5-fluorouracil

    PubMed Central

    Singh, Sima; Kotla, Niranjan G; Tomar, Sonia; Maddiboyina, Balaji; Webster, Thomas J; Sharma, Dinesh; Sunnapu, Omprakash

    2015-01-01

    Targeted drug delivery plays a significant role in disease treatment associated with the colon, affording therapeutic responses for a prolonged period of time with low side effects. Colorectal cancer is the third most common cancer in both men and women with an estimated 102,480 cases of colon cancer and 40,340 cases of rectal cancer in 2013 as reported by the American Cancer Society. In the present investigation, we developed an improved oral delivery system for existing anticancer drugs meant for colon cancer via prebiotic and probiotic approaches. The system comprises three components, namely, nanoparticles of drug coated with natural materials such as guar gum, xanthan gum (that serve as prebiotics), and probiotics. The natural gums play a dual role of protecting the drug in the gastric as well as intestinal conditions to allow its release only in the colon. In vitro results obtained from these experiments indicated the successful targeted delivery of 5-fluorouracil to the colon. Electron microscopy results demonstrated that the prepared nanoparticles were spherical in shape and 200 nm in size. The in vitro release data indicated that the maximum release occurs at pH 7.2 and 7.4 with 93% of the drug released in the presence of 4% (w/v) of rat cecal content. In vivo results conclude a practical mechanism to maintain the integrity and intactness of the intestinal/colonic microflora, in the face of a “chemical attack” by oral colon-targeted drug delivery for colon cancer treatment. PMID:26648721

  14. Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: A matched-pair analysis

    SciTech Connect

    Das, Prajnan . E-mail: PrajDas@mdanderson.org; Lin, Edward H.; Bhatia, Sumita; Skibber, John M.; Rodriguez-Bigas, Miguel A.; Feig, Barry W.; Chang, George J.; Hoff, Paulo M.; Eng, Cathy; Wolff, Robert A.; Delclos, Marc E.; Krishnan, Sunil; Janjan, Nora A.; Crane, Christopher H.

    2006-12-01

    Purpose: To retrospectively compare the acute toxicity, pathologic response, relapse rates, and survival in rectal cancer patients treated with preoperative radiotherapy (RT) and either concurrent capecitabine or concurrent protracted infusion 5-fluorouracil (5-FU). Methods: Between June 2001 and February 2004, 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT and concurrent capecitabine, followed by mesorectal excision. These patients were individually matched by clinical T and N stage (as determined by endoscopic ultrasound and CT scans) with 89 control patients treated with preoperative RT and concurrent protracted infusion 5-FU between September 1997 and August 2002. Results: In each group, 5 patients (6%) had Grade 3-4 toxicity during chemoradiotherapy. The pathologic complete response rate was 21% with capecitabine and 12% with protracted infusion 5-FU (p = 0.19). Of the 89 patients in the capecitabine group and 89 in the 5-FU group, 46 (52%) and 55 (62%), respectively, had downstaging of the T stage after chemoradiotherapy (p = 0.20). The estimated 3-year local control (p = 0.15), distant control (p = 0.86), and overall survival (p = 0.12) rate was 94.4%, 86.3%, and 89.8% for patients treated with capecitabine and 98.6%, 86.6%, and 96.4% for patients treated with protracted infusion 5-FU, respectively. Conclusion: Preoperative concurrent capecitabine and concurrent protracted infusion 5-FU were both well tolerated, with similar, low rates of Grade 3-4 acute toxicity. No significant differences were seen in the pathologic response, local and distant recurrence, or overall survival among patients treated with preoperative RT and concurrent capecitabine compared with those treated with RT and concurrent protracted infusion 5-FU.

  15. A nanomedicine-promising approach to provide an appropriate colon-targeted drug delivery system for 5-fluorouracil.

    PubMed

    Singh, Sima; Kotla, Niranjan G; Tomar, Sonia; Maddiboyina, Balaji; Webster, Thomas J; Sharma, Dinesh; Sunnapu, Omprakash

    2015-01-01

    Targeted drug delivery plays a significant role in disease treatment associated with the colon, affording therapeutic responses for a prolonged period of time with low side effects. Colorectal cancer is the third most common cancer in both men and women with an estimated 102,480 cases of colon cancer and 40,340 cases of rectal cancer in 2013 as reported by the American Cancer Society. In the present investigation, we developed an improved oral delivery system for existing anticancer drugs meant for colon cancer via prebiotic and probiotic approaches. The system comprises three components, namely, nanoparticles of drug coated with natural materials such as guar gum, xanthan gum (that serve as prebiotics), and probiotics. The natural gums play a dual role of protecting the drug in the gastric as well as intestinal conditions to allow its release only in the colon. In vitro results obtained from these experiments indicated the successful targeted delivery of 5-fluorouracil to the colon. Electron microscopy results demonstrated that the prepared nanoparticles were spherical in shape and 200 nm in size. The in vitro release data indicated that the maximum release occurs at pH 7.2 and 7.4 with 93% of the drug released in the presence of 4% (w/v) of rat cecal content. In vivo results conclude a practical mechanism to maintain the integrity and intactness of the intestinal/colonic microflora, in the face of a "chemical attack" by oral colon-targeted drug delivery for colon cancer treatment. PMID:26648721

  16. Low-dose total body irradiation versus combination chemotherapy for lymphomas with follicular growth pattern.

    PubMed

    Meerwaldt, J H; Carde, P; Burgers, J M; Monconduit, M; Thomas, J; Somers, R; Sizoo, W; Glabbeke, M V; Duez, N; de Wolf-Peeters, C

    1991-10-01

    The treatment of Non-Hodgkin's lymphomas with follicular growth pattern and advanced stage of disease remains controversial. Treatments varying from no initial treatment up to aggressive combination chemotherapy have been advocated. The EORTC Lymphoma Cooperative Group has performed a randomized prospective trial comparing short duration low dose total body irradiation (TBI) vs combination chemotherapy (CHVmP) + consolidation radiotherapy. Ninety-three patients were entered; of 84 evaluable patients, 44 received TBI and 40 CHVmP. Complete remission (CR) rates were 36%--TBI and 55%--CHVmP, but overall response rates were identical, 76 versus 69%. No significant difference in freedom from progression or survival was observed. No unexpected toxicity was seen. Although numbers are small, we cannot conclude that aggressive combination chemo-radiotherapy resulted in a better survival. Our analysis confirms that there is a constant risk of relapse. Other approaches should be explored if survival benefit is the ultimate goal in treatment of this patient population. PMID:1938514

  17. Modified irinotecan and infusional 5-fluorouracil (mFOLFIRI) in patients with refractory advanced pancreas cancer (APC): a single-institution experience.

    PubMed

    Bupathi, M; Ahn, D H; Wu, C; Ciombor, K K; Stephens, J A; Reardon, J; Goldstein, D A; Bekaii-Saab, T

    2016-04-01

    Pancreatic adenocarcinoma is the fourth leading cause of cancer death. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in outcome measures with acceptable toxicities when combined with 5-fluorouracil (5-FU)/leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in advanced pancreas cancer (APC). We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs), and Kaplan-Meier methods were used to calculate the median progression-free survival (PFS) and overall survival (OS). Forty patients were included in this analysis. Patients received 1-5 lines of prior therapy (25 % with more than 3 lines of prior therapy). The mean age at diagnosis was 60, and 98 % had ECOG of 1. The mean CA 19-9 at the start of therapy was 33,169 U/ml. The median PFS was 2.59 months [95 % confidence interval (CI) (1.90, 3.54)], and OS was 4.75 months [95 % CI (3.14, 8.98)]. The most common AEs included fatigue (98 %), neuropathy (83 %), anorexia (68 %), nausea (60 %) and constipation (55 %). Grade 3 toxicities included fatigue (13 %) and rash (3 %). There were no observed grade 4 toxicities. In this single-institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in a heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC. PMID:26995224

  18. [A case of sarcomatoid malignant peritoneal mesothelioma responding to combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine(CYVADIC)].

    PubMed

    Kusama, Toshiyuki; Kodaka, Taiichi; Tsunemine, Hiroko; Akasaka, Hiroshi; Koizumi, Naoki; Fujimoto, Koji; Sakano, Shigeru; Ito, Rieko; Kondo, Takeshi; Kitazawa, Sohei; Yamamura, Hisako; Takahashi, Katsuhito

    2009-03-01

    A 66-year-old woman was seen at our hospital because of abdominal fullness. A computed tomography(CT)revealed massive tumors in abdominal cavity. The patient underwent surgery consisting of tumorectomy, segmental gastrectomy, partial resection of small intestin, transverse colectomy, left oophorectomy and gastrostomy. By using immunohistochemical staining, the patient was diagnosed as sarcomatoid malignant peritoneal mesothelioma. Rapidly abdominal fullness occurred as of 22 days after the operation, and an abdominal CT revealed the massive recurrent tumors. We started a combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC). The recurrent tumors showed remarkable reduction after the two courses of CYVADIC chemotherapy. Although we next started carboplatin and paclitaxel combination chemotherapy, she died due to rapidly progression of the disease with disseminated intravascular coagulation after 132 days of the operation. Malignant mesothelioma, especially sarcomatoid mesothelioma, is known to have a poor prognosis. However, our case suggests that we could improve the prognosis of sarcomatoid malignant mesothelioma by aggressive chemotherapy.

  19. Pregnancies and menstrual function before and after combined radiation (RT) and chemotherapy (TVPP) for Hodgkin's disease

    SciTech Connect

    Lacher, M.J.; Toner, K.

    1986-01-01

    The menstrual cycle, pregnancies, and offspring were evaluated before and after initial combined radiation (RT) and chemotherapy with thiotepa, vinblastine, vincristine, procarbazine, and prednisone (TVPP), in 34 women between the ages of 18 and 44 (median 26.5 years) treated for Stage II and Stage III Hodgkin's disease. The median range of follow-up is 83.1 months (range 40.5-140). After therapy 94.1% (32/34) continued to menstruate. Two of the four patients over the age of 35 ceased to menstruate. All patients under the age of 35 continued to menstruate (30/30). Age at the time of diagnosis was the only factor affecting change in menses with a significant probability (p = .001) that women greater than 30 years of age will experience some change in menstrual pattern. Seventeen pregnancies occurred in 12 women after therapy; 2 had 4 elective abortions; 10 delivered 12 children with normal physical development; 1 will deliver six months from now. Twelve of thirteen patients who wanted to become pregnant have conceived. The ability to become pregnant and deliver normal children after intensive treatment with combined radiation and chemotherapy (RT/TVPP) was comparable to the patients' pretreatment record.

  20. Multifunctional Superparamagnetic Iron Oxide Nanoparticles for Combined Chemotherapy and Hyperthermia Cancer Treatment

    PubMed Central

    Quinto, Christopher A.; Mohindra, Priya; Tong, Sheng

    2015-01-01

    Superparamagnetic iron oxide nanoparticles (SPIOs) have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with PEG length. With a core size of 14 nm, the SPIOs could generate sufficient heat to raise the local temperature to 43°C, enough to trigger apoptosis in cancer cells. Further, we found that DOX-loaded SPIOs resulted in cell death comparable to free DOX, and that the combined effect of DOX and SPIO-induced hyperthermia enhanced cancer cell death in vitro. This study demonstrates the potential of using phospholipid-PEG coated SPIOs for chemotherapy-hyperthermia combinatorial cancer treatment with increased efficacy. PMID:26154916

  1. Nanocomposite hydrogel incorporating gold nanorods and paclitaxel-loaded chitosan micelles for combination photothermal-chemotherapy.

    PubMed

    Zhang, Nan; Xu, Xuefan; Zhang, Xue; Qu, Ding; Xue, Lingjing; Mo, Ran; Zhang, Can

    2016-01-30

    Development of combination photothermal-chemotherapy platform is of great interest for enhancing antitumor efficacy and inhibiting tumor recurrence, which supports selective and dose-controlled delivery of heat and anticancer drugs to tumor. Here, an injectable nanocomposite hydrogel incorporating PEGylated gold nanorods (GNRs) and paclitaxel-loaded chitosan polymeric micelles (PTX-M) is developed in pursuit of improved local tumor control. After intratumoral injection, both GNRs and PTX-M can be simultaneously delivered and immobilized in the tumor tissue by the thermo-sensitive hydrogel matrix. Exposure to the laser irradiation induces the GNR-mediated photothermal damage confined to the tumor with sparing the surrounding normal tissue. Synergistically, the co-delivered PTX-M shows prolonged tumor retention with the sustained release of anticancer drug to efficiently kill the residual tumor cells that evade the photothermal ablation due to the heterogeneous heating in the tumor region. This combination photothermal-chemotherapy presents superior effects on suppressing the tumor recurrence and prolonging the survival in the Heps-bearing mice, compared to the photothermal therapy alone.

  2. Effect of L-histidinol on the metabolism of 5-fluorouracil in the BALB/c x DBA/8 F1 murine tumor system.

    PubMed

    Sawyer, R C; Stolfi, R L; Martin, D S

    1988-12-01

    L-Histidinol, a structural analogue of histidine, which transiently inhibits proliferation, can protect cells from the toxic effects of proliferation-dependent chemotherapeutic agents such as 5-fluorouracil (FUra). In the BALB/c x DBA/8 F1 (hereafter called CD8F1) murine tumor system, L-histidinol protected mice from FUra-induced leukopenia, weight loss, and mortality; however, the therapeutic index was not improved since L-histidinol also protected the tumor against the toxic effects of FUra. In order to understand the mechanism of this protection, we examined the effects of L-histidinol on the metabolism of FUra. Results indicate that L-histidinol had no effect on the phosphoribosyl pyrophosphate levels in tumor, the activation of FUra to nucleotides or levels of free 5-fluorodeoxyuridine monophosphate in either tumor or bone marrow. L-Histidinol (7 mg/mouse, every 2 h for 5 doses) reduced RNA and DNA synthesis, as measured by 32P incorporation in vivo, by approximately one-half in tumor, and by 70% in bone marrow. This in turn resulted in reduced incorporation of FUra into RNA in both tumor and bone marrow. At 2 h, 4 h, and 24 h after FUra administration the level of FUra in RNA was 24-37% less in both tumor and bone marrow of mice that received L-histidinol with FUra. Using 32P as a monitor of overall RNA synthesis, the [3H]FUra/32P ratio remained unchanged, suggesting that the reduction of FUra incorporation into RNA was due to decreased RNA synthesis rather than a decrease in the number of FUra molecules per RNA chain. In contrast, L-histidinol had no effect on the in vivo inhibition of thymidylate synthetase by 5-fluorodeoxyuridine monophosphate as measured by the incorporation of [3H]-2'-deoxyuridine into DNA or on the percentages of thymidylate synthetase in the free versus 5-fluorodeoxyuridine monophosphate-bound state. We conclude that L-histidinol reduces FUra toxicity by reducing FUra incorporation into RNA. Since the major mechanism of action in the

  3. Hyaluronic acid-functionalized polymeric nanoparticles for colon cancer-targeted combination chemotherapy

    NASA Astrophysics Data System (ADS)

    Xiao, Bo; Han, Moon Kwon; Viennois, Emilie; Wang, Lixin; Zhang, Mingzhen; Si, Xiaoying; Merlin, Didier

    2015-10-01

    Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments demonstrated that the introduction of HA to the NP surface endowed NPs with colon cancer-targeting capability and markedly increased cellular uptake efficiency compared with chitosan-coated NPs. Importantly, the combined delivery of CPT and CUR in one HA-functionalized NP exerted strong synergistic effects. HA-CPT/CUR-NP (1 : 1) showed the highest antitumor activity among the three HA-CPT/CUR-NPs, resulting in an extremely low combination index. Collectively, our findings indicate that this HA-CPT/CUR-NP can be exploited as an efficient formulation for colon cancer-targeted combination chemotherapy.Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments

  4. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging

    PubMed Central

    Glasgow, Micah D. K.; Chougule, Mahavir B.

    2016-01-01

    Nanotechnology and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug’s therapeutic effectiveness while reducing adverse side effects associated with high dosage by improving their pharmacokinetics. Taking advantage of molecular markers over-expressing on tumor tissues compared to normal cells, an “active” molecular marker targeted approach would be beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concentration at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging. PMID:26554150

  5. Adjuvant Chemoradiation for Gastric Cancer Using Epirubicin, Cisplatin, and 5-Fluorouracil Before and After Three-Dimensional Conformal Radiotherapy With Concurrent Infusional 5-Fluorouracil: A Multicenter Study of the Trans-Tasman Radiation Oncology Group

    SciTech Connect

    Leong, Trevor; Joon, Daryl Lim; Willis, David; Jayamoham, Jayasingham; Spry, Nigel; Harvey, Jennifer; Di Iulio, Juliana; Milner, Alvin; Mann, G. Bruce; Michael, Michael

    2011-03-01

    Purpose: The INT0116 study has established postoperative chemoradiotherapy as the standard of care for completely resected gastric adenocarcinoma. However, the optimal chemoradiation regimen remains to be defined. We conducted a prospective, multicenter study to evaluate an alternative chemoradiation regimen that combines more current systemic treatment with modern techniques of radiotherapy delivery. Methods and Materials: Patients with adenocarcinoma of the stomach who had undergone an R0 resection were eligible. Adjuvant therapy consisted of one cycle of epirubicin, cisplatin, and 5-FU (ECF), followed by radiotherapy with concurrent infusional 5-FU, and then two additional cycles of ECF. Radiotherapy was delivered using precisely defined, multiple-field, three-dimensional conformal techniques. Results: A total of 54 assessable patients were enrolled from 19 institutions. The proportion of patients commencing Cycles 1, 2, and 3 of ECF chemotherapy were 100%, 81%, and 67% respectively. In all, 94% of patients who received radiotherapy completed treatment as planned. Grade 3/4 neutropenia occurred in 66% of patients with 7.4% developing febrile neutropenia. Most neutropenic episodes (83%) occurred in the post-radiotherapy period during cycles 2 and 3 of ECF. Grade 3/4 gastrointestinal toxicity occurred in 28% of patients. In all, 35% of radiotherapy treatment plans contained protocol deviations that were satisfactorily amended before commencement of treatment. At median follow-up of 36 months, the 3-year overall survival rate was estimated at 61.6%. Conclusions: This adjuvant regimen using ECF before and after three-dimensional conformal chemoradiation is feasible and can be safely delivered in a cooperative group setting. A regimen similar to this is currently being compared with the INT0116 regimen in a National Cancer Institute-sponsored, randomized Phase III trial.

  6. Electrochemiluminescent (ECL) [Ru(bpy)3](2+)/PAMAM dendrimer reactions: coreactant effect and 5-fluorouracil/dendrimer complex formation.

    PubMed

    Jimenez-Ruiz, Aila; Grueso, Elia; Perez-Tejeda, Pilar; Muriel-Delgado, Fernando; Torres-Marquez, Concepcion

    2016-10-01

    Electrogenerated chemiluminescence (ECL) reactions between tris(2,2'-bipyridine)ruthenium(II) and PAMAM dendrimers of the full (G1.0) and half (G1.5) generations were carried out in an aqueous medium at pH 6.1 and 10.0. In the absence of 5-fluoro-1H,3H-pyrimidine-2,4-dione (5-fluorouracil, 5-Fu) (coreactant effect study), the ECL efficiency trends as a function of [G1.0] and [G1.5] at pH 6.1 and 10.0 revealed that PAMAM dendrimers are about 100 (G1.5, pH 6.1), 60 (G1.5, pH 10.0), 26 (G1.0, pH 10.0) and 13 (G1.0, pH 6.1) times more efficient as ECL coreactants than oxalate anion is. Moreover, ECL reactions were done in the presence of several solutions of 5-Fu at a fixed concentration of the G1.0 and G1.5 dendrimers at pH 6.1 and 10.0 (binding study). The ECL efficiency trends as a function of [5-Fu] highlighted a dendrimer/5-Fu binding. Therefore, one of the most remarkable and novel findings of this work is the potential of PAMAM dendrimers to be used as both sensors and biosensors in an aqueous medium in the presence of a suitable sensitizer. Redox potentials of the [Ru(bpy)3](3+/2+) couple were also determined in the absence and presence of 5-Fu at both pHs. In the absence of 5-Fu the positive or negative shift of redox potentials showed the influence of the repulsive or attractive electrostatic long-range and short-range interactions between the charged dendrimer surface and the oxidized and reduced forms of the couple. In the presence of 5-Fu the trends of redox potentials highlighted the existence of a charged dendrimer/5-Fu species. Graphical Abstract ECL emission for the [Ru(bpy)3](2+)/ G1.0 dendrimer reaction in the presence of the 5-Fu at pH 6.1. PMID:27518715

  7. The relationship of bleb morphology and the outcome of needle revision with 5-fluorouracil in failing filtering bleb.

    PubMed

    Lee, Yung-Sung; Wu, Shiu-Chen; Tseng, Hsiao-Jung; Wu, Wei-Chi; Chang, Shirley H L

    2016-09-01

    To investigate the risk factors for failure of needling revision with 5-fluorouracil (5-FU) and to identify the correlation of outcomes of needling revision and the morphological features of dysfunctional filtration blebs using Moorfields bleb grading system.This retrospective, nonrandomized, comparative case-control study included 41 consecutive patients (41 eyes) who underwent 5-FU needling revision for failed or failing filtration blebs between July 2012 and August 2014 in Chang Gung Memorial Hospital, a referral center in Taiwan. The main outcome measures were the bleb survival and the correlation factors of bleb morphology before revision. The secondary outcome measure was the identification of any study factor associated with bleb failure.Forty-one eyes of 41 patients were included in this study. The most frequent glaucoma diagnoses were 10 cases (24%) of neovascular glaucoma and 8 cases (19%) of chronic open-angle glaucoma. Survival of bleb at 6, 12, and 24 months was 42%, 39%, and 23%. Fourteen cases (34%) maintained overall success at the last follow-up, with an average follow-up of 22.7 ± 9.4 months (range: 12-48 months). The central bleb area and height were significantly different between the successful needling group and the failed needling group (P = 0.03 and 0.04, respectively). Further trend test confirmed that smaller central bleb extension and flatter height were associated with a higher chance of failure (P = 0.02 and 0.02, respectively). Time from initial trabeculectomy to needling of less than 4 months and higher intraocular pressure (IOP) in the first postoperative week also led to significantly higher risk for failure (P = 0.01 and 0.03, respectively).A small central area and the flat height of dysfunctional blebs were more likely to fail after the needle revision. Cautious case selections, taking account of the time from the initial filtering surgery and postoperative IOP, may improve the surgical outcome. PMID:27603345

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

    SciTech Connect

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

    2011-11-01

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

  9. Electrochemiluminescent (ECL) [Ru(bpy)3](2+)/PAMAM dendrimer reactions: coreactant effect and 5-fluorouracil/dendrimer complex formation.

    PubMed

    Jimenez-Ruiz, Aila; Grueso, Elia; Perez-Tejeda, Pilar; Muriel-Delgado, Fernando; Torres-Marquez, Concepcion

    2016-10-01

    Electrogenerated chemiluminescence (ECL) reactions between tris(2,2'-bipyridine)ruthenium(II) and PAMAM dendrimers of the full (G1.0) and half (G1.5) generations were carried out in an aqueous medium at pH 6.1 and 10.0. In the absence of 5-fluoro-1H,3H-pyrimidine-2,4-dione (5-fluorouracil, 5-Fu) (coreactant effect study), the ECL efficiency trends as a function of [G1.0] and [G1.5] at pH 6.1 and 10.0 revealed that PAMAM dendrimers are about 100 (G1.5, pH 6.1), 60 (G1.5, pH 10.0), 26 (G1.0, pH 10.0) and 13 (G1.0, pH 6.1) times more efficient as ECL coreactants than oxalate anion is. Moreover, ECL reactions were done in the presence of several solutions of 5-Fu at a fixed concentration of the G1.0 and G1.5 dendrimers at pH 6.1 and 10.0 (binding study). The ECL efficiency trends as a function of [5-Fu] highlighted a dendrimer/5-Fu binding. Therefore, one of the most remarkable and novel findings of this work is the potential of PAMAM dendrimers to be used as both sensors and biosensors in an aqueous medium in the presence of a suitable sensitizer. Redox potentials of the [Ru(bpy)3](3+/2+) couple were also determined in the absence and presence of 5-Fu at both pHs. In the absence of 5-Fu the positive or negative shift of redox potentials showed the influence of the repulsive or attractive electrostatic long-range and short-range interactions between the charged dendrimer surface and the oxidized and reduced forms of the couple. In the presence of 5-Fu the trends of redox potentials highlighted the existence of a charged dendrimer/5-Fu species. Graphical Abstract ECL emission for the [Ru(bpy)3](2+)/ G1.0 dendrimer reaction in the presence of the 5-Fu at pH 6.1.

  10. Cleaning Efficiencies of Three Cleaning Agents on Four Different Surfaces after Contamination by Gemcitabine and 5-fluorouracile.

    PubMed

    Böhlandt, Antje; Groeneveld, Svenja; Fischer, Elke; Schierl, Rudolf

    2015-01-01

    Occupational exposure to antineoplastic drugs has been documented for decades showing widespread contamination in preparation and administration areas. Apart from preventive measures, efficient cleaning of surfaces is indispensable to minimize the exposure risk. The aim of this study was to evaluate the efficiency of three cleaning agents after intentional contamination by gemcitabine (GEM) and 5-fluorouracile (5-FU) on four different surface types usually installed in healthcare settings. Glass, stainless steel, polyvinylchloride (PVC), and laminated wood plates were contaminated with 20 ng/μl GEM and 2 ng/μl 5-FU solutions. Wipe samples were analyzed for drug residues after cleaning with a) distilled water, b) aqueous solution containing sodium dodecyl sulfate (10 mM) and 2-propanol (SDS-2P), and c) Incides N (pre-soaked) alcoholic wipes. Quantification was performed by high-performance liquid chromatography (HPLC) for GEM and gas chromato-graphy-tandem mass spectrometry (GCMS/MS) for 5-FU. Recovery was determined and cleaning efficiency was calculated for each scenario. Mean recoveries were 77-89% for GEM and 24-77% for 5-FU and calculated cleaning efficiencies ranged between 95 and 100% and 89 and 100%, respectively. Residual drug amounts were detected in the range nd (not detected) - 84 ng GEM/sample and nd - 6.6 ng 5-FU/sample depending on surface type and cleaning agent. Distilled water and SDS-2P had better decontamination outcomes than Incides N wipes on nearly all surface types, especially for GEM. Regarding 5-FU, the overall cleaning efficiency was lower with highest residues on laminated wood surfaces. The tested cleaning procedures are shown to clean glass, stainless steel, PVC, and laminated wood with an efficiency of 89-100% after contamination with GEM and 5-FU. Nevertheless, drug residues could be verified by wipe samples. Pure distilled water and SDS in an alcoholic-aqueous solution expressed an efficient cleaning performance, especially with

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

    PubMed Central

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

    1996-01-01

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

  12. Overcoming therapeutic resistance in pancreatic cancer is not a simple mix of PDT and chemotherapy: Evaluation of PDT-chemotherapy combinations in 3D tumor models

    NASA Astrophysics Data System (ADS)

    Celli, Jonathan P.; Petrovic, Ljubica; Massdodi, Iqbal; Rizvi, Imran; Hasan, Tayyaba

    2013-03-01

    The dismal survival statistics for pancreatic cancer are due in large part to the notoriously poor response of these tumors to conventional therapies. Here we examine the ability of photodynamic therapy (PDT), using the photosensitizer verteporfin to enhance of the efficacy of traditional chemotherapy agents and/or eradicate populations that are nonresponsive to these agents. Using an in vitro 3D tumor model of pancreatic cancer combined with an imaging-based methodology for quantifying therapeutic response, we specifically examine PDT combination treatments with gemcitabine and oxaliplatin. We show that our 3D cell culture model recapitulates a more clinically-relevant dose response to gemcitabine, with minimal cytotoxic response even at high doses. The same cultures exhibit modest response to PDT treatments, but are also less responsive to this modality relative to our previous reports of monolayer dose response in the same cells. In combination we found no evidence of any enhancement in efficacy of either PDT or gemcitabine treatment regardless of dose or sequence (PDT before gemcitabine, or gemcitabine before PDT). However, when oxaliplatin chemotherapy was administered immediately after treatment with 2.5J/cm2 verteporfin PDT, there was an observable enhancement in response that appears to exceed the additive combination of either treatment alone and suggesting there may be a synergistic interaction. This observation is consistent with previous reports of enhanced efficacy in combinations of PDT with platinum-based chemotherapy. The contrast in results between the combinations examined here underscores the need for rational design of mechanism-based PDT combinations.

  13. Overcoming tumor resistance to cisplatin through micelle-mediated combination chemotherapy.

    PubMed

    Zhou, Dongfang; Cong, Yuwei; Qi, Yanxin; He, Shasha; Xiong, Hejian; Wu, Yanjuan; Xie, Zhigang; Chen, Xuesi; Jing, Xiabin; Huang, Yubin

    2015-01-01

    The main obstacles to cancer therapy are the inability to target cancer cells and the acquired drug resistance after a period of chemotherapy. Reduced drug uptake and DNA repair are the two main mechanisms involved in cisplatin resistance. In the present investigation, canthaplatin, a Pt(iv) pro-drug of cisplatin and a protein phosphatase 2A (PP2A) inhibitor (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester), was designed and delivered using PEG-b-PLGA micelles for combination chemotherapy. Polymer/canthaplatin micelles facilitated the delivery of the drug into cancer cells through endocytosis and diminished DNA repair by PP2A inhibition, resulting in enhanced anti-tumor efficiency and excellent reversal ability of tumor resistance to cisplatin both in vitro and in vivo. Additionally, the polymer/canthaplatin micelles could prolong drug residence in the blood and decrease the side effects when compared to cisplatin.

  14. Multifunctional Gold Nanostar Conjugates for Tumor Imaging and Combined Photothermal and Chemo-therapy

    PubMed Central

    Chen, Haiyan; Zhang, Xin; Dai, Shuhang; Ma, Yuxiang; Cui, Sisi; Achilefu, Samuel; Gu, Yueqing

    2013-01-01

    Uniform gold nanostars (Au NS) were conjugated with cyclic RGD (cRGD) and near infrared (NIR) fluorescence probe (MPA) or anti-cancer drug (DOX) to obtain multi-functional nanoconstructs, Au-cRGD-MPA and Au-cRGD-DOX respectively. The NIR contrast agent Au-cRGD-MPA was shown to have low cytotoxicity. Using tumor cells and tumor bearing mice, these imaging nanoparticles demonstrated favorable tumor-targeting capability mediated by RGD peptide binding to its over-expressed receptor on the tumor cells. The multi-therapeutic analogue, Au-cRGD-DOX, integrates targeting tumor, chemotherapy and photo-thermotherapy into a single system. The synergistic effect of photo-thermal therapy and chemotherapy was demonstrated in different tumor cell lines and in vivo using S180 tumor-bearing mouse models. The viability of MDA-MB-231 cells was only 40 % after incubation with Au-cRGD-DOX and irradiation with NIR light. Both tail vein and intratumoral injections showed Au-cRGD-DOX treated mice exhibiting the slowest tumor increase. These results indicate that the multifunctional nanoconstruct is a promising combined therapeutic agent for tumor-targeting treatment, with the potential to enhance the anti-cancer treatment outcomes. PMID:24019851

  15. Evaluation of Platinum Chemotherapy in Combination with HER2-Targeted α-Particle Radiation

    PubMed Central

    Baidoo, Kwamena E.; Shih, Joanna H.; Wong, Karen J.; Brechbiel, Martin W.

    2013-01-01

    Abstract The studies described herein assess the potential of combining platinum-based chemotherapy with high-linear energy transfer (LET) α-particle-targeted radiation therapy using trastuzumab as the delivery vehicle. An initial study explored the combination of cisplatin with 213Bi-trastuzumab in the LS-174T i.p. xenograft model. This initial study determined the administration sequence of cisplatin and 213Bi-trastuzumab. Cisplatin coinjected with 213Bi-trastuzumab increased the median survival (MS) to 90 days versus 65 days for 213Bi-trastuzumab alone. Toxicity was observed with a weight loss of 17.6% in some of the combined treatment groups. Carboplatin proved to be better tolerated. Maximal therapeutic benefit, that is, a 5.1-fold increase in MS, was obtained in the group injected with 213Bi-trastuzumab, followed by carboplatin 24 hours later. This was further improved by administration of multiple weekly doses of carboplatin. The MS achieved with administration of 3 doses of carboplatin was 180 days versus 60 days with 213Bi-trastuzumab alone. The combination of carboplatin with 212Pb radioimmunotherapy was also evaluated. The therapeutic efficacy of 212Pb-trastuzumab (58-day MS) increased when the mice were pretreated with carboplatin 24 hours prior (157-day MS). These results again demonstrate the necessity of empirically determining the administration sequence when combining therapeutic modalities. PMID:23758610

  16. Marginal effects of glucose, insulin and insulin-like growth factor on chemotherapy response in endothelial and colorectal cancer cells

    PubMed Central

    VOLKOVA, EKATERINA; ROBINSON, BRIDGET A.; WILLIS, JINNY; CURRIE, MARGARET J.; DACHS, GABI U.

    2014-01-01

    Resistance to chemotherapy is a major clinical issue for patients with colorectal cancer. Obesity has been associated with a poorer outcome and is a possible mechanism of resistance. The aim of the present study was to investigate the effect of obesity-related factors on the cell response to standard chemotherapy in stromal and colorectal cancer cells. Viability was measured following the treatment of colorectal cancer cell lines (WiDr and SW620) and stromal cells (human microvascular endothelial cells) in vitro with 5-fluorouracil, irinotecan and oxaliplatin under obesity-related conditions [elevated levels of insulin, insulin-like growth factor-1 (IGF-1) and glucose] and compared with non-elevated conditions. Obesity-related conditions alone increased cell viability and in selected cases, accumulation of the transcription factor, hypoxia-inducible factor-1. However, these conditions did not consistently increase resistance to the chemotherapy agents tested. The combination of IGF-1 and extremely low-dose chemotherapy significantly induced cell viability in WiDr colorectal cancer cells. These in vitro results may have clinical importance in an environment of increasing rates of obesity and colorectal cancer, and the frequent under-dosing of obese cancer patients. PMID:24396438

  17. "CAMP" combination chemotherapy for unresectable non-oat cell bronchogenic carcinoma.

    PubMed

    Lad, T; Sarma, P R; Diekamp, U; Tichler, T; Chawla, M; Krauss, S; Zawila, P; Nelson, R

    1979-01-01

    Experience with camp chemotherapy of 84 unresectable non-oat cell lung cancer patients is described. Fourteen (27%) of 51 patients with measurable lesions responded (3 CR, 11 PR) for a median response duration of 5 months with a range of 1 to 19+ months. Median survival of responders was 370 days, but response was not independent of performance status. Survival of patients without measurable lesions was less favorable than that of even nonresponders, suggesting prediction of response to CAMP by site of metastasis. Preliminary results of a randomized prospective trial of the CAMP combination versus CCNU as a single agent for patients with good performance status fail to show a difference in survival.

  18. Sequential hemibody and local irradiation with combination chemotherapy for small cell lung carcinoma: a preliminary analysis

    SciTech Connect

    Powell, B.L.; Jackson, D.V. Jr.; Scarantino, C.W.; Pope, E.; Choplin, R.; Craig, J.B.; Atkins, J.N.; Cooper, M.R.; Hopkins, J.O.; McMahan, R.

    1985-03-01

    Sequential hemibody irradiation (SHB) was integrated with combination chemotherapy and local irradiation (LRT) in the induction and consolidation phases of a therapeutic protocol for small cell lung carcinoma (SCLC). Forty-one previously untreated patients were entered into this program. Among 38 evaluable patients (20 with limited disease (LD) and 18 with extensive disease (ED)), the overall response rate was 63% (90% in LD and 33% in ED patients). The estimated overall survival is 8.1 months. The major toxicity has been myelosuppression - especially thrombocytopenia. The frequency of previously described acute radiation syndromes and radiation pneumonitis associated with hemibody irradiation have been substantially decreased at the current dosage with premedication and shielding techniques.

  19. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282

    SciTech Connect

    Cohen, Steven J. . E-mail: S_Cohen@fccc.edu; Dobelbower, Ralph; Lipsitz, Stuart; Catalano, Paul J.; Sischy, Benjamin; Smith, Thomas J.; Haller, Daniel G.

    2005-08-01

    Purpose: The median survival time of patients with locally advanced adenocarcinoma of the pancreas is 8-10 months. Radiation therapy has been used to improve local control and palliate symptoms. This randomized study was undertaken to determine whether the addition of 5-fluorouracil (5-FU) and mitomycin-C (MMC) to radiation therapy improves outcome in this patient population. Patients and Methods: One hundred fourteen patients were randomized to receive 59.4 Gy external beam radiotherapy in 1.8 Gy fractions alone or in combination with 5-FU (1,000 mg/m{sup 2}/day for 4 days by continuous infusion Days 2-5 and 28-31) and MMC (10 mg/m{sup 2} on Day 2). Results: One hundred four patients were evaluable for efficacy. Hematologic and nonhematologic toxicities were more common in the combination arm. The response rates were 6% in the radiation therapy arm and 9% in the combination arm. There were no differences in median disease-free survival time (DFS) or overall survival time (OS) between the combination and radiation therapy alone arms: 5.1 vs. 5.0 months, respectively, for DFS (p = 0.19) and 8.4 vs. 7.1 months, respectively, for OS (p = 0.16). Conclusion: The addition of 5-FU and MMC to radiotherapy increased toxicity without improving DFS or OS in patients with locally advanced pancreatic cancer. Alternative drugs for radiosensitization may improve outcome.

  20. Osseous metastasis of cutaneous squamous cell carcinoma treated successfully with oxaliplatin, tegafur and leucovorin combination chemotherapy: a case report

    PubMed Central

    Xu, Hong-wei; Ren, Feng; Chen, Wei; Wang, Ying-jie; Chen, Jin; Xie, Zhi-hui; Yang, Jin-hu; Chu, Jian-jun; You, Xu-yang

    2012-01-01

    Bone metastasis from cutaneous squamous cell carcinoma (SCC) is rare. We report a case of cutaneous SCC which was diagnosed by the presence of bone metastasis and treated with combination chemotherapy. A 53 year male had tissue contusion and persistent ulcer in the multiple regions of body for about 30 years and treat with Chinese Herbal Drugs in several hospitals, however, did not thorough cure. He was referred to our hospital for a dermatological examination in March 2009. Excisional biopsy and positron emission tomography-computed tomography (PET-CT) scan showed an invasive cutaneous SCC concomitant bone metastasis. Surgical treatment is limited, because of multiple cancerous ulcer and metastatic spreading. Therefore, we proceed to treat with oxaliplatin, tegafur and leucovorin (LV) combination chemotherapy and other adjuvant therapy. About 5 months following chemotherapy, the general situation of the patient was improved. Further cycle of chemotherapy resulted in complete disappearance of the tumor masses (confirmed by PET-CT). So far, there was no evidence of local recurrence or distant metastasis. This report indicates that the combination chemotherapy of oxaliplatin, tegafur and LV seems to have a considerable therapeutic effect for cutaneous SCC concomitant malignant bone metastasis. PMID:22328953

  1. EMP combination chemotherapy and low-dose monotherapy in advanced prostate cancer.

    PubMed

    Kitamura, Tadaichi; Nishimatsu, Hiroaki; Hamamoto, Toshiaki; Tomita, Kyoichi; Takeuchi, Takumi; Ohta, Nobutaka

    2002-02-01

    Many chemotherapeutic regimens combined with estramustine phosphate (EMP) have been elaborated for the treatment of hormone-refractory prostate cancer over 30 years. However, older EMP-based combination chemotherapies with vinblastine, vinorelbine, doxorubicin or cyclophosphamide showed relatively low PSA response rate (25-58%) accompanied with high toxicities. On the other hand, newly developed EMP-based combination regimens with etoposide, pacitaxel, carboplatin or docetaxel demonstrated promising PSA response rate (43-77%) with moderate to severe toxicity in the rate of thromboembolic event (5-18%) and of neutropenia (9-41%). Treatment-related death was less in the latter combination group (5/615, 0.8%) than that in the former group (3/234, 1.3%). Of note, in the docetaxel combination with EMP, PSA response rate is as high as 77% with high rate (41%) of neutropenia but no treatment-related death was observed. Docetaxel combination with EMP seems to be the best regimen, though not completely justified by randomized trials, to be selected in the modern era, which will be followed by paclitaxel, carboplatin and EMP combination with PSA response rate of 71%. In addition, an interim report in 83 patients was presented. They were not consecutively enrolled but were treated on low-dose EMP monotherapy for previously untreated advanced prostate cancer in Department of Urology of Tokyo University and our 21 affiliated hospitals. Overall PSA response rate was as high as 93.4% out of 76 assessable patients. However, overall toxicity rate was abnormally high (39.5%) with drug discontinuation rate of 32.1%. The reason of low drug compliance may be attributed to gastrointestinal symptoms. To overcome the low drug compliance, appropriate patients for EMP administration should be selected by using gene analysis on the basis of sophisticated tailor-made medicine.

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

    PubMed

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

    2011-09-01

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

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

    PubMed

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

    2011-09-01

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

  4. Neoadjuvant chemotherapy for high-grade advanced gastric cancer.

    PubMed

    Yonemura, Y; Sawa, T; Kinoshita, K; Matsuki, N; Fushida, S; Tanaka, S; Ohoyama, S; Takashima, T; Kimura, H; Kamata, T

    1993-01-01

    Fifty-five patients with high-grade advanced gastric cancer in whom the presence of stage IV was confirmed by preoperative diagnostic imaging were treated with PMUE therapy by a combined use of cisplatin (CDDP) 75 mg/m2, mitomycin C (MMC) 10 mg/body, etoposide 150 mg/body, and UFT (a combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil in a molar ratio of 1:4) 400 mg/day. CDDP and MMC was administered intravenously on the first day, followed by etoposide 50 mg/day on the 3rd, 4th, and 5th days. All the patients had measurable lesions that were evaluated by computed tomography scanning before and after the treatments. These patients were allocated randomly to two groups. Of these cases, 29 belonged to the neoadjuvant chemotherapy (NAC) group to whom PMUE therapy was given preoperatively; the remaining 26 patients underwent operation first and received PMUE thereafter (control group). Background factors did not differ significantly between the two groups. The response rate was higher in the NAC group than in the control group (62% in the former versus 35% in the latter). The resectability rates were 79% and 88% in the NAC and control groups, respectively. However, the rate of potentially curable cases was higher in the NAC group than in the control group (38% in the former versus 15% in the latter). Among the nonresection cases, the prognosis was highly unfavorable in both groups. In the resection cases, however, the survival rate was significantly better in the NAC group than in the control group. These results may indicate that in patients with high-grade, advanced gastric cancer initial chemotherapy (neoadjuvant chemotherapy) and then surgery should be considered. PMID:8511923

  5. New potential chemotherapy for ovarian cancer - Combined therapy with WP 631 and epothilone B.

    PubMed

    Bukowska, Barbara; Rogalska, Aneta; Marczak, Agnieszka

    2016-04-15

    Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is combined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. Combined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually based on platinum-containing agent (carboplatin or cisplatin) and a member of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has been expanded with bevacizumab, monoclonal antibody directed to Vascular Endothelial Growth Factor (VEGF). Another drug combination with promising perspectives is WP 631 given together with epothilone B (Epo B). WP 631 is a bisanthracycline composed of two molecules of daunorubicin linked with a p-xylenyl linker. Epo B is a 16-membered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well established. However, the combination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturbing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding combined therapy based on WP 631 and Epo B as a potential way of ovarian cancer treatment. PMID:26944437