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Sample records for 5-fluorouracil induced encephalopathy

  1. 5-fluorouracil induced pericarditis.

    PubMed

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

    2011-04-15

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

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

    PubMed

    De Anda, Mariana Catalina; Domínguez, Judith Guadalupe

    2013-03-15

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

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

    PubMed

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

    2011-11-01

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

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

    PubMed

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

    2010-01-01

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

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

    PubMed Central

    2014-01-01

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

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

    PubMed

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

    2014-09-25

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

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

    PubMed

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

    2015-03-01

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

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

    PubMed

    Yousef, Hany N; Aboelwafa, Hanaa R

    2017-02-08

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

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

    PubMed

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

    2011-04-01

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

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    1994-07-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  14. 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

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

    PubMed

    Eftekhar, Ebrahim; Jaberie, Hajar; Naghibalhossaini, Fakhraddin

    2016-01-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed

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

    2013-11-01

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

  19. 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

  20. 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

  1. 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

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

    PubMed

    Höllriegel, Robert; Fischer, Julia; Schuler, Gerhard

    2014-01-01

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

  3. 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.

  4. 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

  5. Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats.

    PubMed

    Rashid, Summya; Ali, Nemat; Nafees, Sana; Hasan, Syed Kazim; Sultana, Sarwat

    2014-04-01

    5-Fluorouracil (5-FU) is a potent antineoplastic agent commonly used for the treatment of various malignancies. It has diverse adverse effects such as cardiotoxicity, nephrotoxicity and hepatotoxicity which restrict its wide and extensive clinical usage. It causes marked organ toxicity coupled with increased oxidative stress and apoptosis. Chrysin (CH), a natural flavonoid found in many plant extracts, propolis, blue passion flower. It has antioxidative and anti-cancerous properties. The present study was designed to investigate the protective effects of CH against 5-FU induced renal toxicity in wistar rats using biochemical, histopathological and immunohistochemical approaches. Rats were subjected to prophylactic oral treatment of CH (50 and 100mg/kg b.wt.) for 21 days against renal toxicity induced by single intraperitoneal administration of 5-FU (150 mg/kg b.wt.). The possible mechanism of 5-FU induced renal toxicity is the induction of oxidative stress; activation of apoptotic pathway by upregulation of p53, bax, caspase-3 and down regulating Bcl-2. However prophylactic treatment of CH decreased serum toxicity markers, increased anti-oxidant armory as well as regulated apoptosis in kidney. Histopathological changes further confirmed the biochemical and immunohistochemical results. Therefore, results of the present finding suggest that CH may be a useful modulator in mitigating 5-FU induced renal toxicity.

  6. 5-Fluorouracil induces diarrhea with changes in the expression of inflammatory cytokines and aquaporins in mouse intestines.

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2014-03-01

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

  8. Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice.

    PubMed

    Yasuda, Masashi; Kato, Shinichi; Yamanaka, Naoki; Iimori, Maho; Utsumi, Daichi; Kitahara, Yumeno; Iwata, Kazumi; Matsuno, Kuniharu; Amagase, Kikuko; Yabe-Nishimura, Chihiro; Takeuchi, Koji

    2012-05-15

    Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouracil (5-FU) in mice. Intestinal mucositis was induced in Nox1 knockout (Nox1KO) and littermate wild-type (WT) mice via single, daily administration of 5-FU for 5 days. In WT mice, 5-FU caused severe intestinal mucositis characterized by a shortening of villus height, a disruption of crypts, a loss of body weight, and diarrhea. In Nox1KO mice, however, the severity of mucositis was significantly reduced, particularly with respect to crypt disruption. The numbers of apoptotic caspase-3- and caspase-8-activated cells in the intestinal crypt increased 24 h after the first 5-FU administration but were overall significantly lower in Nox1KO than in WT mice. Furthermore, the 5-FU-mediated upregulation of TNF-α, IL-1β, and NOX1 and the production of reactive oxygen species were significantly attenuated in Nox1KO mice compared with that in WT mice. These findings suggest that NOX1 plays an important role in the pathogenesis of 5-FU-induced intestinal mucositis. NOX1-derived ROS production following administration of 5-FU may promote the apoptotic response through upregulation of inflammatory cytokines.

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

    PubMed

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

    2009-05-01

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

  10. 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.

  11. 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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2014-09-01

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

  15. Lipoic acid induces p53-independent cell death in colorectal cancer cells and potentiates the cytotoxicity of 5-fluorouracil.

    PubMed

    Dörsam, Bastian; Göder, Anja; Seiwert, Nina; Kaina, Bernd; Fahrer, Jörg

    2015-10-01

    Alpha-lipoic acid (LA), which plays a pivotal role in mitochondrial energy metabolism, is an endogenous dithiol compound with an array of antioxidative functions. It has been shown that LA triggers cell death in tumor cell lines, whereas non-transformed cells are hardly affected. In the present study, we analyzed the cytotoxicity of LA on colorectal cancer (CRC) cells differing in their p53 status and investigated a putative synergistic effect with the anticancer drug 5-fluorouracil (5-FU). We show that LA induces a dose-dependent decrease in cell viability, which was independent of the p53 status as attested in isogenic p53-proficient and p53-deficient cell lines. This effect was largely attributable to cell death induction as revealed by Annexin-V/PI staining. LA-treated HCT116 cells underwent caspase-dependent and caspase-independent cell death, which was blocked by the pan-caspase inhibitor zVAD and the RIP-kinase inhibitor Necrostatin-1, respectively. In CaCO-2 and HT29 cells, LA induced caspase-dependent cell demise via activation of caspase-9, caspase-3 and caspase-7 with subsequent PARP-1 cleavage as demonstrated by immunoblot analysis, activity assays and pan-caspase inhibition. Interestingly, LA treatment did neither activate p53 nor induced genotoxic effects as shown by lack of DNA strand breaks and phosphorylation of histone 2AX. Finally, we provide evidence that LA increases the cytotoxic effect induced by the anticancer drug 5-FU as revealed by significantly enhanced cell death rates in HCT116 and CaCO-2 cells. Collectively, these findings demonstrate that LA induces CRC cell death independent of their p53 status and potentiates the cytotoxicity of 5-FU without causing DNA damage on its own, which makes it a candidate for tumor therapy.

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

    PubMed

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

    2008-06-01

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

  17. 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.

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

    PubMed Central

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

    2017-01-01

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

  19. [Chemopreventive effects of 5-fluorouracil and lactoferrin on goldfish intestinal carcinogenesis induced by 1,2-dimethylhydrazine].

    PubMed

    Takase, Kiyomi; Kakuta, Izuru

    2011-01-01

    The present study was carried out to examine the chemopreventive effects of 5-fluorouracil (5-FU) and lactoferrin (LF) on goldfish intestinal carcinogenesis induced by 1,2-dimethylhydrazine (DMH). DMH was given to fish by intraperitoneal injection in a dosage of 15 mg/kg body weight once a week for 6 weeks. Eight weeks after the initial DMH injection, fish were randomly divided into 2 groups, control and LF-treated groups. Control fish fed a commercial diet. LF- treated fish fed a commercial diet with bovine lactoferrin (oral administration at 200 mg/kg body weight/day). Ten weeks after the initial DMH injection, each was divided into 2 groups, saline- and 5-FU- treated groups. Physiological saline for freshwater fish (0.75% NaCl solution) in the saline-treated fish and 5-FU dissolved in 0.75% NaCl solution in the 5-FU-treated (75 mg/kg body weight) fish were injected intramuscularly three times every other day, respectively. The mean number of precancer cell foci (PCF) per intestine was 2.7 in DMH treated fish. PCF showed broader distribution in the entire intestine derived from DMH-treated fish. LF-only-treatment has no effect on the number of PCF. Mean number of PCF in 5-FU-only-treated fish decreased in comparison with that of the saline-treated control group, though no statistically significant reduction in PCF was found. But if 5-FU treatment was added to LF pretreatment, a statistically significant reduction in the number of PCF was observed. Pretreatment with LF for 2 weeks also reduced the deleterious side effects of 5-FU.

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

    PubMed Central

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

    2015-01-01

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

  1. Over-expression of TSC-22 (TGF-beta stimulated clone-22) markedly enhances 5-fluorouracil-induced apoptosis in a human salivary gland cancer cell line.

    PubMed

    Uchida, D; Kawamata, H; Omotehara, F; Miwa, Y; Hino, S; Begum, N M; Yoshida, H; Sato, M

    2000-06-01

    We have recently isolated TSC-22 (transforming growth factor-beta-stimulated clone-22) cDNA as an anticancer, drug-inducible (with vesnarinone) gene in a human salivary gland cancer cell line, TYS. We have also reported that TSC-22 negatively regulates the growth of TYS cells and that down-regulation of TSC-22 in TYS cells plays a major role in salivary gland tumorigenesis (Nakashiro et al, 1998). In this study, we transfected TYS cells with an expression vector encoding the TSC-22-GFP (green fluorescent protein) fusion protein, and we established TSC-22-GFP-expressing TYS cell clones. Next, we examined (a) the subcellular localization of the fusion protein, (b) the sensitivity of the transfectants to several anticancer drugs (5-fluorouracil, cis-diaminedichloroplatinum, peplomycin), and (c) induction of apoptotic cell death in the transfectants by 5-fluorouracil treatment. The TSC-22-GFP fusion protein was clearly localized to the cytoplasm, but not to the nucleus. Over-expression of the TSC-22-GFP fusion protein did not affect cell growth, but significantly increased the sensitivity of the cells to the anticancer drugs (p < 0.01; one-way ANOVA). Furthermore, over-expression of the TSC-22-GFP fusion protein markedly enhanced 5-fluorouracil-induced apoptosis. These findings suggest that over-expression of TSC-22-GFP protein in TYS cells enhances the chemosensitivity of the cells via induction of apoptosis.

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

    PubMed

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

    2012-10-01

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

  3. 5-Fluorouracil-induced bilateral persistent serpentine supravenous hyperpigmented eruption, bilateral mottling of palms and diffuse hyperpigmentation of soles.

    PubMed

    Suvirya, Swastika; Agrawal, Avinash; Parihar, Anit

    2014-10-21

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

  4. 5-Fluorouracil-induced vasculitic injury manifesting as a multiorgan dysfunction in a patient with esophageal carcinoma.

    PubMed

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

    2015-01-01

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

  5. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent, 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n=8-10): Saline+Water; 5-FU+Skim Milk; 5-FU+Live TH-4; 5-FU+Supernatant TH-4; and 5-FU+Dead TH-4. 5-FU (150mg.kg(-1)) was administered by a single intraperitoneal injection on day 0; animals were killed on day 4. Treatments were administered daily from days -2 to 3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villous height and area; crypt depth and area, mitotic count and crypt fission; biochemical determination of sucrase and myeloperoxidase (MPO) activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalised mitotic counts compared with 5-FU+Skim milk controls. Live and supernatant TH-4 reduced crypt fission by 69% and 48% (p< 0.05), respectively, compared to 5-FU+Skim Milk controls. No significant differences (p> 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalised mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterised by increased crypt fission, such as colorectal carcinoma.

  6. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n = 8–10): Saline + Water; 5-FU + Skim Milk; 5-FU+ Live TH-4; 5-FU + Supernatant TH-4; and 5-FU + Dead TH-4.5-FU (150 mg.kg-1) was administered by a single intraperitoneal injection on day zero; animals were killed on day four. Treatments were administered daily from days -2 to +3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villus height and area; crypt depth and area, mitotic count and crypt fission;biochemical determination of sucrase and myeloperoxidase (MPO)activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalized mitotic counts compared with 5-FU + Skim Milk controls. Live and Supernatant TH-4 reduced crypt fission by 69% and 48% (p < 0.05), respectively, compared to 5-FU + Skim Milk controls. No significant differences (p > 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalized mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 Supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterized by increased crypt fission,such as colorectal carcinoma.

  7. 5-Fluorouracil-induced apoptosis in colorectal cancer cells is caspase-9-dependent and mediated by activation of protein kinase C-δ

    PubMed Central

    MHAIDAT, NIZAR M.; BOUKLIHACENE, MOHAMMED; THORNE, RICK F.

    2014-01-01

    Elucidation of the molecular mechanisms by which 5-fluorouracil (5-FU) induces apoptosis is required in order to understand the resistance of colorectal cancer (CRC) cells to 5-FU. In the current study, 5-FU-induced apoptosis was assessed using the propidium iodide method. Involvement of protein kinase C (PKC) was assessed by evaluating the extent of their activation in CRC, following treatment with 5-FU, using biochemical inhibitors and western blot analysis. The results revealed that 5-FU induces varying degrees of apoptosis in CRC cells; HCT116 cells were identified to be the most sensitive cells and SW480 were the least sensitive. In addition, 5-FU-induced apoptosis was caspase-dependent as it appeared to be initiated by caspase-9. Furthermore, PKCɛ was marginally expressed in CRC cells and no changes were observed in the levels of cleavage or phosphorylation following treatment with 5-FU. The treatment of HCT116 cells with 5-FU increased the expression, phosphorylation and cleavage of PKCδ. The inhibition of PKCδ was found to significantly inhibit 5-FU-induced apoptosis. These results indicated that 5-FU induces apoptosis in CRC by the activation of PKCδ and caspase-9. In addition, the levels of PKCδ activation may determine the sensitivity of CRC to 5-FU. PMID:25013487

  8. [Cardiac toxicity of 5-fluorouracil].

    PubMed

    Fournier, C; Benahmed, M; Blondeau, M

    1989-02-01

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

  9. 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

  10. A novel setup for the determination of absolute cross sections for low-energy electron induced strand breaks in oligonucleotides - The effect of the radiosensitizer 5-fluorouracil*

    NASA Astrophysics Data System (ADS)

    Rackwitz, Jenny; Ranković, Miloš Lj.; Milosavljević, Aleksandar R.; Bald, Ilko

    2017-02-01

    Low-energy electrons (LEEs) play an important role in DNA radiation damage. Here we present a method to quantify LEE induced strand breakage in well-defined oligonucleotide single strands in terms of absolute cross sections. An LEE irradiation setup covering electron energies <500 eV is constructed and optimized to irradiate DNA origami triangles carrying well-defined oligonucleotide target strands. Measurements are presented for 10.0 and 5.5 eV for different oligonucleotide targets. The determination of absolute strand break cross sections is performed by atomic force microscopy analysis. An accurate fluence determination ensures small margins of error of the determined absolute single strand break cross sections σ SSB . In this way, the influence of sequence modification with the radiosensitive 5-Fluorouracil (5FU) is studied using an absolute and relative data analysis. We demonstrate an increase in the strand break yields of 5FU containing oligonucleotides by a factor of 1.5 to 1.6 compared with non-modified oligonucleotide sequences when irradiated with 10 eV electrons.

  11. Efficacy of Sucralfate Mouth Wash in Prevention of 5-fluorouracil Induced Oral Mucositis: A Prospective, Randomized, Double-Blind, Controlled Trial.

    PubMed

    Ala, Shahram; Saeedi, Majid; Janbabai, Ghasem; Ganji, Reza; Azhdari, Elham; Shiva, Afshin

    2016-01-01

    Sucralfate has been used for the prevention and treatment of radiotherapy- and chemotherapy-induced stomatitis and mucositis in a number of studies, but the results are contradictory. To answer such discrepancies, the present study was designed to evaluate the efficacy of sucralfate mouthwash in prevention of 5-fluorouracil (5-FU)-induced oral mucositis in patients with gastrointestinal malignancies. Patients with gastrointestinal cancers receiving 5-FU-based chemotherapy regimens were included in this randomized, blinded, controlled trial and were randomly allocated to either sucralfate mouthwash (every 6 h) or placebo. The patients were visited at fifth and tenth day of trial; the presence and severity of oral mucositis and the intensity of pain were assessed. The patients receiving sucralfate experienced lower frequency and severity of mucositis (76% vs. 38.5%, P = 0.005 and 84 vs. 38.5%, P < 0.001, respectively) and less intense pain (2.5 ± 2.2 vs. 5.08 ± 3.82, P = 0.004 and 1.33 ± 0.86 vs. 4.12 ± 3.5, P = 0.001, respectively) compared with the placebo group both at day 5 and day 10. Within the sucralfate group, a decrease in frequency and severity of mucositis was observed throughout the trial period, while in the placebo group no such effect was observed. Sucralfate mouthwash reduced the frequency and severity of 5-FU-induced oral mucositis in patients with gastrointestinal malignancies compared with placebo, indicating its efficacy in the prevention of chemotherapy-induced mucositis.

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

    PubMed

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

    2016-12-01

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

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

    PubMed

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

    2015-01-01

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

  14. 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.

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

    PubMed

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

    2009-04-18

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

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

    PubMed

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

    2016-12-01

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

  17. Resveratrol induces chemosensitization to 5-fluorouracil through up-regulation of intercellular junctions, Epithelial-to-mesenchymal transition and apoptosis in colorectal cancer.

    PubMed

    Buhrmann, Constanze; Shayan, Parviz; Kraehe, Patricia; Popper, Bastian; Goel, Ajay; Shakibaei, Mehdi

    2015-11-01

    5-Fluorouracil (5-FU), a common chemotherapeutic agent used for the treatment of colorectal cancer (CRC), by itself has inadequate response rates; highlighting the need for novel and improved treatment regimens for these patients. Resveratrol, a naturally-occurring polyphenol, has been linked with chemosensitizing potential and anticancer properties; however, the underlying mechanisms for these effects remain poorly understood. The effect of resveratrol in parental CRC cell lines (HCT116, SW480) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R, SW480R) was examined by MTT assays, intercellular junction formation and apoptosis by electron- and immunoelectron microscopy, nuclear factor-kappaB (NF-κB) and NF-κB regulated gene products by western blot analysis in a 3D-alginate microenvironment. Resveratrol blocked the proliferation of all four CRC cell lines and synergized the invasion inhibitory effects of 5-FU. Interestingly, resveratrol induced a transition from 5-FU-induced formation of microvilli to a planar cell surface, which was concomitant with up-regulation of desmosomes, gap- and tight junctions (claudin-2) and adhesion molecules (E-cadherin) expression in HCT116 and HCT116R cells. Further, resveratrol significantly attenuated drug resistance through inhibition of epithelial-mesenchymal transition (EMT) factors (decreased vimentin and slug, increased E-cadherin) and down-regulation of NF-κB activation and its translocation to the nucleus and abolished NF-κB-regulated gene end-products (MMP-9, caspase-3). Moreover, this suppression was mediated through inhibition of IκBα kinase and IκBα phosphorylation and degradation. Our results demonstrate that resveratrol can potentiate the anti-tumor effects of 5-FU on CRC cells by chemosensitizing them, inhibiting an EMT phenotype via up-regulation of intercellular junctions and by down-regulation of NF-κB pathway.

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

    PubMed

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

    2011-01-01

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

  19. 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.

  20. Prophylactic pretreatment of mice with hematopoietic growth factors induces expansion of primitive cell compartments and results in protection against 5-fluorouracil-induced toxicity.

    PubMed

    de Haan, G; Donte, B; Engel, C; Loeffler, M; Nijhof, W

    1996-06-01

    The aim of this study was to expand the primitive and committed hematopoietic cell compartments in vivo in order to confer resistance of the blood cell forming system against the cytotoxic, cell cycle specific drug 5-fluorouracil (5-FU). Possible chemoprotective effects of such a pretreatment could result from increased numbers of hematopoietic cells, present before 5-FU administration. In addition, we hypothesized that an enhanced number of primitive and progenitor calls would result in a reduced cycling activity, ie, 5-FU sensitivity, of these same cells, due to normal physiological feedback loops. Administration of stem cell factor (SCF) plus interleukin-11 (IL-11) to mice was shown to result in expansion of the various immature cell compartments in marrow and, in particular, spleen. The total body content of the primitive cobblestone area forming cells (CAFC)-day 28 was increased to 140%, whereas the more committed cells (CAFC-day 7, erythroid and granuloid progenitors) were increased to 500%. This in vivo expansion resulted in a decreased 5-FU sensitivity of the hematopoietic system. In particular, mice that had received 5-FU 24 hours after discontinuation of growth factor pretreatment showed significantly less toxicity of committed cell stages. Compared with mice not pretreated, it appeared that in pretreated mice, 24 hours after 5-FU administration, the absolute number, but also the fraction of surviving CAFC, was much higher in both marrow and spleen. This was caused by a decrease in the cycling activity of all primitive cell subsets. To explore the possible use of this finding in a chemotherapeutic setting, we determined the interval between two subsequent doses of 5-FU (160 mg/kg) that was required to prevent drug-induced mortality. When control mice received a second dose of 5-FU 7, 10, or 14 days after the first, respectively 0%, 20%, and 80% survived. In contrast, 40% and 100% of mice that received SCF + IL-11 before the first dose of 5-FU, survived a

  1. Pneumocystis Carinii Pneumonia Following 5-Fluorouracil Administration

    PubMed Central

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

    1987-01-01

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

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

    PubMed Central

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

    2011-01-01

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

  3. Treatment with Saccharomyces boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in 5-fluorouracil-induced intestinal mucositis in mice.

    PubMed

    Justino, Priscilla F C; Melo, Luis F M; Nogueira, Andre F; Costa, Jose V G; Silva, Luara M N; Santos, Cecila M; Mendes, Walber O; Costa, Marina R; Franco, Alvaro X; Lima, Aldo A; Ribeiro, Ronaldo A; Souza, Marcellus H L P; Soares, Pedro M G

    2014-05-01

    Intestinal mucositis is an important toxic side effect of 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii is known to protect from intestinal injury via an effect on the gastrointestinal microbiota. The objective of the present study was to evaluate the effect of S. boulardii on intestinal mucositis induced by 5-FU in a murine model. Mice were divided into saline, saline (control)+5-FU or 5-FU+S. boulardii (16 × 10⁹ colony-forming units/kg) treatment groups, and the jejunum and ileum were removed after killing of mice for the evaluation of histopathology, myeloperoxidase (MPO) activity, and non-protein sulfhydryl group (mainly reduced glutathione; GSH), nitrite and cytokine concentrations. To determine gastric emptying, phenol red was administered orally, mice were killed 20 min after administration, and the absorbance of samples collected from the mice was measured by spectrophotometry. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following oral administration. S. boulardii significantly reversed the histopathological changes in intestinal mucositis induced by 5-FU and reduced the inflammatory parameters: neutrophil infiltration (control 1·73 (SEM 0·37) ultrastructural MPO (UMPO)/mg, 5-FU 7·37 (SEM 1·77) UMPO/mg and 5-FU+S. boulardii 4·15 (SEM 0·73) UMPO/mg); nitrite concentration (control 37·00 (SEM 2·39) μm, 5-FU 59·04 (SEM 11·41) μm and 5-FU+S. boulardii 37·90 (SEM 5·78) μm); GSH concentration (control 477·60 (SEM 25·25) μg/mg, 5-FU 270·90 (SEM 38·50) μg/mg and 5-FU+S. boulardii 514·00 (SEM 38·64) μg/mg). Treatment with S. Boulardii significantly reduced the concentrations of TNF-α and IL-1β by 48·92 and 32·21 % in the jejunum and 38·92 and 61·79 % in the ileum. In addition, S. boulardii decreased the concentrations of chemokine (C-X-C motif) ligand 1 by 5-fold in the jejunum and 3-fold in the ileum. Interestingly, S. boulardii reduced the delay in gastric emptying

  4. Influence of rhG-CSF scheduling on megakaryocytopoietic recovery following 5-fluorouracil-induced hematotoxicity in splenectomized B6D2F1 mice.

    PubMed

    Scheding, S; Media, J E; Nakeff, A

    1998-01-01

    Recombinant human granulocyte colony-stimulating factor, rhG-CSF, is widely applied to ameliorate neutropenia following chemotherapy. However, rhG-CSF can exert negative effects on megakaryocytopoiesis that might cause a delay of megakaryocyte recovery. Therefore, the present study was designed to test different rhG-CSF administration protocols with regard to their megakaryocytic inhibitory potential in a 5-fluorouracil (5-FU)-induced experimental model system. Splenectomized B6D2F1 mice received a single injection of 5-FU (150 mg/kg) on day 0 followed by 50 micrograms/kg/day rhG-CSF given daily for either zero, four, or eight days. Five days after 5-FU, bone marrow and blood hematopoiesis were reduced significantly when compared with controls, independent of whether or not animals received rhG-CSF. However, nine days after 5-FU, granulopoietic recovery from 5-FU-induced toxicity was faster for rhG-CSF-treated versus untreated mice as demonstrated by higher values for colony forming unit-granulocyte macrophage (CFU-GM) and granulocytes (CFU-GM: 7.2 +/- 0.4 versus 5 +/- 0.6 x 10(4)/femur, granulocytes: 4.3 +/- 2 versus 1.4 +/- 0.4 x 10(5)/ml, respectively). Furthermore, significant mobilization of CFU-megakaryocyte (CFU-Meg) and CFU-GM into the peripheral blood was induced by the eight-day administration of rhG-CSF following 5-FU (day 9: 911 +/- 102 CFU-Meg/ml, 2330 +/- 152 CFU-GM/ml). However, megakaryocytic cells in these same mice were considerably lower when compared with those of animals receiving no rhG-CSF (CFU-Meg: 2.7 +/- 0.2 x 10(3) versus 4.2 +/- 0.2 x 10(3)/femur; small acetylcholinesterase positive (SAChE+) cells: 4.9 +/- 0.3 x 10(3) versus 7.3 +/- 0.9 x 10(3)/femur; megakaryocytes: 2.5 +/- 0.2 x 10(3) versus 4.1 +/- 0.7 x 10(3)/femur; platelets: 2.67 +/- 0.5 x 10(9) versus 3.1 +/- 0.5 x 10(9)/ml, respectively). On the other hand, the shortening of the rhG-CSF treatment from eight to four days caused a rapid granulopoietic recovery comparable to animals

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

    PubMed

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

    2014-06-01

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

  6. Acquisition of 5-fluorouracil resistance induces epithelial-mesenchymal transitions through the Hedgehog signaling pathway in HCT-8 colon cancer cells

    PubMed Central

    LIU, YANJUN; DU, FANGFANG; ZHAO, QIANNAN; JIN, JIAN; MA, XIN; LI, HUAZHONG

    2015-01-01

    Colon cancer has a high incidence in individuals >60-years-old. The commonly used chemotherapeutic agent, 5-fluorouracil (5-FU), has gradually lost its potency in treating colorectal cancer following the acquisition of resistance. Drug resistance is usually associated with epithelial-mesenchymal transitions (EMTs) in cancer cells. In the present study, the EMT phenotypes of two colon cancer cell lines, wild-type (HCT-8/WT) and 5-FU-resistant (HCT-8/5-FU), were characterized following the analysis of cellular migration, proliferation, morphology and molecular changes. In order to further clarify the mechanism of EMT in HCT-8/5-FU cells, the effect of EMT pathway inhibitors upon drug sensitivity was investigated. The results revealed that the Hedgehog signaling pathway inhibitor, GDC0449, reversed drug resistance. Therefore, inhibition of the Hedgehog pathway may provide a novel chemotherapeutic strategy for the treatment of patients with 5-FU-resistant colon cancer. PMID:26137127

  7. CXCL12/CXCR4 axis induced miR-125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer

    PubMed Central

    Yu, Xinfeng; Shi, Wenna; Zhang, Yuhang; Wang, Xiaohui; Sun, Shiyue; Song, Zhiyu; Liu, Man; Zeng, Qiao; Cui, Shuxiang; Qu, Xianjun

    2017-01-01

    The activation of CXCL12/CXCR4 axis is associated with potential progression of cancer, such as invasion, metastasis and chemoresistance. However, the underlying mechanisms of CXCL12/CXCR4 axis and cancer progression have been poorly explored. We hypothesized that miRNAs might be critical downstream mediators of CXCL12/CXCR4 axis involved in cancer invasion and chemoresistance in CRC. In human CRC cells, we found that the activation of CXCL12/CXCR4 axis promoted epithelial-mesenchymal transition (EMT) and concurrent upregulation of miR-125b. Overexpression of miR-125b robustly triggered EMT and cancer invasion, which in turn enhanced the expression of CXCR4. Importantly, the reciprocal positive feedback loop between CXCR4 and miR-125b further activated the Wnt/β-catenin signaling by targeting Adenomatous polyposis coli (APC) gene. There was a negative correlation of the expression of miR-125b with APC mRNA in paired human colorectal tissue specimens. Further experiments indicated a role of miR-125b in conferring 5-fluorouracil (5-FU) resistance in CRC probably through increasing autophagy both in vitro and in vivo. MiR-125b functions as an important downstream mediator upon the activation of CXCL12/CXCR4 axis that involved in EMT, invasion and 5-FU resistance of CRC. These findings shed a new insight into the role of miR-125b and provide a potential therapeutic target in CRC. PMID:28176874

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

    PubMed

    McDonald, S G; Peterka, E S

    1983-01-01

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

  9. 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.

  10. A simultaneous determination method for 5-fluorouracil and its metabolites in human plasma with linear range adjusted by in-source collision-induced dissociation using hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry.

    PubMed

    Ishii, Hideaki; Shimada, Miki; Yamaguchi, Hiroaki; Mano, Nariyasu

    2016-11-01

    We applied a new technique for quantitative linear range shift using in-source collision-induced dissociation (CID) to complex biological fluids to demonstrate its utility. The technique was used in a simultaneous quantitative determination method of 5-fluorouracil (5-FU), an anticancer drug for various solid tumors, and its metabolites in human plasma by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). To control adverse effects after administration of 5-FU, it is important to monitor the plasma concentration of 5-FU and its metabolites; however, no simultaneous determination method has yet been reported because of vastly different physical and chemical properties of compounds. We developed a new analytical method for simultaneously determining 5-FU and its metabolites in human plasma by LC/ESI-MS/MS coupled with the technique for quantitative linear range shift using in-source CID. Hydrophilic interaction liquid chromatography using a stationary phase with zwitterionic functional groups, phosphorylcholine, was suitable for separation of 5-FU from its nucleoside and interfering endogenous materials. The addition of glycerin into acetonitrile-rich eluent after LC separation improved the ESI-MS response of high polar analytes. Based on the validation results, linear range shifts by in-source CID is the reliable technique even with complex biological samples such as plasma. Copyright © 2016 John Wiley & Sons Ltd.

  11. Comparison of the therapeutic effects of the dietary and topical forms of Zizyphus jujuba extract on oral mucositis induced by 5-fluorouracil: A golden hamster model

    PubMed Central

    Koohi-Hosseinabadi, Omid; Andisheh-Tadbir, Azadeh; Bahadori, Parisa; Sepehrimanesh, Masood; Mardani, Maryam

    2015-01-01

    Background Oral mucositis (OM) is a common inflammatory complication among cancerous patients as an adverse effect of chemotherapy and radiotherapy. The aim of this study was to evaluate the effects and identify the appropriate route of administration of extract of Zizyphus jujuba in 5-flurouracile induced OM induction in golden hamster. Material and Methods In a prospective randomized double blind animal study, OM was induced in 56 male golden hamsters by 5-FU (60 mg/kg) on days 0, 5, and 10 of the study. The cheek pouch was scratched with a sterile needle on once daily on days 3 and 4. On days 14-17, 300 mg/kg dietary and 20% Z. jujuba gel and gel base groups were treated and then compared with a control group. Microscopic scores and pouch content of malondialdehyde (MDA), plus activities of superoxide dismutase and myeloperoxidase in pouch tissue were evaluated. Results Histopathology scores of mucositis were lower in the systemic and 20% Z. jujuba gel groups than the gel base and control groups (P<0.05). Also, lower MDA level and higher activities of MPO and SOD were detected in the systemic and 20% Z. jujuba gel groups in comparison to the gel base and control groups (P<0.001). Conclusions The use of Z. jujuba hydroalcoholic extract in systemic and topical forms may be associated with reduced intensity of OM, diminished concentration of MDA, and increased activity of MPO and SOD on induced OM in golden hamster undergoing 5-FU consumption. Key words:Oral mucositis, 5-flurouracil, Zizyphus jujube, oxidative stress, histopathology score. PMID:26155351

  12. The carcinostatic effects of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil (UFT) on tongue carcinoma induced by 4-nitroquinoline 1-oxide (4NQO) in rats.

    PubMed

    Katakura, A; Shiozaki, Y; Kouda, H; Hatada, K; Tonogi, M; Takaki, T; Yamane, G; Noma, H

    1991-11-01

    UFT is a carcinostatic agent used in adjuvant chemotherapy for head and neck cancer. In the present study. UFT was given orally to treat tongue carcinoma in rats induced by 4-nitroquinoline 1-oxide. The antitumor effects of UFT were studied macroscopically and histologically. In addition, the antitumor effects of UFT were evaluated in relationship to lesions of the clinical and, invasive types, and to there vascular structure. In clinical lesions, the antitumor effect of UFT was higher in extrovert tumor-mass lesions and lower in ulcerous lesions. With regard to vascular structure, the effect was higher in cases demonstrating irregular net-like patterns and branch-like patterns and lower in cases in which the pattern had been destroyed. There was a correlation between antitumor effect and invasive type. As invasive tendency the 3H-thymidine labeling index, and mitotic index increased, antitumor effect and degree of tumor cell degeneration decreased.

  13. Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.

    PubMed

    Kobuchi, Shinji; Ito, Yukako; Okada, Kae; Imoto, Kazuki; Takada, Kanji

    2013-09-01

    To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine-induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration-time curve (AUC) and elimination half-life (t 1/2) in CRC rats (10.02 ± 0.37 μg h mL(-1), 0.30 ± 0.02 h, respectively) were significantly lower than that in control rats (13.46 ± 1.20 μg h mL(-1), 0.52 ± 0.05 h, respectively), whereas total plasma clearance (CLtot) in CRC rats (2.01 ± 0.07 L h(-1) kg(-1)) was significantly increased compared with that in control rats (1.54 ± 0.14 L h(-1) kg(-1)). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20 % lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t 1/2 and an increase in CLtot after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.

  14. Bioavailability and feasibility of subcutaneous 5-fluorouracil.

    PubMed

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

    1993-09-01

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

  15. Bioavailability and feasibility of subcutaneous 5-fluorouracil.

    PubMed Central

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

    1993-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2010-09-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2012-07-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2009-08-01

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

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

    PubMed

    Markova, Nadezhda; Enchev, Venelin; Ivanova, Galya

    2010-12-23

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

  1. 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

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

    NASA Astrophysics Data System (ADS)

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

    2011-09-01

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

  3. 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.

  4. 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.

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

    SciTech Connect

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

    2014-01-14

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-01-01

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

  8. Metronidazole-induced encephalopathy in a patient with Crohn's disease

    PubMed Central

    Kim, Jihye; Park, Jae Yong; Hong, Seung Wook; Lee, Joo Young; Kang, Jin Woo; Hwang, Seongjun; Ko, Sang-Bae; Im, Jong Pil; Kim, Joo Sung

    2017-01-01

    Metronidazole is a widely used antibiotic for the treatment of anaerobic bacterial infections. Metronidazole-induced encephalopathy (MIEP) is a rare but potentially reversible disease. The mechanism of MIEP remains unclear, and differences in the neurotoxic effects of oral versus intravenous (IV) metronidazole administration have not yet been determined. We report the case of a Crohn's disease (CD) patient who experienced encephalopathy immediately after a single IV dose of metronidazole following long-term exposure to the oral form of the drug. The 64-year-old man with intractable CD experienced a sudden change in mental status, aphasia, and muscle weakness after IV administration of metronidazole. He had previously taken metronidazole orally for 13 years and received intermittent IV metronidazole treatments for CD exacerbation. Brain magnetic resonance imaging (MRI) showed high-intensity signals in the bilateral medial thalamus and the midbrain and pontine tegmentum on fluid-attenuated inversion recovery images. After discontinuation of metronidazole, the high-intensity brain MRI signals resolved and the patient's mental status dramatically improved; however, the patient exhibited mild cognitive dysfunction 2 months after the onset of encephalopathy. PMID:28239323

  9. 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.

  10. 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

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

    PubMed

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

    2006-11-01

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

  12. 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.

  13. 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.

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

    PubMed

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

    2014-02-01

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

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

    PubMed

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

    2014-01-01

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

  16. Recurrent contrast-induced encephalopathy following coronary angiography.

    PubMed

    Spina, Roberto; Simon, Neil; Markus, Romesh; Muller, David W M; Kathir, Krishna

    2017-02-01

    Contrast-induced encephalopathy (CIE) is an acute and reversible neurological disturbance associated with the intra-arterial administration of iodinated contrast medium during cardiac catheterisation. It may manifest with encephalopathy, motor and sensory disturbances; vision disturbances, including cortical blindness, ophthalmoplegia, aphasia; and seizures. Disruption of the blood-brain barrier and direct neuronal toxicity are believed to be implicated in the pathophysiology of the syndrome. Symptoms appear soon after contrast administration and resolve completely within 24-48 h. Risk factors may include hypertension, diabetes mellitus, renal impairment, the administration of large volumes of iodinated contrast, percutaneous coronary intervention or selective angiography of internal mammary grafts and previous adverse reaction to iodinated contrast. On cerebral imaging, CIE may mimic subarachnoid haemorrhage or cerebral ischaemia, but imaging may be normal. Prognosis is excellent with supportive management alone. CIE may recur, but re-challenge with iodinated contrast without adverse effects has been documented. CIE is a diagnosis of exclusion and is an important clinical entity to consider in the differential diagnosis of stroke following cardiac catheterisation. Physicians should be aware of it and consider it prior to initiating thrombolysis.

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

    PubMed Central

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

    2015-01-01

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

  18. 5-Fluorouracil-radiation interactions in human colon adenocarcinoma cells

    SciTech Connect

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

    1995-07-15

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

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

    PubMed

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

    2015-01-22

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

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

    PubMed

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

    2007-04-18

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

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

    PubMed

    Radwan, Awwad A; Alanazi, Fares K

    2014-08-26

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    1989-01-01

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

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

    PubMed

    Jedrzychowska, Adriana; Dołegowska, Barbara

    2013-01-01

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

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

    PubMed

    Singh, B N; Jayaswal, S B

    2008-04-01

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

  6. 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.

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

    PubMed

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

    2009-05-01

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

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

    PubMed

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

    1979-01-01

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

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

    PubMed

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

    1994-01-01

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

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

    PubMed

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

    2016-03-01

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

  11. 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.

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

    PubMed

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

    2014-12-01

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

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

    PubMed

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

    2012-05-01

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

  14. Metronidazole-induced encephalopathy after prolonged metronidazole course for treatment of C. difficile colitis

    PubMed Central

    Godfrey, Mark S; Finn, Arkadiy; Zainah, Hadeel; Dapaah-Afriyie, Kwame

    2015-01-01

    A 65-year-old woman with a diagnosis of Clostridium difficile colitis undergoing prolonged treatment with metronidazole was admitted to hospital for altered mentation, slurred speech and weakness. She was diagnosed with metronidazole-induced encephalopathy, confirmed with brain MRI and improved when the offending agent was removed. This case report highlights encephalopathy as a complication of prolonged metronidazole treatment, which has become more common in clinical practice for the treatment of C. difficile infection. PMID:25596288

  15. Metronidazole-induced encephalopathy after prolonged metronidazole course for treatment of C. difficile colitis.

    PubMed

    Godfrey, Mark S; Finn, Arkadiy; Zainah, Hadeel; Dapaah-Afriyie, Kwame

    2015-01-16

    A 65-year-old woman with a diagnosis of Clostridium difficile colitis undergoing prolonged treatment with metronidazole was admitted to hospital for altered mentation, slurred speech and weakness. She was diagnosed with metronidazole-induced encephalopathy, confirmed with brain MRI and improved when the offending agent was removed. This case report highlights encephalopathy as a complication of prolonged metronidazole treatment, which has become more common in clinical practice for the treatment of C. difficile infection.

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

    PubMed

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

    1994-08-01

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

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

    PubMed

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

    2015-07-15

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

  18. Valproate-induced hyperammonemic encephalopathy with normal liver function.

    PubMed

    Rath, Amitav; Naryanan, T Jaishree; Chowdhary, G V S; Murthy, J M K

    2005-06-01

    Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy. We retrospectively analyzed the case records of 5 patients of epilepsy on valproate with hyperammonemic encephalopathy. Of the 5 patients, 3 were on monotherapy. The mean valproate dose was 1250 mg/day and the duration of therapy ranged between 4 and 90 days. Alteration in the sensorium was the presenting clinical feature. The risk factors included high initial dose (2), long-term valproate therapy (1), and long-term valproate therapy with concomitant topiramate (1). There was good correlation between the fall in serum ammonia levels and clinical improvement. Hyperammonemic encephalopathy should be suspected in patients on valproate with altered sensorium. Response to treatment is rewarding.

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

    PubMed

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

    2016-12-21

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

  20. [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.

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

    PubMed Central

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

    1990-01-01

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

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

    PubMed

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

    2017-03-08

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

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

    PubMed

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

    2013-01-01

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

  4. 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

  5. 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.

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

    PubMed

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

    2016-11-20

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

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

    PubMed

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

    2016-05-01

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

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

    SciTech Connect

    Doong, S.L.

    1988-01-01

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

  9. 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

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

    PubMed

    Bukkitgar, Shikandar D; Shetti, Nagaraj P

    2016-08-01

    A novel sensor for the determination of 5-fluorouracil was constructed by electrochemical deposition of methylene blue on surface of carbon paste electrode. The electrode surface morphology was studied using Atomic force microscopy and XRD. The electrochemical activity of modified electrode was characterized using cyclic voltammetry and differential pulse method. The developed sensor shows impressive enlargement in sensitivity of 5-fluorouracil determination. The peak currents obtained from differential pulse voltammetry was linear with concentration of 5-fluorouracil in the range 4×10(-5)-1×10(-7)M and detection limit and quantification limit were calculated to be 2.04nM and 6.18nM respectively. Further, the sensor was successfully applied in pharmaceutical and biological fluid sample analysis.

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

    PubMed

    Patel, Pinaki B; Thakkar, Vasudev R

    2015-03-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Markova, Nadezhda; Enchev, Venelin; Timtcheva, Iliana

    2005-03-10

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2012-08-28

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

  17. Glyphosate-surfactant herbicide-induced reversible encephalopathy.

    PubMed

    Malhotra, R C; Ghia, D K; Cordato, D J; Beran, R G

    2010-11-01

    Glyphosate-surfactant (GlySH) is a commonly used herbicide that has been used in attempted suicide. Most reports of GlySH toxicity in patients have followed ingestion of the commercial product "Round-up" (Monsanto Ltd; Melbourne, Victoria, Australia), which consists of a mixture of glyphosate (as a isopropylanine salt) and a surfactant (polyoxyethyleneamine). Ingestion of Round-up is reported to cause significant toxicity including nausea, vomiting, oral and abdominal pain. Renal and hepatic impairment and pulmonary oedema may also occur. Impaired consciousness and encephalopathy have been reported as sequelae but there are limited data on the central nervous system (CNS) effects of Round-up toxicity. We report a 71-year-old male who attempted suicide with GlySH and developed a prolonged but reversible encephalopathy suggestive of acute CNS toxicity.

  18. Epinephrine-induced posterior reversible encephalopathy syndrome: a case report.

    PubMed

    Gharabawy, Ramez; Pothula, Vijayasimha R; Rubinshteyn, Vladimir; Silverberg, Michael; Gave, Asaf A

    2011-09-01

    Posterior reversible encephalopathy syndrome (PRES) is a rare disorder that is usually associated with hypertensive crises. It is often missed but may be diagnosed by head computed tomographic (CT) scan or magnetic resonance imaging. An adolescent man presented for elective right shoulder arthroscopic bankart repair. Arthroscopy was performed using a solution of normal saline with 3.3 mg/L of epinephrine for irrigation. Postoperatively, the patient presented with hypertension and epileptiform activity. A CT scan of the head showed PRES.

  19. 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.

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

    PubMed

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

    2016-08-01

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

  1. 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...

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

    PubMed

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

    2012-05-01

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

  3. 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.

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

    PubMed

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

    2011-01-01

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

  5. 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.

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Purim, Ofer; Sulkes, Aaron; Brenner, Baruch

    2007-07-01

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

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

    PubMed Central

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

    1977-01-01

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

  9. Comparative Analysis of the Antineoplastic Activity of C60 Fullerene with 5-Fluorouracil and Pyrrole Derivative In Vivo

    NASA Astrophysics Data System (ADS)

    Lynchak, O. V.; Prylutskyy, Yu I.; Rybalchenko, V. K.; Kyzyma, O. A.; Soloviov, D.; Kostjukov, V. V.; Evstigneev, M. P.; Ritter, U.; Scharff, P.

    2017-01-01

    The antitumor activity of pristine C60 fullerene aqueous solution (C60FAS) compared to 5-fluorouracil (5-FU) and pyrrole derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2.5-dione (MI-1) cytostatic drugs was investigated and analyzed in detail using the model of colorectal cancer induced by 1.2-dimethylhydrazine (DMH) in rats. The number, size, and location of the tumors were measured, and the pathology was examined. It was found that the number of tumors and total lesion area decreased significantly under the action of C60FAS and MI-1. Because these drugs have different mechanisms of action, their simultaneous administration can potentially increase the effectiveness and significantly reduce the side effects of antitumor therapy.

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

    NASA Astrophysics Data System (ADS)

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

    2013-11-01

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

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

    PubMed

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

    2015-07-01

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

  12. 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

  13. 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

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

    PubMed Central

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

    2014-01-01

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

  15. 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.

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

    PubMed

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

    2016-09-01

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

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

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

    PubMed

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

    2000-11-01

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

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

    PubMed

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

    2016-05-01

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

  19. Ertapenem-Induced Encephalopathy in a Patient With Normal Renal Function

    PubMed Central

    Sutton, S. Scott; Jumper, Mark; Cook, Sean; Edun, Babatunde; Wyatt, Michael D.

    2017-01-01

    Drug-induced neurotoxicity is a rare adverse reaction associated with ertapenem. Encephalopathy is a type of neurotoxicity that is defined as a diffuse disease of the brain that alters brain function or structure. We report a patient with normal renal function who developed ertapenem-induced encephalopathy manifesting as altered mental status, hallucinations, and dystonic symptoms. The patient’s symptoms improved dramatically following ertapenem discontinuation, consistent with case reports describing ertapenem neurotoxicity in renal dysfunction. Since clinical evidence strongly suggested ertapenem causality, we utilized the Naranjo Scale to estimate the probability of an adverse drug reaction to ertapenem. Our patient received a Naranjo Scale score of 7, suggesting a probable adverse drug reaction, with a reasonable temporal sequence to support our conclusion. PMID:28203577

  20. 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

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

    PubMed

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

    2017-03-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

    Goncalves, J C

    1975-01-01

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

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

    PubMed

    Stewart, T; Pavlakis, N; Ward, M

    2010-04-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2008-11-01

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

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

    PubMed Central

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

    1992-01-01

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

  9. Tranilast reduces serum IL-6 and IL-13 and protects against thioacetamide-induced acute liver injury and hepatic encephalopathy.

    PubMed

    Abdelaziz, Rania R; Elkashef, Wagdi F; Said, Eman

    2015-07-01

    Hepatic encephalopathy is a serious neuropsychiatric disorder usually affecting either acute or chronic hepatic failure patients. Hepatic encephalopathy was replicated in a validated rat model to assess the potential protective efficacy of tranilast against experimentally induced hepatic encephalopathy. Thioacetamide injection significantly impaired hepatic synthetic, metabolic and excretory functions with significant increase in serum NO, IL-6 and IL-13 levels and negative shift in the oxidant/antioxidant balance. Most importantly, there was a significant increase in serum ammonia levels with significant astrocytes' swelling and vacuolization; hallmarks of hepatic encephalopathy. Tranilast administration (300 mg/kg, orally) for 15 days significantly improved hepatic functions, restored oxidant/antioxidant balance, reduced serum NO, IL-6 and IL-13 levels. Meanwhile, serum ammonia significantly declined with significant reduction in astrocytes' swelling and vacuolization. Several mechanisms can be implicated in the observed hepato- and neuroprotective potentials of tranilast, such as its anti-inflammatory potential, its antioxidant potential as well as its immunomodulatory properties.

  10. Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature

    PubMed Central

    Panwar, Ajay; Pandit, Alak; Das, Susanta Kumar; Joshi, Bhushan

    2016-01-01

    Metronidazole is an antimicrobial agent mainly used in the treatment of several protozoal and anaerobic infections, additionally, is often used in hepatic encephalopathy and Crohn disease. Apart from peripheral neuropathy, metronidazole can also cause symptoms of central nervous system dysfunction like ataxic gait, dysarthria, seizures, and encephalopathy which may result from both short term and chronic use of this drug and is collectively termed as “metronidazole induced encephalopathy”(MIE). Neuroimaging forms the backbone in clinching the diagnosis of this uncommon entity, especially in cases where there is high index of suspicion of intoxication. Although typical sites of involvement include cerebellum, brain stem and corpus callosum, however, lesions of other sites have also been reported. Once diagnosed, resolution of findings on Magnetic Resonance Imaging (MRI) of the Brain along with clinical improvement remains the mainstay of monitoring. Here we review the key clinical features and MRI findings of MIE as reported in medical literature. We also analyze implication of use of this drug in special situations like hepatic encephalopathy and brain abscess and discuss our experience regarding this entity. PMID:27504340

  11. Brain-derived neurotrophic factor and interleukin-6 levels in the serum and cerebrospinal fluid of children with viral infection-induced encephalopathy.

    PubMed

    Morichi, Shinichiro; Yamanaka, Gaku; Ishida, Yu; Oana, Shingo; Kashiwagi, Yasuyo; Kawashima, Hisashi

    2014-11-01

    We investigated changes in the brain-derived neurotrophic factor (BDNF) and interleukin (IL)-6 levels in pediatric patients with central nervous system (CNS) infections, particularly viral infection-induced encephalopathy. Over a 5-year study period, 24 children hospitalized with encephalopathy were grouped based on their acute encephalopathy type (the excitotoxicity, cytokine storm, and metabolic error types). Children without CNS infections served as controls. In serum and cerebrospinal fluid (CSF) samples, BDNF and IL-6 levels were increased in all encephalopathy groups, and significant increases were noted in the influenza-associated and cytokine storm encephalopathy groups. Children with sequelae showed higher BDNF and IL-6 levels than those without sequelae. In pediatric patients, changes in serum and CSF BDNF and IL-6 levels may serve as a prognostic index of CNS infections, particularly for the diagnosis of encephalopathy and differentiation of encephalopathy types.

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

    PubMed

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

    2016-01-01

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

  13. 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.

  14. Poloxamer 188 and propylene glycol-based rectal suppository enhances anticancer effect of 5-fluorouracil in mice.

    PubMed

    Paek, Seung-Hwan; Xuan, Jing-Ji; Choi, Han-Gon; Park, Byung Chul; Lee, Yoon-Seok; Jeong, Tae-Cheon; Jin, Chun Hua; Oh, Yu-Kyoung; Kim, Jung-Ae

    2006-05-01

    The tumoricidal and apoptosis-inducing activities of 5-fluorouracil (5-FU) have been demonstrated in experimental and clinical investigations. Clinically, the 5-FU suppository form has been widely adopted for its advantages of less systemic toxicity, higher local tissue concentrations, and reduced first-pass effect. In this study, we investigated the feasibility of rectal administration of 5-FU suppository based on poloxamer 188 (P188) and propylene glycol (PG) and its anticancer effect on the murine experimental cancer models. The rectal suppository was made with 70% P188 and 30% PG, which was a solid phase at room temperature and instantly melted at physiological temperature. The treatment with the 5-FU suppository was more effective than the oral route in decreasing the volume of rectal cancer in mice. In addition, the survival rate of the mice with rectal cancer was higher in the group treated with the 5-FU suppository than in the group treated with 5-FU orally. Furthermore, in mice skin cancers induced by inoculation of murine CT-26 colon carcinoma cells, the anticancer effect of 5-FU was significantly enhanced by the rectal administration of the suppository than by oral treatment. Taken together, the results suggest that a poloxamer gel system with 5-FU/P188/PG is an effective rectal dosage form for the treatment of both rectal and non-rectal cancers.

  15. 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.

  16. Overexpression of ECRG4 enhances chemosensitivity to 5-fluorouracil in the human gastric cancer SGC-7901 cell line.

    PubMed

    Jiang, Cheng-Ping; Wu, Bi-Hua; Wang, Bai-Qiang; Fu, Mao-Yong; Yang, Ming; Zhou, Yue; Liu, Fu

    2013-08-01

    The aim of this study was to examine the effects of esophageal cancer-related gene 4 (ECRG4) expression levels on chemotherapeutic sensitivity of gastric cancer cells. A SGC-7901 cell system with tetracycline-inducible ECRG4 expression (SGC-7901/ECRG4) was successfully established. ECRG4 mRNA and protein expression levels were detected using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Chemosensitivity to 5-fluorouracil (5-FU) was examined by cell proliferation assay and cell apoptosis assay. ECRG4 mRNA and protein expression levels were significantly upregulated in SGC-7901/ECRG4 cells induced with tetracycline. Compared with control cells, the growth inhibition rate of cells with ECRG4 overexpression was significantly increased when treated with 5-FU. Treatment with 5 μmol/l 5-FU resulted in 15.2 % apoptotic cells, whereas such treatment after overexpression of ECRG4 resulted in 44.5 % apoptotic cells. In conclusion, overexpression of ECRG4 enhanced the chemosensitivity of gastric cancer SGC-7901 cells to 5-FU through induction of apoptosis.

  17. 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

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

    PubMed

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

    2010-03-01

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

  19. 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.

  20. 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

  1. Hashimoto's encephalopathy.

    PubMed

    Chen, H C; Marsharani, U

    2000-05-01

    Hashimoto's encephalopathy is a subacute condition associated with autoimmune thyroiditis. Its presentation varies from focal neurologic deficits to global confusion. Unlike encephalopathy associated with hypothyroidism, Hashimoto's encephalopathy responds to steroid therapy and not thyroxine replacement.

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

    NASA Astrophysics Data System (ADS)

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

    2012-11-01

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

  3. Ifosfamide-induced Encephalopathy Precipitated by Aprepitant: A Rarely Manifested Side Effect of Drug Interaction

    PubMed Central

    Kataria, Pritam Sureshchandra; Kendre, Pradip Piraji; Patel, Apurva A.

    2017-01-01

    Central nervous system (CNS) toxicity has been reported in approximately 10%–30% of patients receiving intravenous infusions of ifosfamide. Encephalopathy is a rare but serious CNS adverse reaction in these patients, and although usually transient and reversible, may cause persistent neurological dysfunction or death. Clinical features range from fatigue and confusion to coma and death. Ifosfamide forms backbone of various treatment regimens including curative treatment and palliative chemotherapy regimen. Precipitation of ifosfamide-induced encephalopathy (IIE) by aprepitant has been reported in the literature rarely. Ifosfamide is moderately emetogenic; hence, aprepitant is used to prevent emesis induced by ifosfamide. We here report a case where a patient of recurrent B-cell Philadelphia-negative acute lymphoblastic lymphoma was given aprepitant to prevent ifosfamide-induced emesis. After 24 h of ifosfamide infusion, the patient developed symptoms of encephalopathy, i.e., headache, vomiting, and one episode of seizure which was followed by disoriented behavior. After doing all routine investigations and neuroimaging, the diagnosis of IIE was kept on clinical grounds, and after looking for the various factors, we came across injection fosaprepitant as the precipitating factor. On the clinical grounds, the patient was treated with hydration and injection methylene blue for above complaints, and the patient recovered without any residual deficit within 48–72 h. Hence, in the presence of causative agent, i.e., ifosfamide and precipitating agent injection fosaprepitant with negative imaging and normal laboratory parameters as well as the early and good response to methylene blue, the diagnosis of IIE precipitated by aprepitant was confirmed.

  4. 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.

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

    PubMed

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

    2015-07-01

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

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed

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

    1999-02-01

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

  8. 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.

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

    PubMed

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

    2005-06-20

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

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

    PubMed

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

    2015-06-10

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

  11. 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.

  12. 5-fluorouracil toxicity in the treatment of colon cancer associated with the genetic polymorphism 2846 A>G (rs67376798).

    PubMed

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

    2016-04-27

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

  13. 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.

  14. 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

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

    PubMed

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

    2011-11-01

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

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

    PubMed

    Singh, Baljit; Chauhan, Nirmala

    2008-09-01

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

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

    PubMed

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

    2015-11-01

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

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

    PubMed

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

    2016-10-01

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

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

    SciTech Connect

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

    2005-03-15

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-11-01

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

  2. 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

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

    PubMed

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

    2017-02-01

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

  4. 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

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

    PubMed

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

    2013-01-01

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

  6. Phospholipid and cholesterol alterations accompany structural disarray in myelin membrane of rats with hepatic encephalopathy induced by thioacetamide.

    PubMed

    Swapna, I; Kumar, K V Sathya Sai; Reddy, P Vijaya Bhaskar; Murthy, Ch R K; Reddanna, P; Senthilkumaran, B

    2006-08-01

    Fulminant hepatic failure is often associated with a wide range of neurological symptoms which are collectively referred to as hepatic encephalopathy. Fulminant hepatic failure with associated hepatic encephalopathy has a poor prognosis with the currently available sure treatment being only liver transplantation. This is largely owing to the lack of understanding of critical factors involved in the etiology of the condition. Lipid changes have been implicated in cerebral derangements characteristic of hepatic encephalopathy. About 79% of the brain lipid is concentrated in the myelin fraction where they play an important role in ion balance and conduction of nerve impulses. Hence, in the present study we aimed to investigate changes in myelin lipid composition and structure. Myelin was isolated by sucrose density gradient centrifugation from cerebral cortex of male Wistar rats (250-300 g body weight) treated with 300 mg/kg body weight thioacetamide administered twice at 24h interval to induce hepatic encephalopathy. Significant decrease was observed in the cholesterol and phospholipids content of myelin from treated rats. Sphingomyelin, phosphatidylserine and phosphatidylethanolamine content also decreased significantly following 18 h of thioacetamide administration. However, phosphatidylcholine levels remained unaltered. Transmission electron microscopic observation of myelin membrane from cerebral cortex sections showed considerable disorganization in myelin structure. Increase in malondialdehyde levels precede lipid changes leading to the speculation that oxidative damage may be the critical factor leading to decrease in the anionic phospholipids. Changes in myelin were evident only in later stages of hepatic encephalopathy indicating that myelin alteration may not play a role in early stages of hepatic encephalopathy. Nevertheless, myelin alteration may have a crucial role to play in various psycho-motor alterations during later stages of hepatic encephalopathy.

  7. Elevated VGKC-Complex Antibodies in a Boy with Fever-Induced Refractory Epileptic Encephalopathy in School-Age Children (FIRES)

    ERIC Educational Resources Information Center

    Illingworth, Marjorie A.; Hanrahan, Donncha; Anderson, Claire E.; O'Kane, Kathryn; Anderson, Jennifer; Casey, Maureen; de Sousa, Carlos; Cross, J. Helen; Wright, Sukvhir; Dale, Russell C.; Vincent, Angela; Kurian, Manju A.

    2011-01-01

    Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and…

  8. H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance.

    PubMed

    Paschall, Amy V; Yang, Dafeng; Lu, Chunwan; Choi, Jeong-Hyeon; Li, Xia; Liu, Feiyan; Figueroa, Mario; Oberlies, Nicholas H; Pearce, Cedric; Bollag, Wendy B; Nayak-Kapoor, Asha; Liu, Kebin

    2015-08-15

    The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colon carcinoma often uses silencing Fas expression as a mechanism of immune evasion. The molecular mechanism under FAS transcriptional silencing in human colon carcinoma is unknown. We performed genome-wide chromatin immunoprecipitation sequencing analysis and identified that the FAS promoter is enriched with H3K9me3 in metastatic human colon carcinoma cells. The H3K9me3 level in the FAS promoter region is significantly higher in metastatic than in primary cancer cells, and it is inversely correlated with Fas expression level. We discovered that verticillin A is a selective inhibitor of histone methyltransferases SUV39H1, SUV39H2, and G9a/GLP that exhibit redundant functions in H3K9 trimethylation and FAS transcriptional silencing. Genome-wide gene expression analysis identified FAS as one of the verticillin A target genes. Verticillin A treatment decreased H3K9me3 levels in the FAS promoter and restored Fas expression. Furthermore, verticillin A exhibited greater efficacy than decitabine and vorinostat in overcoming colon carcinoma resistance to FasL-induced apoptosis. Verticillin A also increased DR5 expression and overcame colon carcinoma resistance to DR5 agonist drozitumab-induced apoptosis. Interestingly, verticillin A overcame metastatic colon carcinoma resistance to 5-fluorouracil in vitro and in vivo. Using an orthotopic colon cancer mouse model, we demonstrated that tumor-infiltrating cytotoxic T lymphocytes are FasL(+) and that FasL-mediated cancer immune surveillance is essential for colon carcinoma growth control in vivo. Our findings determine that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing and resultant colon carcinoma immune evasion and progression.

  9. Cyclin E and histone H3 levels are regulated by 5-fluorouracil in a DNA mismatch repair-dependent manner

    PubMed Central

    Chung, Heekyung; Chaudhry, Joy; Lopez, Claudia G

    2010-01-01

    Several studies indicate that the DNA mismatch repair (MMR) system may trigger cytotoxicity upon 5-fluorouracil (5-FU) recognition, but signaling pathways regulated by MMR in response to 5-FU are unknown. We hypothesize that recognition of 5-FU in DNA by MMR proteins trigger specific signaling cascades that results in slowing of the cell cycle and cell death. Whole human genome cDNA microarrays were used to examine relative signaling responses induced in MMR-proficient cells after 5-FU (5 µM) treatment for 24 hours. Analysis revealed 43 pathways differentially affected by 5-FU compared to control (p < 0.05), including cyclin and cell cycle regulation involving G1-S cell cycle transition, activation of Src, MAP K, p53 and base excision repair. In particular, 5-FU upregulated cyclins E1 and E2 (≥1.4-fold) and downregulated cdc25C, cyclins B1 and B2, histone H2A, H2B and H3 (≤-1.4-fold) over control. Cell cycle analysis revealed a G1/S arrest by 5-FU that was congruent with increased cyclin E and decreased cdc25C protein expression. Importantly, with knockdown of hMLH1 and hMSH2, we observed that decreased histone H3 expression by 5-FU was dependent on hMLH1. Additionally, 5-FU treatment dramatically decreased levels of several histone H3 modifications. Our data suggest that 5-FU induces a G1/S arrest by regulating cyclin E and cdc25C expression and MMR recognition of 5-FU in DNA may modulate cyclin E to affect the cell cycle. Furthermore, MMR recognition of 5-FU reduces histone H3 levels that could be related to DNA access by proteins and/or cell death during the G1/S phase of the cell cycle. PMID:20930505

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

    PubMed

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

    2016-06-01

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

  11. 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 ...

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

    PubMed

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

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2011-02-01

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

  14. 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

  15. Phase I trial of escalating-dose cisplatin with 5-fluorouracil and concurrent radiotherapy in Chinese patients with esophageal cancer.

    PubMed

    Lin, Qiang; Gao, Xian-Shu; Qiao, Xue-Ying; Zhou, Zhi-Guo; Zhang, Ping; Chen, Kun; Zhao, Yan-Nan; Asaumi, Junichi

    2008-02-01

    We defined the maximum-tolerated dose (MTD) of chemoradiotherapy (cisplatin (CDDP) with 5-fluorouracil (5-FU) and concurrent chemoradiotherapy) for Chinese patients with esophageal cancer. Twenty-one previously untreated patients with primary esophageal cancer were entered into this study. Escalating doses of CDDP with 5-FU were administered in a modified Fibonacci sequence, with concurrent conventional fractionation radiotherapy (CFR) of 60 Gy or 50 Gy. The starting doses were CDDP 37.5 mg/m2 on day 1, and 5-FU 500 mg/m2 on days 1-5, respectively. The regimen was repeated 4 times every 28 days. If no dose-limiting toxicity (DLT) was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be 1 dose level below the level at which DLT appeared. DLT was grade 3 radiation-induced esophagitis at a dose level of CDDP 60 mg/m2 with 5-FU 700 mg/m2 and concurrent 60 Gy CFR. MTD was defined as CDDP 52.5 mg/m2 with 5-FU 700 mg/m2 and concurrent 50 Gy CFR. The MTD of CDDP with 5-FU and in concurrent chemoradiotherapy for Chinese patients with esophageal cancer is CDDP 52.5 mg/m2 on day 1 and 5FU 700 mg/m2 on days 1-5, repeated 4 times every 28 days, and concurrent 50 Gy CFR. Further evaluation of this regimen in a prospective phase II trial is ongoing.

  16. 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.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  19. 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.

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

    PubMed Central

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

    2011-01-01

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

  1. 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.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-01-01

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

  5. 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.

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

    PubMed

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

    2012-01-01

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

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

    PubMed

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

    2008-10-22

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2015-01-08

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

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

    PubMed

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

    2011-06-01

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

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

    PubMed

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

    1997-03-01

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2012-05-01

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

  14. 5-Fluorouracil delivery from metal-ion mediated molecularly imprinted cryogel discs.

    PubMed

    Çetin, Kemal; Denizli, Adil

    2015-02-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2015-01-01

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

  18. 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

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

    NASA Astrophysics Data System (ADS)

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

    2004-12-01

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

  20. 5-fluorouracil in lethal mutagenesis of foot-and-mouth disease virus.

    PubMed

    Agudo, Rubén; Arias, Armando; Domingo, Esteban

    2009-06-01

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

  1. Precipitants of hepatic encephalopathy induce rapid astrocyte swelling in an oxidative stress dependent manner.

    PubMed

    Lachmann, Vera; Görg, Boris; Bidmon, Hans Jürgen; Keitel, Verena; Häussinger, Dieter

    2013-08-15

    Hepatic encephalopathy (HE) is seen as the clinical manifestation of a low grade cerebral edema with formation of reactive oxygen and nitrogen species (RNOS). Astrocyte swelling is a crucial event and in cultured astrocytes HE-relevant factors almost instantaneously induce the formation of RNOS. However, short term effects of ammonia, inflammatory cytokines and RNOS on the volume of astrocytes and other brain cells as well as the underlying mechanisms are largely unknown, although a pathogenic link between RNOS formation and swelling in HE has been proposed. This issue was addressed in the present study by means of live-cell volume microscopy of brain cells in vitro. Ammonia, diazepam and pro-inflammatory cytokines such as tumor-necrosis factor-α (TNF-α), interferon-γ, interleukin-1β induced within 20min astrocyte swelling by about 25% accompanied by nuclear swelling of similar magnitude. Astrocyte swelling in response to NH4Cl, TNF-α or diazepam was abolished by the antioxidant epigallocatechin-gallate pointing to an involvement of RNOS. NH4Cl-induced astrocyte swelling was sensitive to inhibition of glutamine synthetase, NADPH oxidase or nitric oxide synthases. In line with a NMDA receptor-, prostanoid- and Ca(2+)-dependence of NH4Cl-induced RNOS formation, Ca(2+) chelation and inhibition of NMDA receptors or cyclooxygenase suppressed NH4Cl-induced astrocyte swelling, whereas the Ca(2+)-ionophore ionomycin, NMDA, glutamate and prostanoids induced rapid astrocyte swelling. NH4Cl also induced swelling of cultured microglia in a glutamine-synthesis dependent way, but had no effect on cell volume of cultured neurons. It is concluded that the pathways which trigger RNOS formation in astrocytes also trigger astrocyte swelling, whereas conversely and as shown previously hypoosmotic astrocyte swelling can induce RNOS formation. This establishes a complex interplay with an auto-amplificatory loop between RNOS formation and astrocyte swelling as an important event in

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

    PubMed Central

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

    2013-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2017-01-01

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

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

    SciTech Connect

    Not Available

    1985-12-01

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

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

    PubMed

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

    2013-09-10

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

  6. 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.

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

    PubMed

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

    2015-01-05

    Some biologically active mixed ligand complexes (1-9) have been synthesized from 5-Fluorouracil (5-FU; A) and amino acids (B) such as glycine (gly), L-alanine (ala) and L-valine (val) with Ni(II), Cu(II) and Zn(II) ions. The synthesized mixed ligand complexes (1-9) were characterized by various physico-chemical, spectral, thermal and morphological studies. 5-Fluorouracil and its mixed ligand complexes have been tested for their in vitro biological activities against some pathogenic bacterial and fungal species by the agar well diffusion method. The in vitro antioxidant activities of 5-Fluorouracil and its complexes have also been investigated by using the DPPH assay method. The results demonstrate that Cu(II) mixed ligand complexes (4-6) exhibit potent biological as well as antioxidant activities compared to 5-Fluorouracil and Ni(II) (1-3) and Zn(II) (7-9) mixed ligand complexes. Further, the cleaving activities of CT DNA under aerobic conditions show moderate activity with the synthesized Cu(II) and Ni(II) mixed ligand complexes (1-6) while no activity is seen with Zn(II) complexes (7-9). Binding studies of CT DNA with these complexes show a decrease in intensity of the charge transfer band to the extent of 5-15% along with a minor red shift. The free energy change values (Δ(‡)G) calculated from intrinsic binding constants indicate that the interaction between mixed ligand complex and DNA is spontaneous.

  8. 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.

  9. 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.

  10. [Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced influenza-virus-associated encephalopathy].

    PubMed

    Funato, Tadao; Kozawa, Kanoko; Kaku, Mitsuo

    2002-02-01

    The mechanism causing influenza-virus-associated encephalopathy is unclear, even though diclofenac metabolites may induce this pathogenesis. CYP2C9 is known as the major cytochrome P450 gene product that catalyzes diclofenac in human liver. It is uncertain whether the mutation of CYP2C9 is associated the pharmacologic effects of diclofenac in influenza infection. Therefore, we applied a simple and rapid procedure involving real-time fluorescence allele-specific PCR(TaqMan-ASA) assay and denaturing HPLC assay to detect the mutation of CYP2C9 gene. A single-base mutation in the CYP2C9 gene was found in one of thirty subjects in the healthy population. We suggest that this mutation in the CYP2C9 gene may be related to diclofenac-induced influenza-virus-associated encephalopathy.

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    1993-12-15

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

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

    PubMed

    Rajinikanth, Paruvathanahalli Siddalingam; Chellian, Jestin

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

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

    PubMed

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

    2014-09-01

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

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

    PubMed

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

    2017-01-01

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

  16. 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

  17. 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

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

    SciTech Connect

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

    1986-03-01

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

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

    PubMed

    Straub, Jürg Oliver

    2010-07-01

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

  20. 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.

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

    PubMed

    Eftekhar, Ebrahim; Naghibalhossaini, Fakhraddin

    2014-01-01

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

  2. 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.

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

    PubMed

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

    2005-01-01

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

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

    PubMed

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

    2010-11-01

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

  5. Effect of adenosine on the supramolecular architecture and activity of 5-fluorouracil

    NASA Astrophysics Data System (ADS)

    Singh, Udai P.; Kashyap, Sujata; Singh, Hari Ji; Mishra, Bhupesh Kumar; Roy, Partha; Chakraborty, Ajanta

    2012-04-01

    The reactions of adenosine (Ad) with 5-halouracils (5XU where X = F for 1, Cl for 2, Br for 3 and I for 4) resulted in the formation of co-crystals 1-4 in monoclinic with P21 space group. Despite of great variation in the halo substituent at the 5th position of the uracil, each structure contains the same number and same type of non-covalent interactions i.e., primary N-H⋯N, N-H⋯O, O-H⋯N, O-H⋯O hydrogen bonds and secondary C-H⋯O and X⋯O interactions within these motifs as well as with neighboring molecules. As compared to Ad the size of cavity increases in co-crystal 1 to accommodate the 5FU as a guest. With the variation of halogen from fluoro to iodo on the uracil, the orientation of the molecules remains the same with a slight difference in the dihedral angle in all the co-crystals 1-4. This study demonstrates that hydrogen-bonded interactions between adenosine and halouracils provide a supramolecular assembly to these co-crystals. Computational studies illustrate that the size of the halo substituents on uracil has no effect on the hydrogen bond interaction energy. It further reveals that the orientation of molecules remain same in both solid phase as well as in the gaseous phase. The antitumor and DNA cleavage activity studies show that the antitumor activity of 5-fluorouracil against MCF-7 breast cancer decreases in the presence of adenosine.

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

    SciTech Connect

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

    2007-07-15

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

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

    SciTech Connect

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

    2009-07-15

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

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

    SciTech Connect

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

    2008-07-01

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

  9. 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.

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

    PubMed

    Cornwell, P A; Barry, B W

    1994-04-01

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

  11. 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.

  12. Co-administration of C-Phycocyanin ameliorates thioacetamide-induced hepatic encephalopathy in Wistar rats.

    PubMed

    Sathyasaikumar, K V; Swapna, I; Reddy, P V B; Murthy, Ch R K; Roy, K R; Dutta Gupta, A; Senthilkumaran, B; Reddanna, P

    2007-01-15

    Fulminant hepatic failure (FHF) is a condition with a sudden onset of necrosis followed by degeneration of hepatocytes, without any previously established liver disease, generally occurring within hours or days. FHF is associated with a wide spectrum of neuropsychiatric alterations ranging from stupor to coma, culminating in death. In the present study FHF was induced in rats by the administration of thioacetamide (TAA). Oxidative stress is thought to play a prominent role in the pathophysiology of cerebral changes during FHF leading to the assumption that antioxidants might offer protection. Hence, in the present study the protective effect of C-Phycocyanin (C-PC), a natural antioxidant, was evaluated on TAA-induced tissue damage. C-Phycocyanin was administered intraperitoneally twice at 24 h interval (50 mg/kg body weight) along with the hepatotoxin TAA (300 mg/kg body weight). The animals were sacrificed 18 h after the second injection of TAA treatment and various biochemical parameters were analysed in liver, serum and brain tissues. These studies revealed significant prevention of TAA-induced liver damage by C-PC, as evidenced by a) increase in survival rate; b) the prevention of leakage of liver enzymes (AAT and AST) and ammonia into serum; c) increase in prothrombin time and d) liver histopathology. Ultrastructural studies of astrocytes of different regions of brain clearly showed a decrease in edema after C-PC treatment. TAA-induced histopathological lesions in different regions of the brain namely cerebral cortex, cerebellum and pons medulla were significantly reduced by the co-administration of C-PC with TAA. Further C-PC treatment resulted in a) decrease in the levels of tryptophan and markers of lipid peroxidation and b) elevation in the activity levels of catalase, glutathione peroxidase in different regions of brain. These studies reveal the potential of C-PC in ameliorating TAA-induced hepatic encephalopathy by improving antioxidant defenses.

  13. [Wernicke's encephalopathy induced by the use of diet pills and unbalanced diet].

    PubMed

    Tóth, Adrián; Aradi, Gabriella; Várallyay, György; Arányi, Zsuzsanna; Bereczki, Dániel; Vastagh, Ildikó

    2014-03-23

    Wernicke's encephalopathy is an acute, potentially life-threatening, neurological syndrome resulting from thiamine deficiency. The disorder is still greatly underdiagnosed and, without prompt treatment, the condition can lead to the chronic form of the disease, Korsakoff's syndrome or even death. In developed countries Wernicke's encephalopathy has been associated with alcoholism, but in recent years there has been an increasing number of non-alcoholic cases. Authors report the case of a 23-year-old woman who developed oculomotor dysfunction, encephalopathy and ataxia as a result of an extreme diet and use of diet pills. The diagnosis of Wernicke's encephalopathy was supported by the resolution of neurological signs after parenteral thiamine replacement. This case is presented because of the rare etiology and diagnostic difficulty, and the latest diagnostic and therapic guidelines are also highlighted.

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

    PubMed Central

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

    2016-01-01

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

  15. Reversible Encephalopathy due to Valproic Acid Induced Hyperammonemia in a Patient with Bipolar I Disorder: A Cautionary Report

    PubMed Central

    Patel, Neel; Landry, Katherine B.; Fargason, Rachel E.; Birur, Badari

    2017-01-01

    Valproic acid (VPA) is an FDA-approved medication widely prescribed for seizures, migraines, and mixed or manic episodes in bipolar disorder. Hyperammonemia is a rare complication of VPA use, which can result in high morbidity and occasionally fatal encephalopathy. The scant literature on Valproate Induced Hyperammonemic Encephalopathy (VIHE) is characterized by acute onset of decreasing level of consciousness, drowsiness, lethargy which in rare instances can lead to seizures, stupor, coma, and persistent morbidity and cortical damage. Below we describe a case report of a patient with Bipolar I Disorder with no primary evidence of hepatic dysfunction that was initiated on VPA and olanzapine to address manic and psychotic symptoms. This patient subsequently developed elevated ammonia (NH4) levels that led to a reversible encephalopathy. This cautionary case report highlights the potential for a rare but serious complication from VPA, a medication increasingly used in both neurologic and neuropsychiatric settings. It is imperative that clinicians perform a thorough physical, neurological and diagnostic evaluation, routinely check NH4 and VPA levels when prescribing these agents and exercise caution when VPA is concomitantly prescribed with antipsychotics and cytochrome P450 inducing antiepileptic medications. PMID:28138203

  16. [Metronidazole-Induced Encephalopathy during Brain Abscess Treatment:Two Case Reports].

    PubMed

    Yokoyama, Yuka; Asaoka, Katsuyuki; Sugiyama, Taku; Uchida, Kazuki; Shimbo, Daisuke; Kobayashi, Satoshi; Itamoto, Koji

    2015-10-01

    Metronidazole is a widely used antibiotic against anaerobic bacteria and protozoa. We report two cases of metronidazole-induced encephalopathy(MIE)during treatment of a brain abscess with metronidazole. The patients developed mental disturbance, and brain MRI showed reversible signals on DWI, FLAIR, and T2. Case 1: A 48-year-old woman was admitted to our hospital with a cerebellar abscess. We initiated treatment with oral metronidazole. After taking the medication, she developed mental disturbance, and her brain MRI showed a hyperintensity within the corpus callosum. We suspected metronidazole toxicity and discontinued metronidazole treatment. The symptoms resolved rapidly within a week, and the hyperintensity on the MRI disappeared. Case 2: A 22-year-old man was admitted to our hospital with a brain abscess. We initiated treatment with oral metronidazole. On day 38, he developed mental disturbance, and his MRI showed hyperintensities within the bilateral dentate nuclei and corpus callosum. These symptoms were consistent with MIE. After cessation of metronidazole, his symptoms and abnormal MRI signals completely disappeared.

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

    PubMed

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

    1993-05-01

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

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

    PubMed Central

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

    2011-01-01

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

  19. 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

  20. 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

  1. 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.

  2. Toxic Encephalopathy

    PubMed Central

    Kim, Jae Woo

    2012-01-01

    This article schematically reviews the clinical features, diagnostic approaches to, and toxicological implications of toxic encephalopathy. The review will focus on the most significant occupational causes of toxic encephalopathy. Chronic toxic encephalopathy, cerebellar syndrome, parkinsonism, and vascular encephalopathy are commonly encountered clinical syndromes of toxic encephalopathy. Few neurotoxins cause patients to present with pathognomonic neurological syndromes. The symptoms and signs of toxic encephalopathy may be mimicked by many psychiatric, metabolic, inflammatory, neoplastic, and degenerative diseases of the nervous system. Thus, the importance of good history-taking that considers exposure and a comprehensive neurological examination cannot be overemphasized in the diagnosis of toxic encephalopathy. Neuropsychological testing and neuroimaging typically play ancillary roles. The recognition of toxic encephalopathy is important because the correct diagnosis of occupational disease can prevent others (e.g., workers at the same worksite) from further harm by reducing their exposure to the toxin, and also often provides some indication of prognosis. Physicians must therefore be aware of the typical signs and symptoms of toxic encephalopathy, and close collaborations between neurologists and occupational physicians are needed to determine whether neurological disorders are related to occupational neurotoxin exposure. PMID:23251840

  3. Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy.

    PubMed

    Mladenović, Dušan; Hrnčić, Dragan; Petronijević, Nataša; Jevtić, Gordana; Radosavljević, Tatjana; Rašić-Marković, Aleksandra; Puškaš, Nela; Maksić, Nebojša; Stanojlović, Olivera

    2014-11-01

    Neurosteroids are involved in the pathogenesis of hepatic encephalopathy (HE). This study evaluated the effects of finasteride, inhibitor of neurosteroid synthesis, on motor, EEG, and cellular changes in rat brain in thioacetamide-induced HE. Male Wistar rats were divided into the following groups: 1) control; 2) thioacetamide-treated group, TAA (300 mg·kg(-1)·day(-1)); 3) finasteride-treated group, FIN (50 mg·kg(-1)·day(-1)); and 4) group treated with FIN and TAA (FIN + TAA). Daily doses of TAA and FIN were administered in three subsequent days intraperitoneally, and in the FIN + TAA group FIN was administered 2 h before every dose of TAA. Motor and reflex activity was determined at 0, 2, 4, 6, and 24 h, whereas EEG activity was registered about 24 h after treatment. The expressions of neuronal (NeuN), astrocytic [glial fibrilary acidic protein (GFAP)], microglial (Iba1), and oligodendrocyte (myelin oligodendrocyte glycoprotein) marker were determined 24 h after treatment. While TAA decreased all tests, FIN pretreatment (FIN + TAA) significantly improved equilibrium, placement test, auditory startle, head shake reflex, motor activity, and exploratory behavior vs. the TAA group. Vital reflexes (withdrawal, grasping, righting and corneal reflex) together with mean EEG voltage were significantly higher (P < 0.01) in the FIN + TAA vs. the TAA group. Hippocampal NeuN expression was significantly lower in TAA vs. control (P < 0.05). Cortical Iba1 expression was significantly higher in experimental groups vs. control (P < 0.05), whereas hippocampal GFAP expression was increased in TAA and decreased in the FIN + TAA group vs. control (P < 0.05). Finasteride improves motor and EEG changes in TAA-induced HE and completely prevents the development of hepatic coma.

  4. Two Half-Sandwiched Ruthenium (II) Compounds Containing 5-Fluorouracil Derivatives: Synthesis and Study of DNA Intercalation

    PubMed Central

    Li, Zhao-Jun; Hou, Yong; Qin, Da-An; Jin, Zhi-Min; Hu, Mao-Lin

    2015-01-01

    Two novel coordination compounds of half-sandwiched ruthenium(II) containing 2-(5-fluorouracil)-yl-N-(pyridyl)-acetamide were synthesized, and their intercalation binding modes with calf thymus DNA were revealed by hyperchromism of ultraviolet-visible spectroscopy; the binding constants were determined according to a Langmuir adsorption equation that was deduced on the base of careful cyclic voltammetry measurements. The two compounds exhibited DNA intercalation binding activities with the binding constants of 1.13×106 M-1 and 5.35 ×105 M-1, respectively. PMID:25789618

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

    PubMed

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

    2006-01-01

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

  6. Evaluation of the therapeutic results of actinic keratosis treated with topical 5% fluorouracil by reflectance confocal laser microscopy: preliminary study*

    PubMed Central

    Ishioka, Priscila; Maia, Marcus; Rodrigues, Sarita Bartholomei; Marta, Alessandra Cristina; Hirata, Sérgio Henrique

    2015-01-01

    Topical treatment for actinic keratosis with 5% fluorouracil has a recurrence rate of 54% in 12 months of follow-up. This study analyzed thirteen actinic keratoses on the upper limbs through confocal microscopy, at the time of clinical diagnosis and after 4 weeks of treatment with fluorouracil. After the treatment was established and evidence of clinical cure was achieved, in two of the nine actinic keratoses, confocal microscopy enabled visualization of focal areas of atypical honeycomb pattern in the epidermis indicating therapeutic failure. Preliminary data suggest the use of confocal microscopy as a tool for diagnosis and therapeutic control of actinic keratosis. PMID:26131881

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

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

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

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

    PubMed

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

    2007-01-01

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

  9. Controlled release of 5-fluorouracil or mitomycin-c from polymer matrix: Preparation by radiation polymerization and in vivo evaluation of the anticancer drug/polymer composites

    NASA Astrophysics Data System (ADS)

    Li, Ximing; Shen, Weiming; Liu, Chengjie; Nishimoto, Sei-Ichi; Kagiya, Tsutomu

    Polymer tablets containing anticancer drugs such as 5-fluorouracil (5-FU) and mitomycin-C (MMC) have been prepared to evaluate the drug-release characteristics in vitro and the effect on local control of mouse solid tumors in vivo. Radiation-induced polymerization of hydrophilic monomers (2-hydroxyethyl methacrylate and related monomers) at low temperature (-80°C) was performed to immobilize 5-FU or MMC in the polymer matrix. The drug was dispersed as microcrystallines within the polymer matrix. The rate of drug release in vitro in buffer solution (pH7.0, 37°C) increased with increase in hydrophilicity of polymer matrix. Appropriate amount of crosslinks within the polymer matrix, as formed by ethylene glycol dimethacrylate (2G) added in the polymerization system, was effective to control the rate of drug release. The drug release became faster upon the addition of increasing amount of water in the radiation-induced polymerization. The tablet consisting of drug/polymer was buried surgically near solid tumors of striate muscle sarcoma (S180) transplanted to Kunming mice and the therapeutic effect of slow releasing drugs was evaluated in vivo by reference to intraperitoneal (i.p.) injection of the corresponding drugs. The slow releasing drugs led to high chemotherapeutic gain for local control of solid tumors with remarkable reduction of toxic side effect of the drugs.

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

    PubMed

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

    2014-02-15

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

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

    PubMed

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

    2013-12-01

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

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

    PubMed

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

    2016-05-01

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

  13. 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.

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

    PubMed

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

    2013-06-07

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

  15. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    2016-02-01

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

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

    PubMed

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

    2012-03-01

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

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

    PubMed

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

    2014-10-01

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

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

    PubMed Central

    Sethuraman, Swaminathan

    2014-01-01

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

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

    PubMed

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

    2016-10-01

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

  3. Diamine oxidase as a marker of intestinal mucosal injury and the effect of soluble dietary fiber on gastrointestinal tract toxicity after intravenous 5-fluorouracil treatment in rats.

    PubMed

    Fukudome, Ian; Kobayashi, Michiya; Dabanaka, Ken; Maeda, Hiromichi; Okamoto, Ken; Okabayashi, Takehiro; Baba, Ryoko; Kumagai, Nana; Oba, Koji; Fujita, Mamoru; Hanazaki, Kazuhiro

    2014-06-01

    The level of plasma diamine oxidase (DAO) activity is associated with the maturation and integrity of small intestinal mucosa. This study in rats investigated whether a decreased level of plasma DAO could reflect the severity of mucosal injury due to intravenous 5-fluorouracil (5-FU) treatment. The beneficial effect of soluble dietary fiber (SDF) on preventing diarrhea after 5-FU treatment was also examined. To induce diarrhea, 5-FU (50 mg/kg/day for four days) was administered via the tail vein with or without SDF supplementation. After 5-FU treatment, the majority of rats developed moderate to severe diarrhea, and levels of plasma DAO activity significantly decreased compared to those of control group (P < 0.05). Scanning electron microscopy revealed disarrangement of the small intestinal villi. Contrarily, the rats supplemented with SDF had diarrhea less frequently (50.0 vs. 91.7 %, P = 0.025) on day five, and DAO activity levels were significantly higher than in those rats administered 5-FU alone (8.25 ± 5.34 vs. 5.50 ± 4.32, P = 0.023). In conclusion, plasma DAO activity decreases in response to severe intestinal mucosal injury after 5-FU treatment, and SDF supplementation might be a practical and useful treatment for reducing the intestinal toxicity of 5-FU.

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

    PubMed

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

    2014-08-01

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

  5. [Wernicke encephalopathy].

    PubMed

    Djelantik, M; Bloemkolk, D; Tijdink, J

    2015-01-01

    Wernicke encephalopathy is an acute neuropsychiatric disease with heterogeneous symptoms, including changes in mental status, ataxia and ocular abnormalities; if left untreated, these symptoms can lead to morbidity and even to mortality. The treatment is thiamine suppletion. Because of the heterogeneity of the symptoms and the high risk of morbidity and mortality if the symptoms are not treated, it is vitally important that on observing a patient's early symptoms the clinician immediately suspects that the symptoms could point to Wernicke encephalopathy.

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

    SciTech Connect

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

    1981-10-15

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

  7. 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

  8. Rare sugar D-allose enhances anti-tumor effect of 5-fluorouracil on the human hepatocellular carcinoma cell line HuH-7.

    PubMed

    Yamaguchi, Fuminori; Kamitori, Kazuyo; Sanada, Keiko; Horii, Mariko; Dong, Youyi; Sui, Li; Tokuda, Masaaki

    2008-09-01

    d-Allose is a novel anti-tumor monosaccharide that causes cell growth inhibition, specifically of the cancer cells, by inducing the tumor suppressor gene thioredoxin interacting protein (TXNIP). The commonly used anti-tumor drug, 5-fluorouracil (5-FU), blocks the cell cycle by inhibiting thymidylate synthase, and is also known to induce TXNIP gene expression. In this study, we examined the synergistic effect of d-allose and 5-FU and the role of TXNIP on cancer cell growth. The treatment of HuH-7 cells with d-allose or 5-FU inhibited the cell growth in a dose-dependent manner (75.2+/-2.7% with 50 mM d-allose and 66.1+/-2.7% with 0.5 mug/ml 5-FU) and d-allose enhanced the anti-tumor effect of 5-FU (55.3+/-1.1 %). TUNEL analysis did not show any evidence of apoptosis with either d-allose or 5-FU treatment. 5-FU suppressed the expression of p27(kip1), p53, and cyclin E, whereas d-allose induced p53 and reduced cyclins D, A, and E. The expression of p27(kip1) remained unchanged by d-allose at transcriptional level, but increased at the protein level suggesting an increase in protein stability by TXNIP. d-Allose and to a lesser extent 5-FU induced TXNIP expression significantly (808.4+/-122.9% and 186.8+/-32.9%, respectively) and the combination of both further enhanced TXNIP expression. As d-allose has no known side effects on normal cells, the combination of d-allose and 5-FU might be a potent candidate for cancer therapy.

  9. 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.

  10. 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.

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

    PubMed

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

    2013-06-01

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

  12. Kinetics of membrane binding and dissociation of 5-fluorouracil by pulsed-field-gradient 19F NMR

    NASA Astrophysics Data System (ADS)

    Yoshii, Noriyuki; Okamura, Emiko

    2009-06-01

    The kinetics of membrane binding and dissociation of an anticancer drug, 5-fluorouracil (5FU) is quantified by high resolution NMR with the pulsed-field-gradient technique. The 19F NMR signal of 5FU is analyzed at 293-313 K by the solution of Bloch equation with exchange terms. The rate constants of 5FU binding and dissociation are 0.2 and 4.1 s -1 at 303 K. The 5FU motion in the vertical direction to the membrane surface is restricted as compared with the lateral diffusion, judging from the activation energy (57 kJ/mol) larger than the lateral diffusion in membrane (26 kJ/mol [E. Okamura, N. Yoshii, J. Chem. Phys. 129 (2008) 215102]).

  13. A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil.

    PubMed

    Méndez, Miguel; Salut, Antonieta; García-Girón, Carlos; Navalon, Marta; Diz, Pilar; García López, Maria José; España, Pilar; de la Torre, Ascensión; Martínez del Prado, Purificación; Duarte, Isabel; Pujol, Eduardo; Arizcun, Alberto; Cruz, Juan Jesús

    2003-11-01

    This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.

  14. 5-Fluorouracil enteric-coated nanoparticles for improved apoptotic activity and therapeutic index in treating colorectal cancer.

    PubMed

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

    2016-10-01

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

  15. 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.

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2013-01-01

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

  18. 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.

  19. 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.

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

    PubMed

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

    2013-08-01

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

  1. Valproic Acid and topiramate induced hyperammonemic encephalopathy in a patient with normal serum carnitine.

    PubMed

    Blackford, Martha G; Do, Stephanie T; Enlow, Thomas C; Reed, Michael D

    2013-04-01

    A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 μmol/L and a peak of 252 μmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 μmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity.

  2. Valproic Acid and Topiramate Induced Hyperammonemic Encephalopathy in a Patient With Normal Serum Carnitine

    PubMed Central

    Blackford, Martha G.; Do, Stephanie T.; Enlow, Thomas C.; Reed, Michael D.

    2013-01-01

    A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 μmol/L and a peak of 252 μmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 μmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity. PMID:23798907

  3. Minimal involvement of the circumventricular organs in the pathogenesis of spontaneously arising and experimentally induced classical bovine spongiform encephalopathy.

    PubMed

    Sisó, S; Martin, S; Konold, T; Hawkins, S A C; Thurston, L; Simmons, M M; Stack, M J; Jeffrey, M; González, L

    2012-01-01

    In sheep infected experimentally with the bovine spongiform encephalopathy (BSE) agent, amplification of infectivity in peripheral organs during early preclinical stages is thought to contribute to high titres of the agent being detected in blood, with subsequent haematogenous neuroinvasion through the circumventricular organs (CVOs). In contrast, little disease-associated prion protein (PrP(d)) or infectivity is detected in the peripheral tissues of cattle during the preclinical and clinical stages of BSE. The aim of this study was to investigate immunohistochemically the role of haematogenous neuroinvasion in cattle with spontaneously arising and experimentally induced BSE. There was almost complete absence of PrP(d) in the peripheral organs of BSE infected cattle. Additionally, there was minimal involvement of the CVOs during preclinical disease and there was progressive caudorostral accumulation of PrP(d) in the brain. These findings do not support haematogenous neuroinvasion in the bovine disease.

  4. Influenza virus-induced encephalopathy in mice: interferon production and natural killer cell activity during acute infection.

    PubMed Central

    Wabuke-Bunoti, M A; Bennink, J R; Plotkin, S A

    1986-01-01

    Mice injected intracerebrally with infectious influenza virus (60 hemagglutinin units) developed lethargy, seizures, comas, and died 2 to 5 days postinfection. As early as 6 h after infection, the cerebrospinal fluid (CSF) in these animals was infiltrated with polymorphonuclear cells, mononuclear leukocytes, and large granular lymphocytes. Potent natural killer (NK) cell activity was observed for both CSF and spleen cell populations over the same period. This NK cell activity correlated with interferon (IFN) levels in the CSF and serum. Treatment of lethally infected mice with either anti-IFN alpha-IFN beta or anti-ganglio-n-tetraoglyceramide antiserum ameliorated the disease, reduced mortality, and effected changes in the relative proportions of inflammatory cell populations infiltrating the CSF. The possible significance of IFN and NK cell activity in the development of this influenza virus-induced encephalopathy is discussed. PMID:2431159

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

    PubMed Central

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

    2015-01-01

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

  6. 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

  7. 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

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

    PubMed

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

    2016-11-02

    Recently, we reported that β-carotene exhibited anticancer activity against human esophageal squamous cell carcinoma cells in vitro. In the present study, we examined a novel therapeutic strategy by combining β-carotene with 5-fluorouracil (5-FU) in human esophageal cancer in vitro and in vivo, and elucidated the underlying mechanisms. We found that the combination of 5-FU and β-carotene displayed greater growth inhibitory effects than did either compound alone in esophageal squamous cell carcinoma (ESCC) cells. In addition, the combination of 5-FU and β-carotene displayed greater tumor growth inhibition in an Eca109 xenograft mouse model than did a single agent with low systemic toxicity. β-Carotene enhanced 5-FU-induced apoptosis. TUNEL staining revealed that the rate of TUNEL-positive cells was markedly increased in tumor tissues after treatment with 5-FU and β-carotene. Western blotting and immunohistochemistry revealed the down-regulation of Bcl-2 and PCNA and the up-regulation of Bax and caspase-3 in tumor tissues. Further studies demonstrated that the combined administration of 5-FU and β-carotene significantly down-regulated the protein levels of Cav-1, p-AKT, p-NF-κB, p-mTOR and p-p70S6K in Eca109 cells more effectively than did 5-FU alone. These data suggested that the combined therapy of 5-FU and β-carotene exerted synergistic antitumor effects in vivo and in vitro and could constitute a novel therapeutic treatment for ESCC.

  9. Neuroprotection by intravenous transplantation of bone marrow mononuclear cells from 5-fluorouracil pre-treated rats in a model of ischemic stroke.

    PubMed

    Li, Yi; Chen, Chun-Hua; Yin, Yu; Mao, Wen-Wei; Hua, Xu-Ming; Cheng, Juan

    2016-10-01

    Our previous studies showed that 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 further explore the potential mechanisms underlying the neuroprotective effects of BMRMNCs in the same model. Rats were intravenously pre-treated with 5-FU, and BMRMNCs were collected 7 days later and subjected to flow cytometry for detection of CD34, CD45 and CD90. Middle cerebral artery occlusion (MCAO) was induced in rats, and BMMNCs and BMRMNCs were independently transplanted via the tail vein at 24 h after MCAO. NISSL staining was performed 14 days after cell transplantation and the viable cells in the hippocampus were counted. Stromal cell-derived factor 1 (SDF-1) mRNA expression was detected in the penumbra at 7 and 14 days after treatment. The contents of pro-inflammatory cytokines and growth factors as well as microvessel density (MVD) were determined at 14 days. Results showed more BMRMNCs were positive for CD34, CD45 and CD90. After transplantation, more viable cells were observed in the hippocampus of BMRMNCs treated rats. In addition, BMRMNCs transplantation significantly increased MVD, reduced pro-inflammatory cytokines and raised growth factors in the penumbra. However, the SDF-1 mRNA expression was comparable between BMRMNCs group and BMMNCs group. Our results indicate that BMRMNCs are likely to more effectively improve the local microenvironment to increase viable cells and elevate angiogenesis, exerting neuroprotective effects on cerebral ischemia in rats.

  10. Ameliorative effect of saffron aqueous extract on hyperglycemia, hyperlipidemia, and oxidative stress on diabetic encephalopathy in streptozotocin induced experimental diabetes mellitus.

    PubMed

    Samarghandian, Saeed; Azimi-Nezhad, Mohsen; Samini, Fariborz

    2014-01-01

    Diabetic encephalopathy is one of the severe complications in patients with diabetes mellitus. Findings indicate that saffron extract has antioxidant properties but its underlying beneficial effects on diabetic encephalopathy were unclear. In the present study, the protective activities of saffron were evaluated in diabetic encephalopathy. Saffron at 40 and 80 mg/kg significantly increased body weight and serum TNF-α and decreased blood glucose levels, glycosylated serum proteins, and serum advanced glycation endproducts (AGEs) levels. Furthermore, significant increase in HDL and decrease (P<0.05) in cholesterol, triglyceride, and LDL were observed after 28 days of treatment. At the end of experiments, the hippocampus tissue was used for determination of glutathione content (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. Furthermore, saffron significantly increased GSH, SOD, and CAT but remarkably decreased cognitive deficit, serum TNF-α, and induced nitric oxide synthase (iNOS) activity in hippocampus tissue. Our findings indicated that saffron extract may reduce hyperglycemia and hyperlipidemia risk and also reduce the oxidative stress in diabetic encephalopathy rats. This study suggested that saffron extract might be a promising candidate for the improvement of chemically induced diabetes and its complications.

  11. Ameliorative Effect of Saffron Aqueous Extract on Hyperglycemia, Hyperlipidemia, and Oxidative Stress on Diabetic Encephalopathy in Streptozotocin Induced Experimental Diabetes Mellitus

    PubMed Central

    Samarghandian, Saeed; Azimi-Nezhad, Mohsen; Samini, Fariborz

    2014-01-01

    Diabetic encephalopathy is one of the severe complications in patients with diabetes mellitus. Findings indicate that saffron extract has antioxidant properties but its underlying beneficial effects on diabetic encephalopathy were unclear. In the present study, the protective activities of saffron were evaluated in diabetic encephalopathy. Saffron at 40 and 80 mg/kg significantly increased body weight and serum TNF-α and decreased blood glucose levels, glycosylated serum proteins, and serum advanced glycation endproducts (AGEs) levels. Furthermore, significant increase in HDL and decrease (P < 0.05) in cholesterol, triglyceride, and LDL were observed after 28 days of treatment. At the end of experiments, the hippocampus tissue was used for determination of glutathione content (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. Furthermore, saffron significantly increased GSH, SOD, and CAT but remarkably decreased cognitive deficit, serum TNF-α, and induced nitric oxide synthase (iNOS) activity in hippocampus tissue. Our findings indicated that saffron extract may reduce hyperglycemia and hyperlipidemia risk and also reduce the oxidative stress in diabetic encephalopathy rats. This study suggested that saffron extract might be a promising candidate for the improvement of chemically induced diabetes and its complications. PMID:25114929

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

    PubMed

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

    2001-06-01

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

  13. Gemcitabine and Cisplatin induced posterior reversible encephalopathy syndrome: A case report with review of literature

    PubMed Central

    Kabre, Rohit Santosh; Kamble, Krishna Marotirao

    2016-01-01

    Posterior reversible encephalopathy syndrome (PRES) is a recently described, scarcely documented clinical entity. PRES is caused by various factors, the most common being hypertension, followed by nonhypertensive causes such as renal diseases and immunosuppressive therapy. Recently, some cases have been reported about the association of increased use of cytotoxic and immunosuppressive agents in cancer patients, and relevant reports have increased with advances in radiological examinations. Here, we report a case of gallbladder cancer with liver metastasis undergoing gemcitabine- and cisplatin-based chemotherapy who presented with complaints of seizures, headache, and bilateral lower limb weakness. Thorough clinical examination, biochemical analysis, and radiological evaluation led to diagnosis of PRES. It is important to recognize this syndrome which will facilitate early diagnosis and prompt symptomatic management. Removal of causative agent is an important aspect of management. Studies are needed to identify factors of adverse prognostic significance and to develop neuroprotective strategies. PMID:27843969

  14. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

    PubMed Central

    Avraham, Y; Grigoriadis, NC; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, EM

    2011-01-01

    BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. PMID:21182490

  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. 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

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

    PubMed

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

    2013-12-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2013-05-01

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

  19. Low-dose 5-fluorouracil adjuvant in laser therapy for HPV lesions in immunosuppressed patients and cases of difficult control.

    PubMed

    Speck, N M G; Ribalta, J C L; Focchi, J; Costa, R R L; Kesselring, F; Freitas, V G

    2004-01-01

    The authors established a protocol for the use of 5-fluorouracil (5FU) adjuvant in lasertherapy for clinical and subclinical HPV infection in immunosuppressed patients, persistent lesions and as reinforcement treatment in cases of poor progress. Sixty-four patients were evaluated, of whom 26 were immunosuppressed, 34 presented persistent lesions and four received intravaginal reinforcement treatment with 2.5 g 5% 5FU every two weeks, or biweekly vulvar reinforcement after lasertherapy. On average, five 5FU courses were used, but in the immunossuppressed patients its use was maintained indefinitely. The rate of complete response was 66%, but the immunossuppressed patients showed less response (46.2%) when compared with the persistent lesion/reinforcement treatment group (78.9%). The responses were positive in the two groups when compared to that with no response. We deem the use of low-dose 5FU an excellent alternative in cases of difficult HPV progress, presenting a low cost and minimal side-effects.

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2014-09-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2017-02-01

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

  5. In vivo distribution of 5-Fluorouracil after peritumoral implantation using a biodegradable micro-device in tumor-bearing mice.

    PubMed

    Zheng, Na; Zhou, Mingyao; Lu, Wen

    2013-09-01

    A novel implantable micro-device was used for delivery of 5-Fluorouracil (5-Fu), which was often used in the treatment of various human malignancies. The biodegradable poly(lactic-co-glycolic) acid (PLGA) was used as material. The purpose of this study was to investigate the efficiency of delivery of 5-Fu to the tumor via this delivery system. The distribution characters of the 5-Fu in tumor, plasma, peritumoral tissue, liver and kidney were compared after peritumoral implantation of micro-device and intraperitoneal injection of solution. After administration of micro-device, the 5-Fu was absorbed into the tumor on Day 1, and Cmax (4.14 μg/g) was reached on Day 6. The half life for the elimination was 4.48 d and the AUC was 46.78 μg × d/g. Similar pharmacokinetic behaviors were observed in plasma, peritumoral tissue, kidney and liver, while the Cmax and the AUC of plasma and these tissues were lower than those of tumor. When administered the solution, 5-Fu was rapidly absorbed into plasma, liver, kidney, spleen and tumor, and rapidly cleared from these tissues after 2 or 4 h. And the AUC in tumor of 5-Fu solution was significantly lower than that of the micro-device. These results indicated that 5-Fu loaded biodegradable micro-device offered a relatively high concentration and long-term delivery of the drug to the tumor site.

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

    PubMed

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

    2015-12-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-02-19

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

  9. Development of rectal delivered thermo-reversible gelling film encapsulating a 5-fluorouracil hydroxypropyl-β-cyclodextrin complex.

    PubMed

    Wang, Lu-Lu; Zheng, Wen-Sheng; Chen, Shao-Hua; Han, Yan-Xing; Jiang, Jian-Dong

    2016-02-10

    We have developed a novel 5-Fluorouracil (5FU) formulation for rectal application to improve its therapeutic efficiency in colorectal cancer. The results indicated that 5FU formed an inclusion complex with Hydroxypropyl-β-Cyclodextrin (HP-β-CD). The stoichiometry of the complex was 1:1, with apparent stability constant of 100.4M(-1). After investigating physicochemical properties of the 5FU-HP-β-CD complex encapsulated with thermo-reversible gelling film, the optimized formulation P407/P188/HPMC/5FU-HP-β-CD (18.5/2.5/0.2/15%) was selected and evaluated. The result showed that the 5FU-HP-β-CD complex increased the solubility of 5FU, prolonged and enhanced its releasing. As compared to the raw drug, the transport efficiency of the 5FU-HP-β-CD complex itself or entrapped in thermo-reversible gelling film were respectively 7.3- and 6.8-fold increased, and the cellular uptake of 5-FU 4.9- and 5.4-fold elevated. There was no irritation or damage to rectal sites in the 10h treatment period. Therefore, this HP-β-CD based formulation might improve the therapeutic effect of 5FU on colon-rectal cancer.

  10. Effect of the microhydration on the tautomerism in the anticarcinogenic drug 5-fluorouracil and relationships with other 5-haloderivatives

    NASA Astrophysics Data System (ADS)

    Muñoz Freán, S.; Alcolea Palafox, M.; Rastogi, V. K.

    2013-12-01

    The 5-fluorouracil (in short 5-FU) mutagenicity was investigated in the isolated state and in the hydrated form through an exhaustive quantum-chemical analysis. The most optimum tautomers of 5-FU were optimized and analyzed. Six of them were related to those of uracils molecule, with the same stability order. The effect of the halogen substitution in position 5 on the uracil ring in the stability of the different tautomers was analyzed. Solvent effects were considered using a variable number (1-10) of explicit water molecules surrounding 5-FU in order to simulate the first hydration shell. More than 100 cluster structures with water were analyzed. A comparative analysis in the different tautomers of the hydration effect on the molecular structure and energetics was carried out. For cases where literature data are available, the computed values were in good agreement with previous experimental and theoretical studies. Depending on the nature of the tautomers, cyclic, distributed, or clustered structures were formed. The deformation and interaction counterpoise (CP)-corrected energies between 5-FU and water molecules were determined. The maximum interaction was found in the enol form T2. The microhydrated environment stabilized remarkably the enol forms T3 and T5 (present in the corresponding nucleoside) more than the canonical keto T1, although this one continues being the most stable. Several relationships with 5-XU derivatives (X = F, Cl, Br, I) between the relative energy of tautomer T2 and the geometric parameters/atomic charges were underlined.

  11. 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.

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

    PubMed

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

    2016-06-01

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

  13. 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.

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

    PubMed

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

    2016-03-10

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

  15. Evaluation of magnetic nanoparticles coated by 5-fluorouracil imprinted polymer for controlled drug delivery in mouse breast cancer model.

    PubMed

    Hashemi-Moghaddam, Hamid; Kazemi-Bagsangani, Saeed; Jamili, Mahdi; Zavareh, Saeed

    2016-01-30

    Nanoparticles (NPs) have been extensively investigated to improve delivery efficiency of therapeutic and diagnostic agents. In this study, magnetic molecularly imprinted polymer (MIP) was synthesized by using polydopamine. Synthesized MIP was used for controlled 5-fluorouracil (5-FU) delivery in a spontaneous model of breast adenocarcinoma in Balb/c mice in the presence of an external magnetic field. Antitumor effectiveness of 5-FU imprinted polymer (5-FU-IP) was evaluated in terms of tumor-growth delay, tumor-doubling time, inhibition ratio, and histopathology. Results showed higher efficacy of 5-FU-IP in the presence of magnetic field upon suppressing tumor growth than free 5-FU and 5-FU-IP without magnetic field. The 5-FU and Fe distribution among tissues were evaluated by high-performance liquid chromatography and flame atomic absorption spectrometry, respectively. The obtained results, showed significantly deposition of 5-FU in the 5-FU-IP treated group with magnetic field. Thus, magnetic 5-FU-IP is promising for breast cancer therapy with high efficacy.

  16. 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

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

    PubMed

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

    2016-12-01

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

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

    PubMed Central

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

    2005-01-01

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

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

    PubMed

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

    2004-06-01

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

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

    PubMed

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

    2016-10-01

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

  1. 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.

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

    PubMed

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

    2017-02-01

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

  3. Crystallization and preliminary X-ray diffraction analysis of Salmonella typhimurium uridine phosphorylase complexed with 5-fluorouracil

    PubMed Central

    Lashkov, A. A.; Gabdoulkhakov, A. G.; Shtil, A. A.; Mikhailov, A. M.

    2009-01-01

    Uridine phosphorylase (UPh; EC 2.4.2.3) catalyzes the phosphorolytic cleavage of the N-glycosidic bond of uridine to form ribose 1-phosphate and uracil. This enzyme also activates pyrimidine-containing drugs, including 5-fluorouracil (5-FU). In order to better understand the mechanism of the enzyme–drug interaction, the complex of Salmonella typhimurium UPh with 5-FU was cocrystallized using the hanging-drop vapour-diffusion method at 294 K. X-ray diffraction data were collected to 2.2 Å resolution. Analysis of these data revealed that the crystal belonged to space group C2, with unit-cell parameters a = 158.26, b = 93.04, c = 149.87 Å, α = γ = 90, β = 90.65°. The solvent content was 45.85% assuming the presence of six hexameric molecules of the complex in the unit cell. PMID:19478441

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

    PubMed Central

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

    1986-01-01

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

  5. Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats.

    PubMed

    Ghiassy, Bentolhoda; Rahimi, Nastaran; Javadi-Paydar, Mehrak; Gharedaghi, Mohammad Hadi; Norouzi-Javidan, Abbas; Dehpour, Ahmad R

    2017-01-01

    Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.

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

    PubMed

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

    2014-11-01

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

  7. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect cattle transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-Type bovine spongiform encephalopathy.

    PubMed

    Hwang, Soyoun; Greenlee, Justin J; Nicholson, Eric M

    2017-01-01

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from the normal cellular prion protein to the pathogenic misfolded conformation (PrPSc). This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions in a variety of biological tissues from humans and animals. Extensive work has been done to demonstrate that RT-QuIC is a rapid, specific, and highly sensitive prion detection assay. RT-QuIC uses recombinant prion protein to detect minute amounts of PrPSc. RT-QuIC has been successfully used to detect PrPSc from different prion diseases with a variety of substrates including hamster, human, sheep, bank vole, bovine and chimeric forms of prion protein. However, recombinant bovine prion protein has not been used to detect transmissible mink encephalopathy (TME) or to differentiate types of bovine spongiform encephalopathy (BSE) in samples from cattle. We evaluated whether PrPSc from TME and BSE infected cattle can be detected with RT-QuIC using recombinant bovine prion proteins, and optimized the reaction conditions to specifically detect cattle TME and to discriminate between classical and atypical BSE by conversion efficiency. We also found that substrate composed of the disease associated E211K mutant protein can be effective for the detection of TME in cattle and that wild type prion protein appears to be a practical substrate to discriminate between the different types of BSEs.

  8. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect cattle transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-Type bovine spongiform encephalopathy

    PubMed Central

    Hwang, Soyoun; Greenlee, Justin J.

    2017-01-01

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from the normal cellular prion protein to the pathogenic misfolded conformation (PrPSc). This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions in a variety of biological tissues from humans and animals. Extensive work has been done to demonstrate that RT-QuIC is a rapid, specific, and highly sensitive prion detection assay. RT-QuIC uses recombinant prion protein to detect minute amounts of PrPSc. RT-QuIC has been successfully used to detect PrPSc from different prion diseases with a variety of substrates including hamster, human, sheep, bank vole, bovine and chimeric forms of prion protein. However, recombinant bovine prion protein has not been used to detect transmissible mink encephalopathy (TME) or to differentiate types of bovine spongiform encephalopathy (BSE) in samples from cattle. We evaluated whether PrPSc from TME and BSE infected cattle can be detected with RT-QuIC using recombinant bovine prion proteins, and optimized the reaction conditions to specifically detect cattle TME and to discriminate between classical and atypical BSE by conversion efficiency. We also found that substrate composed of the disease associated E211K mutant protein can be effective for the detection of TME in cattle and that wild type prion protein appears to be a practical substrate to discriminate between the different types of BSEs. PMID:28225797

  9. 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.

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

    PubMed Central

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

    2016-01-01

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

  11. Neuropathological changes in auditory brainstem nuclei in cattle with experimentally induced bovine spongiform encephalopathy.

    PubMed

    Fukuda, S; Okada, H; Arai, S; Yokoyama, T; Mohri, S

    2011-01-01

    Bovine spongiform encephalopathy (BSE) is characterized by the appearance of spongy lesions in the brain, particularly in the brainstem nuclei. This study evaluated the degenerative changes observed in the central auditory brainstem of BSE-challenged cattle. The neuropathological changes in the auditory brainstem nuclei were assessed by determining the severity of vacuolation and the presence of disease-associated prion protein (PrP(Sc)). Sixteen female Holstein-Friesian calves, 2-4 months of age, were inoculated intracerebrally with BSE agent. BSE-challenged animals developed the characteristic clinical signs of BSE approximately 18 months post inoculation (mpi) and advanced neurological signs after 22 mpi. Before the appearance of clinical signs (i.e. at 3, 10, 12 and 16 mpi), vacuolar change was absent or mild and PrP(Sc) deposition was minimal in the auditory brainstem nuclei. The two cattle sacrificed at 18 and 19 mpi had no clinical signs and showed mild vacuolar degeneration and moderate amounts of PrP(Sc) accumulation in the auditory brainstem pathway. In the animals challenged with BSE agent that developed clinical sings (i.e. after 20 mpi), spongy changes were more prominent in the nucleus of the inferior colliculus compared with the other nuclei of the auditory brainstem and the medial geniculate body. Neuropathological changes characterized by spongy lesions accompanied by PrP(Sc) accumulation in the auditory brainstem nuclei of BSE-infected cattle may be associated with hyperacusia.

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

    PubMed Central

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

    2013-01-01

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

  13. 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.

  14. Study of the interactions of PAMAM G3-NH2 and G3-OH dendrimers with 5-fluorouracil in aqueous solutions.

    PubMed

    Buczkowski, Adam; Waliszewski, Dariusz; Urbaniak, Pawel; Palecz, Bartlomiej

    2016-05-30

    The results of spectroscopic measurements (increase in solubility, equilibrium dialysis, (1)H NMR titration) and calorimetric measurements (isothermal titration ITC) indicate spontaneous (ΔG<0) bonding of 5-fluorouracil by both cationic PAMAM G3-NH2 dendrimer and hydroxyl PAMAM G3-OH dendrimer in aqueous solutions. PAMAM G3-NH2 dendrimer bonds about n= 25±8 drug molecules. Some of them n1= 5±1 are bonded by terminal amine groups with equilibrium constant K1= 3890±930, while the remaining ones n2= 24 ±3 are bonded by amide groups with equilibrium constant K2= 110±30. Hydroxyl PAMAM G3-OH dendrimer bonds n=6.0±1.6 molecules of 5-fluorouracil through tertiary amine groups with equilibrium constant K= 65±10. The parameters of bonding 5-fluorouracil by PAMAM G3-NH2 and G3-OH dendrimer were compared with those of bonding this drug by the macromolecules of PAMAM of generations G4-NH2, G5-NH2 and G5-OH.

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

    PubMed Central

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

    1998-01-01

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

  16. 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

  17. 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

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

    SciTech Connect

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

    1993-04-02

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

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

    PubMed Central

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

    2016-01-01

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

  20. 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

  1. 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

  2. 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.

  3. 5-Fluorouracil acetic acid/beta-cyclodextrin conjugates: drug release behavior in enzymatic and rat cecal media.

    PubMed

    Udo, Koichi; Hokonohara, Kazuhiro; Motoyama, Keiichi; Arima, Hidetoshi; Hirayama, Fumitoshi; Uekama, Kaneto

    2010-03-30

    5-Fluorouracil-1-acetic acid (5-FUA) was prepared and covalently conjugated to beta-cyclodextrin (beta-CyD) through ester or amide linkage, and the drug release behavior of the conjugates in enzymatic solutions and rat cecal contents were investigated. The 5-FUA/beta-CyD ester conjugate was slowly hydrolyzed to 5-FUA in aqueous solutions (half lives (t(1/2))=38 and 17h at pH 6.8 and 7.4, respectively, at 37 degrees C), whereas the amide conjugate was hardly hydrolyzed at these physiological conditions, but hydrolyzed only in strong alkaline solutions (>0.1M NaOH) at 60 degrees C. Both ester and amide conjugates were degraded in solutions of a sugar-degrading enzyme, alpha-amylase, to 5-FUA/maltose and triose conjugates, but the release of 5-FUA was only slight in alpha-amylase solutions. In solutions of an ester-hydrolyzing enzyme, carboxylic esterase, the ester conjugate was hydrolyzed to 5-FUA at the same rate as that in the absence of the enzyme, whereas the amide conjugate was not hydrolyzed by the enzyme. On the other hand, 5-FUA was rapidly released when the ester conjugate was firstly hydrolyzed by alpha-amylase, followed secondly by carboxylic esterase. The results indicated that the ester conjugate was hydrolyzed to 5-FUA in a consecutive manner, i.e. it was firstly hydrolyzed to the small saccharide conjugates, such as the maltose conjugate, by alpha-amylase, and the resulting small saccharide conjugates having less steric hindrance was susceptible to the action of carboxylic esterase, giving 5-FUA. The in vitro release behavior of the ester conjugate was clearly reflected in the hydrolysis in rat cecal contents and in the in vivo release after oral administration to rats.

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

    PubMed

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

    2005-12-01

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

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

    PubMed

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

    2013-12-01

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

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

    PubMed Central

    2012-01-01

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

  7. 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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2001-12-01

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

  10. Gene expression in colorectal cancer and in vitro chemosensitivity to 5-fluorouracil: a study of 88 surgical specimens.

    PubMed

    Yoshinare, Kentaro; Kubota, Tetsuro; Watanabe, Masahiko; Wada, Norihito; Nishibori, Hideki; Hasegawa, Hirotoshi; Kitajima, Masaki; Takechi, Teiji; Fukushima, Masakazu

    2003-07-01

    To predict the sensitivity of colorectal cancer to 5-fluorouracil (5-FU), we compared the gene expression of surgically obtained colorectal cancer specimens with chemosensitivity to 5-FU as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. Eighty-eight patients with advanced and/or metastatic colorectal cancer provided written informed consent and entered the trial from September 2000 to October 2001. Fresh surgical specimens were used for the MTT assay, and sensitivity to 5-FU was evaluated at a cutoff concentration of 50 microg/ml and 48-h incubation time. Frozen samples were stored at - 80 degrees C until mRNA analysis of thymidylate synthetase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), es-nucleoside transporter (NT), and E2F1 by real-time RT-PCR. The correlations between the variables were analyzed, and the predictive value of these mRNAs was assessed statistically using a receiver operating characteristic (ROC) curve. NT and DPD, TP and DPD, and TP and NT mRNA expression levels correlated significantly, while TS and E2F1 showed no correlations. High NT expression was associated with low sensitivity to 5-FU (P < 0.013), as were high DPD and E2F1 expression (P < 0.022 for both). High TP mRNA expression correlated with low sensitivity to 5-FU (P < 0.034), although high TS mRNA expression did not. ROC curves indicated that DPD and NT mRNAs were possible predictors of sensitivity to 5-FU, with cutoff values of 0.6 and 0.4, respectively. The sensitivity of colorectal cancer to 5-FU may be regulated by DPD, the rate-limiting enzyme of catabolism, and NT, an important transmembrane transporter of nucleosides.

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

    PubMed

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

    2009-03-01

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

  12. 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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2009-10-01

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

  15. 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.

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

    PubMed

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

    2015-07-01

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

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

    NASA Astrophysics Data System (ADS)

    Gomaa, Iman E.; Abdel Gaber, Sara A.; Bhatt, Samarth; Liehr, Thomas; Glei, Michael; El-Tayeb, Tarek A.; Abdel-Kader, Mahmoud H.

    2015-02-01

    This study evaluates tumour cell-killing efficacy of metallic gold nanoparticles (AuNPs)-mediated photo-thermal therapy (PTT) in comparison to 5-fluorouracil (5-FU) as a standard chemotherapeutic drug. It also focuses on the possible genetic abnormalities of both drugs in normal blood lymphocytes. Both 5-FU and light-activated spherical AuNPs of 15± nm diameter were used to target MCF-7 breast cancer cell line. Alkaline comet assay, standard karyotyping and multiplex fluorescent in situ hybridization were applied in order to investigate the respective possible genotoxic and mutagenic side effects that might result from the application of each therapeutic modality. Results showed that the LC25 of AuNPs-mediated PTT was achieved at a concentration of 100 µM for 12-h incubation and exposure to light energy of 50 J/cm2, while the same cytotoxic effect was obtained by incubating the MCF-7 cells with the same concentration of the chemotherapeutic drug 5-FU for 24 h. On the other hand, AuNPs showed insignificant genotoxic effect of DNA damage represented by 4.6 % in comparison to 18.58 % exerted by 5-FU. The chromosomal studies resulted in normal karyotypes for cells treated with AuNPs-mediated PTT, while those treated with 5-FU showed several types of numerical as well as structural chromosomal aberrations. In conclusion, compared to 5-FU, light-activated AuNPs-mediated PTT provides considerable efficacy in breast cancer cells killing with no genetic side effects under the proposed experimental conditions.

  18. Novel microbially triggered colon specific delivery system of 5-Fluorouracil: statistical optimization, in vitro, in vivo, cytotoxic and stability assessment.

    PubMed

    Dev, Rakesh Kumar; Bali, Vikas; Pathak, Kamla

    2011-06-15

    The present study aimed to statistically optimize a colon specific formulation of 5-Fluorouracil for the treatment of colon cancer. A 3(2) full factorial design was used for optimization. The independent variables employed were amount of pectin and amount of starch paste, each at three levels. The evaluated responses were hardness, percent cumulative drug release (% CDR) at 5th h and t(90%) (time required for 90% of drug release). Drug release studies were carried out using change over media [pH 1.2, 7.4 and 6.5 in presence of 4% (w/v) rat caecal contents]. The optimized formulation was subjected to in vivo roentgenographic studies in New Zealand white rabbits to analyze the in vivo behaviour of the developed tablets. This formulation was also evaluated for cytotoxic potential using HT-29 human colon cancer cell lines. Pharmacokinetic studies in New Zealand white rabbits were conducted to determine the extent of systemic exposure provided by the developed formulation in comparison to an immediate release tablet. The optimized formulation consisting of pectin (66.67%, w/w) and starch paste (15%, w/w) released negligible amount of drug at pH 1.2 and pH 7.4 whereas significant (p < 0.05) drug release was observed at pH 6.5 in presence of 4% (w/v) rat caecal contents. Roentgenographic studies corroborated the in vitro observations, thus providing the "proof of concept". Pharmacokinetic studies revealed significant reduction in systemic exposure and cytotoxicity studies demonstrated enhanced cellular uptake of drug by the developed formulation. Shelf life of the formulation was found to be 2.83 years. The results of the study established pectin-based coated matrix tablet to be a promising system for the colon specific delivery of 5-FU so as to treat colon carcinoma.

  19. TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients.

    PubMed

    Kandioler, Daniela; Mittlböck, Martina; Kappel, Sonja; Puhalla, Harald; Herbst, Friedrich; Langner, Cord; Wolf, Brigitte; Tschmelitsch, Jörg; Schippinger, Walter; Steger, Günther; Hofbauer, Friedrich; Samonigg, Hellmut; Gnant, Michael; Teleky, Bela; Kührer, Irene

    2015-08-01

    We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344-3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

  20. 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

  1. 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

  2. [Anesthetic Management of a Parturient with Eclampsia, Posterior Reversible Encephalopathy Syndrome and Pulmonary Edema due to Pregnancy-induced Hypertension].

    PubMed

    Aida, Junko; Okutani, Hiroai; Oda, Yutaka; Okutani, Ryu

    2015-08-01

    A 27-year-old woman with mental retardation was admitted to a nearby hospital for an abrupt onset of seizure. Physical examination revealed remarkable hypertension and pregnancy with estimated gestational age of 28th week. Severe pulmonary edema and hypoxia led to a diagnosis of pregnancy-induced hypertension (PIH) accompanied by eclampsia. She was orotracheally intubated because of refractory seizure and hypoxemia, and transferred to our hospital for further treatment. Besides severe hypoxia and hypercapnea, an enhanced lesion was detected in the left posterior cerebrum by brain MRI. No abnormal findings were detected in the fetus, with heart rate of 150 beats x min. She was diagnosed with posterior reversible encephalopathy syndrome (PRES) caused by PIH and emergency cesarean section under general anesthesia was scheduled. A male newborn was delivered with Apgar score of 1/4 (1/5 min), followed by starting continuous infusion of nicardipine for controlling hypertension. Chest X-P on completion of surgery revealed remarkably alleviated pulmonary edema. She received intensive treatment and continued positive pressure ventilation for four days after delivery. She recovered with no neurological deficits and her child was well without any complications.

  3. A novel 5-fluorouracil-resistant human esophageal squamous cell carcinoma cell line Eca-109/5-FU with significant drug resistance-related characteristics.

    PubMed

    Zhang, Chi; Ma, Qunfeng; Shi, Yinan; Li, Xue; Wang, Ming; Wang, Junfeng; Ge, Jianlin; Chen, Zhinan; Wang, Ziling; Jiang, Hong

    2017-05-01

    5-Fluorouracil (5-FU) is used for the clinical treatment of esophageal squamous cell carcinomas (ESCCs), yet it also induces chemoresistant cancer cells during treatment, which leads to the failure of the therapy. To further explore the resistance mechanism of 5-FU in ESCC, we established the 5-FU-resistant ESCC cell line Eca-109/5-FU, which was prepared by the stepwise exposure to increasing 5-FU concentrations. MTT assay and nude mouse xenograft models were used to test the drug resistance and proliferation of Eca-109 and Eca-109/5-FU cells in vitro and in vivo. Apoptosis and cell cycle distribution were determined using flow cytometry. Drug resistance-related proteins were detected by western blotting. Metabolomic profiles were obtained from nuclear magnetic resonance (NMR) tests. In regards to Eca-109/5-FU, the decreased susceptibility to 5-FU was determined in vitro and in vivo with slower rate of proliferation. Drug resistance-related proteins (multidrug resistance-associated protein 1 and ATP-binding cassette superfamily G member 2), epithelial-to-mesenchymal transition (EMT)-related proteins (E-cadherin and vimentin) and cancer stem cell-related proteins (prominin-1 and hyaluronate receptor) exhibited significant differences between the two cell lines. The 5-FU-resistant cell line Eca-109/5-FU achieved the ability to tolerate 5-FU, which may depend on significant drug resistance-related characteristics, such as EMT and cancer stem cell-like properties. The metabolism of Eca-109/5-FU was altered, and more than 15 metabolites was found to contribute to the difference in the metabolite profile, such as lactate, glutamate, taurine, glutamine, proline, aspartate, methanol, cystine, glycine and uracil. Our results identified that the resistant cell line Eca-109/5-FU showed quite different characteristics compared with the parental Eca-109 cells. The Eca-109/5-FU cell line provides an experimental model for further steps to select chemotherapeutic

  4. [Clinical Characteristics of Metronidazole-induced Encephalopathy: A Report of Two Cases and a Review of 32 Japanese Cases in the Literature].

    PubMed

    Kato, Hideaki; Sosa, Hiroko; Mori, Masaaki; Kaneko, Takeshi

    2015-09-01

    Metronidazole is an antibiotic classically used against most anaerobic bacteria and protozoa. Because an intravenous form of metronidazole has recently entered the market, the use of this antibiotic is attracting renewed interest in many clinical settings in Japan. However, neurotoxicity is a major adverse event: in the central nervous system metronidazole-induced encephalopathy is a rare but serious condition. We performed a literature review of 34 cases including 2 of our cases, 25 from domestic conference abstracts, and 7 cases presented in full research papers. The mean patient age was 64.7 years. The conditions most commonly treated with metronidazole were brain abscess (35.3%), liver abscess (17.6%), and Clostridium difficile infection (14.7%). The most common predisposing conditions were liver dysfunction (26.5%), diabetes and other metabolic disorders (20.6%), and hematologic or solid organ malignancy (14.7%). The mean period of administration before the onset of encephalopathy symptoms was 61.3 days, and the mean total dose was 95.9g. The initial chief complaints were dysarthria (in 70.6% of the cases) and ataxia (61.8%); 82.4% of the cases were diagnosed on the basis of MRI (T2-weighted or FLAIR imaging). The key imaging finding was high intensity in the dentate nucleus bilaterally (82.4%). Stopping the metronidazole led to symptom remission within 8.5 days, but the MRI changes remained longer than the clinical symptoms. Two patients (6.0%) developed irreversible disturbance of consciousness. Although the mechanisms of this type of encephalopathy have not yet been elucidated, localized nerve-cell edema is likely caused by decreased metronidazole metabolism associated with liver and metabolic dysfunction. Careful observation for neurologic signs should be conducted during the treatment of brain abscesses associated with metronidazole administration, because patients with brain abscesses are naturally at high risk of metronidazole-induced encephalopathy.

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

    PubMed Central

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

    2016-01-01

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

  6. Formulation and characterization of 5-Fluorouracil enteric coated nanoparticles for sustained and localized release in treating colorectal cancer.

    PubMed

    Tummala, Shashank; Satish Kumar, M N; Prakash, Ashwati

    2015-07-01

    5-Fluorouracil is used in the treatment of colorectal cancer along with oxaliplatin as first line treatment, but it is having lack of site specificity and poor therapeutic effect. Also toxic effects to healthy cells and unavailability of major proportion of drug at the colon region remain as limitations. Toxic effects prevention and drug localization at colon area was achieved by preparing enteric-coated chitosan polymeric nanoparticles as it can be delivered directly to large bowel. Enteric coating helps in preventing the drug degradation at gastric pH. So the main objective was to prepare chitosan polymeric nanoparticles by solvent evaporation emulsification method by using different ratios of polymer (1:1, 1:2, 1:3, 1:4). Optimized polymer ratio was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), entrapment efficiency and particle size and further subjected to enteric coating. In vitro drug release studies were done using dialysis bag technique using simulated fluids at various pH (1.2, 4.5, 7.5, 7.0) to mimic the GIT tract. 5-FU nanoparticles with drug: polymer ratio of 1:2 and 1:3 has shown better particle size (149 ± 1.28 nm and 138 ± 1.01 nm respectively), entrapment efficiency (48.12 ± 0.08% and 69.18 ± 1.89 respectively). 5-FU E1 has shown better drug release after 4 h and has shown 82% drug release till 24 h in a sustained manner comparable to the non-enteric coated tablets, which released more than 50% of the drug before entering the colon region. So we can conclude that nanoparticles prepared by this method using the same polymer with the optimized ratio can represent as potential drug delivery approach for effective delivery of the active pharmaceutical ingredient to the colorectal tumors.

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

    PubMed

    Ponce-Cusi, Richard; Calaf, Gloria M

    2016-02-01

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

  8. 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.

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

    PubMed Central

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

    1996-01-01

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

  10. 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

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

    PubMed Central

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

    2000-01-01

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

  12. 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.

  13. 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

  14. Thermosensitive hydrogel based on chitosan and its derivatives containing medicated nanoparticles for transcorneal administration of 5-fluorouracil

    PubMed Central

    Fabiano, Angela; Bizzarri, Ranieri; Zambito, Ylenia

    2017-01-01

    A thermosensitive ophthalmic hydrogel (TSOH) – fluid at 4°C (instillation temperature), semisolid at 35°C (eye temperature), which coupled the dosing accuracy and administration ease of eyedrops with the increased ocular bioavailability of a hydrogel – was prepared by gelling a chitosan hydrochloride (ChHCl) solution (27.8 mg/mL) medicated with 1.25 mg/mL 5-fluorouracil (5-FU) with β-glycerophosphate 0.8 mg/mL. Polymer mixtures, where Ch was partially (10%, 15%, or 20%) replaced by quaternary ammonium–chitosan conjugates (QA-Ch) or thiolated derivatives thereof, were also used to modulate 5-FU-release properties of TSOH. Also, Ch-based nanoparticles (NPs; size after lyophilization and redispersion 341.5±15.2 nm, polydispersity 0.315±0.45, ζ-potential 10.21 mV) medicated with 1.25 mg/mL 5-FU prepared by ionotropic cross-linking of Ch with hyaluronan were introduced into TSOH. The 5-FU binding by TSOH polymers in the sol state was maximum with plain Ch (31.4%) and tended to decrease with increasing QA presence in polymer mixture. 5-FU release from TSOH with or without NPs was diffusion-controlled and linear in √t. The different TSOH polymers were compared on a diffusivity basis by comparing the slopes of √t plots. These showed a general decrease with NP-containing TSOH, which was the most marked with the TSOH, where Ch was 20% replaced by the derivative QA-Ch50. This formulation and that not containing NP were instilled in rabbits and the 5-FU transcorneal penetration was measured by analyzing the aqueous humor. Both TSOH solutions increased the area under the curve (0–8 hours) 3.5 times compared with the plain eyedrops, but maximum concentration for the NP-free TSOH was about 0.65 µg/mL, followed by a slow decline, while the NP-containing one showed a plateau (0.25–0.3 µg/mL) in a time interval of 0.5–7 hours. This is ascribed to the ability of this TSOH to control drug release to a zero order and that of NPs to be internalized by corneal

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

    PubMed

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

    2016-01-01

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

  16. Thermosensitive hydrogel based on chitosan and its derivatives containing medicated nanoparticles for transcorneal administration of 5-fluorouracil.

    PubMed

    Fabiano, Angela; Bizzarri, Ranieri; Zambito, Ylenia

    2017-01-01

    A thermosensitive ophthalmic hydrogel (TSOH) - fluid at 4°C (instillation temperature), semisolid at 35°C (eye temperature), which coupled the dosing accuracy and administration ease of eyedrops with the increased ocular bioavailability of a hydrogel - was prepared by gelling a chitosan hydrochloride (ChHCl) solution (27.8 mg/mL) medicated with 1.25 mg/mL 5-fluorouracil (5-FU) with β-glycerophosphate 0.8 mg/mL. Polymer mixtures, where Ch was partially (10%, 15%, or 20%) replaced by quaternary ammonium-chitosan conjugates (QA-Ch) or thiolated derivatives thereof, were also used to modulate 5-FU-release properties of TSOH. Also, Ch-based nanoparticles (NPs; size after lyophilization and redispersion 341.5±15.2 nm, polydispersity 0.315±0.45, ζ-potential 10.21 mV) medicated with 1.25 mg/mL 5-FU prepared by ionotropic cross-linking of Ch with hyaluronan were introduced into TSOH. The 5-FU binding by TSOH polymers in the sol state was maximum with plain Ch (31.4%) and tended to decrease with increasing QA presence in polymer mixture. 5-FU release from TSOH with or without NPs was diffusion-controlled and linear in √t. The different TSOH polymers were compared on a diffusivity basis by comparing the slopes of √t plots. These showed a general decrease with NP-containing TSOH, which was the most marked with the TSOH, where Ch was 20% replaced by the derivative QA-Ch50. This formulation and that not containing NP were instilled in rabbits and the 5-FU transcorneal penetration was measured by analyzing the aqueous humor. Both TSOH solutions increased the area under the curve (0-8 hours) 3.5 times compared with the plain eyedrops, but maximum concentration for the NP-free TSOH was about 0.65 µg/mL, followed by a slow decline, while the NP-containing one showed a plateau (0.25-0.3 µg/mL) in a time interval of 0.5-7 hours. This is ascribed to the ability of this TSOH to control drug release to a zero order and that of NPs to be internalized by corneal cells.

  17. 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

  18. A Polymeric Prodrug of 5-Fluorouracil-1-Acetic Acid Using a Multi-Hydroxyl Polyethylene Glycol Derivative as the Drug Carrier

    PubMed Central

    Sun, Xun; Gong, Tao; Zhang, Zhirong

    2014-01-01

    Purpose Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, which limits the application of PEG for drug conjugation purposes. To increase the drug loading and prolong the retention time of 5-fluorouracil (5-Fu), a macromolecular prodrug of 5-Fu, 5-fluorouracil-1 acid-PAE derivative (5-FA-PAE) was synthesized and tested for the antitumor activity in vivo. Methods PEG with a molecular weight of 38 kDa was selected to synthesize the multi-hydroxyl polyethylene glycol derivative (PAE) through an addition reaction. 5-fluorouracil-1 acetic acid (5-FA), a 5-Fu derivative was coupled with PEG derivatives via ester bond to form a macromolecular prodrug, 5-FA-PAE. The in vitro drug release, pharmacokinetics, in vivo distribution and antitumor effect of the prodrug were investigated, respectively. Results The PEG-based prodrug obtained in this study possessed an exceedingly high 5-FA loading efficiency of 10.58%, much higher than the maximum drug loading efficiency of unmodified PEG with the same molecular weight, which was 0.98% theoretically. Furthermore, 5-FA-PAE exhibited suitable sustained release in tumors. Conclusion This study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives. PMID:25389968

  19. [Liver injury and hepatic encephalopathy induced by the herbal medicine Hochuekkito].

    PubMed

    Negishi, Ryoju; Ichikawa, Takeshi; Tawa, Yoshiyuki; Fujimura, Akira; Tanaka, Sayo; Tenmoku, Akira; Akazawa, Kimika; Kanno, Masataka; Sasaki, Hiroshi; Okubo, Sae; Machida, Nobuaki; Fukuda, Yuh; Oi, Itaru; Fujino, Masayuki A

    2014-06-01

    A 57-year-old man was admitted with pruritus and jaundice following treatment for fatigue with the herbal medicine Hochuekkito. The patient was prescribed prednisolone and ursodeoxycholic acid, but he developed progressive cholestasis that required intravenous methylprednisolone pulse therapy. After treatment with plasma exchange for prolonged prothrombin time, the patient recovered; however, his liver function deteriorated because of liver injury induced by trimethoprim-sulfamethoxazole for pneumocystis pneumonia. After reduction of trimethoprim-sulfamethoxazole, his liver function almost returned to normal by day 130 of admission. It has remained normal for 10 months since then. Therefore, when prescribing Hochuekkito, the possibility of drug-induced liver injury should be taken in account.

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

    PubMed

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

    2016-05-01

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

  1. 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

  2. Effects of intraduodenal feeding of a branched-chain amino acid-rich solution on ammonia-induced encephalopathy in liver-injured rats.

    PubMed

    Hayashi, S; Watanabe, A; Shiota, T; Obata, T; Takei, N; Sakata, T; Nagashima, H

    1982-12-01

    A preventive effect of intraduodenal prefeeding of a branched-chain amino acid (BCAA)-rich solution on ammonia-induced encephalopathy was investigated with carbon tetrachloride CC14-injured rats with the elevated levels of blood ammonia. Five out of six cirrhotic rats, to which an electrolyte solution alone was preinfused for 24 hours, fell into coma following ammonia acetate injection and two comatose rats died. However, no cirrhotic rats preinfused with a BCAA-rich solution died and only two out of the six showed coma with complete recovery. The similar preventive effect could not be observed in rats with acute liver injury.

  3. Autoimmune encephalopathies

    PubMed Central

    Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep

    2014-01-01

    Over the last 10 years the continual discovery of novel forms of encephalitis associated with antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of twelve autoimmune encephatilic disorders, grouped by syndromes and approached from a clinical perspective. Anti-NMDAR encephalitis, several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti-NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases. PMID:25315420

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

    PubMed

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

    2008-12-01

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

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

    PubMed

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

    2016-03-10

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

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

    PubMed

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

    2016-09-01

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

  7. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-type bovine spongiform encephalopathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from normal cellular prion protein to pathogenic misfolded conformation. This conversion has been used for in vitro assays including serial protein misfolding amplification...

  8. Chronic traumatic encephalopathy.

    PubMed

    Omalu, Bennet

    2014-01-01

    Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative syndrome, which is caused by single, episodic, or repetitive blunt force impacts to the head and transfer of acceleration-deceleration forces to the brain. CTE presents clinically as a composite syndrome of mood disorders and behavioral and cognitive impairment, with or without sensorimotor impairment. Symptoms of CTE may begin with persistent symptoms of acute traumatic brain injury (TBI) following a documented episode of brain trauma or after a latent period that may range from days to weeks to months and years, up to 40 years following a documented episode of brain trauma or cessation of repetitive TBI. Posttraumatic encephalopathy is distinct from CTE, can be comorbid with CTE, and is a clinicopathologic syndrome induced by focal and/or diffuse, gross and/or microscopic destruction of brain tissue following brain trauma. The brain of a CTE sufferer may appear grossly unremarkable, but shows microscopic evidence of primary and secondary proteinopathies. The primary proteinopathy of CTE is tauopathy, while secondary proteinopathies may include, but are not limited to, amyloidopathy and TDP proteinopathy. Reported prevalence rates of CTE in cohorts exposed to TBI ranges from 3 to 80% across age groups.

  9. 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

  10. Detection and discrimination of classical and atypical L-type bovine spongiform encephalopathy by real-time quaking-induced conversion.

    PubMed

    Orrú, Christina D; Favole, Alessandra; Corona, Cristiano; Mazza, Maria; Manca, Matteo; Groveman, Bradley R; Hughson, Andrew G; Acutis, Pier Luigi; Caramelli, Maria; Zanusso, Gianluigi; Casalone, Cristina; Caughey, Byron

    2015-04-01

    Statutory surveillance of bovine spongiform encephalopathy (BSE) indicates that cattle are susceptible to both classical BSE (C-BSE) and atypical forms of BSE. Atypical forms of BSE appear to be sporadic and thus may never be eradicated. A major challenge for prion surveillance is the lack of sufficiently practical and sensitive tests for routine BSE detection and strain discrimination. The real-time quaking-induced conversion (RT-QuIC) test, which is based on prion-seeded fibrillization of recombinant prion protein (rPrPSen), is known to be highly specific and sensitive for the detection of multiple human and animal prion diseases but not BSE. Here, we tested brain tissue from cattle affected by C-BSE and atypical L-type bovine spongiform encephalopathy (L-type BSE or L-BSE) with the RT-QuIC assay and found that both BSE forms can be detected and distinguished using particular rPrPSen substrates. Specifically, L-BSE was detected using multiple rPrPSen substrates, while C-BSE was much more selective. This substrate-based approach suggests a diagnostic strategy for specific, sensitive, and rapid detection and discrimination of at least some BSE forms.

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

    PubMed

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

    2000-05-01

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

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

    PubMed

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

    2009-12-01

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

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

    PubMed Central

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

    2013-01-01

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

  14. 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

  15. [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.

  16. Intensified inflammatory reaction of actinic keratoses after single application of topical 5-fluorouracil in a patient treated with nilotinib for chronic myeloid leukemia.

    PubMed

    Schmid-Wendtner, Monika-Hildegard; Wendtner, Clemens M

    2009-01-01

    Actinic keratoses frequently occur in sun-exposed areas of the skin and, today, a variety of therapeutic options are available, including topical application of 5-fluorouracil (5-FU). Usually, 5-FU ointment needs to be applied twice daily for 2-4 weeks to achieve a therapeutic skin reaction. Here, we report on an immediate inflammatory reaction after single application of topical 5-FU in a patient receiving systemic treatment with the multitargeted tyrosine kinase inhibitor nilotinib for chronic myeloid leukemia. This side effect of nilotinib is new and might be of clinical relevance. We, therefore, discuss possible modes of action including other reports about different tyrosine kinase inhibitors which led to regression of aggravation of actinic keratoses.

  17. 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.

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

    PubMed

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

    2011-11-01

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

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

    SciTech Connect

    Ohnuma, Hiroyuki; Sato, Yasushi; Hirakawa, Masahiro; Okagawa, Yutaka; Osuga, Takahiro; Hayashi, Tsuyoshi; Sato, Tsutomu; Miyanishi, Koji; Kobune, Masayoshi; Takimoto, Rishu; Sagawa, Tamotsu; Hori, Masakazu; Someya, Masanori; Nakata, Kensei; Sakata, Koh-ichi; Takayama, Tetsuji; Kato, Junji

    2015-10-01

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

  20. 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.

  1. Aptamer and 5-fluorouracil dual-loading Ag2S quantum dots used as a sensitive label-free probe for near-infrared photoluminescence turn-on detection of CA125 antigen.

    PubMed

    Jin, Hui; Gui, Rijun; Gong, Jun; Huang, Wenxue

    2017-06-15

    In this article, Ag2S quantum dots (QDs) were prepared by a facile aqueous synthesis method, using thiourea as a new sulfur precursor. Based on electrostatic interactions, 5-fluorouracil (5-Fu) was combined with the aptamer of CA125 antigen to fabricate aptamer/5-Fu complex. The surface of as-prepared Ag2S QDs was modified with polyethylenimine, followed by combination with the aptamer/5-Fu complex to form Ag2S QDs/aptamer/5-Fu hybrids. During the combination of Ag2S QDs with aptamer/5-Fu complex, near-infrared (NIR) photoluminescence (PL) of QDs (peaked at 850nm) was markedly reduced under excitation at 625nm, attributed to photo-induced electron transfer from QDs to 5-Fu. However, the addition of CA125 induced obvious NIR PL recovery, which was ascribed to the strong binding affinity of CA125 with its aptamer, and the separation of aptamer/5-Fu complex from the surface of QDs. Hence, the Ag2S QDs/aptamer/5-Fu hybrids were developed as a novel NIR PL turn-on probe of CA125. In the concentration range of [CA125] from 0.1 to 10(6)ngmL(-1), there were a good linear relationship between NIR PL intensities of Ag2S QDs and Log[CA125], and a low limit of detection of 0.07ngmL(-1). Experimental results revealed the highly selective and sensitive NIR PL responses of this probe to CA125, over other potential interferences. In real human body fluids, this probe also exhibited superior analytical performance, together with high detection recoveries.

  2. Diagnostic Value of Magnetic Resonance Spectroscopy in Radiation Encephalopathy Induced by Radiotherapy for Patients with Nasopharyngeal Carcinoma: A Meta-Analysis.

    PubMed

    Chen, Wang-Sheng; Li, Jian-Jun; Hong, Lan; Xing, Zeng-Bao; Wang, Fen; Li, Chang-Qing

    2016-01-01

    In this study, articles in English and Chinese were selected from available electronic databases prior to September 2014. The metabolic concentrations and patterns of N-acetylaspartic acid (NAA), Choline (Cho), Creatine (Cr), NAA/Cr, NAA/Cho, and Cho/Cr ratios in radiotherapy-induced radiation encephalopathy by proton magnetic resonance spectroscopy were extracted. A meta-analysis was performed to quantitatively synthesize findings of these studies. Weighted mean difference (WMD) and 95% confidence intervals (95%CIs) were calculated using random or fixed effective models. Heterogeneity between studies was assessed using the Cochrane Q test and I (2) statistics. The results indicated that a total of 4 researches involving 214 patients met inclusion criteria. Depending on methodologies of selected studies, control groups were referred to as healthy subjects. The combined analysis revealed that there was no significant difference in value of Cr between radiotherapy group and healthy control group (WMD = -1.483, 95% CI: -67.185-64.219, p = 0.965). However, there were significant difference in values of NAA (WMD = -18.227, 95%CI: -36.317--0.137, p = 0.048), Cho (WMD = 38.003, 95%CI: 5.155-70.851, p = 0.023), NAA/Cr (WMD = -1.175, 95%CI: -1.563--0.787, p = 0.000), NAA/Cho (WMD = -1.108, 95%CI: -2.003-0.213, p = 0.015), and Cho/Cr (WMD = -0.773, 95%CI: 0.239-1.307, p = 0.005). In conclusion, MRS can be regarded as an effective and feasible imaging test for radiotherapy-induced radiation encephalopathy in NPC patients.

  3. Bovine Spongiform Encephalopathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE), also referred to as “mad cow disease” is a chronic, non-febrile, neuro-degenerative disease affecting the central nervous system. The transmissible spongiform encephalopathies (TSEs) of domestic animals, of which BSE is a member includes scrapie of sheep...

  4. Induction therapy with cetuximab plus docetaxel, cisplatin, and 5-fluorouracil (ETPF) in patients with resectable nonmetastatic stage III or IV squamous cell carcinoma of the oropharynx. A GERCOR phase II ECHO-07 study.

    PubMed

    Chibaudel, Benoist; Lacave, Roger; Lefevre, Marine; Soussan, Patrick; Antoine, Martine; Périé, Sophie; Belloc, Jean-Baptiste; Banal, Alain; Albert, Sébastien; Chabolle, Frédéric; Céruse, Philippe; Baril, Philippe; Gatineau, Michel; Housset, Martin; Moukoko, Rachel; Benetkiewicz, Magdalena; de Gramont, Aimery; Bonnetain, Franck; Lacau St Guily, Jean

    2015-05-01

    Induction TPF regimen is a standard treatment option for squamous cell carcinoma (SCC) of the oropharynx. The efficacy and safety of adding cetuximab to induction TPF (ETPF) therapy was evaluated. Patients with nonmetastatic resectable stage III/IV SCC of the oropharynx were treated with weekly cetuximab followed the same day by docetaxel and cisplatin and by a continuous infusion of 5-fluorouracil on days 1-5 (every 3 weeks, 3 cycles). The primary endpoint was clinical and radiological complete response (crCR) of primary tumor at 3 onths. Secondary endpoints were crCR rates, overall response, pathological CR, progression-free survival, overall survival, and safety. Forty-two patients were enrolled, and 41 received ETPF. The all nine planned cetuximab doses and the full three doses of planned chemotherapy were completed in 31 (76%) and 36 (88%) patients, respectively. Twelve (29%) patients required dose reduction. The crCR of primary tumor at the completion of therapy was observed in nine (22%) patients. ETPF was associated with a tumor objective response rate (ORR) of 58%. The most frequent grade 3-4 toxicities were as follows: nonfebrile neutropenia (39%), febrile neutropenia (19%), diarrhea (10%), and stomatitis (12%). Eighteen (44%) patients experienced acne-like skin reactions of any grade. One toxic death occurred secondary to chemotherapy-induced colitis with colonic perforation. This phase II study reports an interesting response rate for ETPF in patients with moderately advanced SCC of the oropharynx. The schedule of ETPF evaluated in this study cannot be recommended at this dosage.

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

    PubMed

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

    2010-09-01

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

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

    SciTech Connect

    Higuchi, Katsuhiko; Komori, Shouko; Tanabe, Satoshi; Katada, Chikatoshi; Azuma, Mizutomo; Ishiyama, Hiromichi; Sasaki, Tohru; Ishido, Kenji; Katada, Natsuya; Hayakawa, Kazushige; Koizumi, Wasaburo

    2014-07-15

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

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

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay

    2016-03-01

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

  8. Metabolic Causes of Epileptic Encephalopathy

    PubMed Central

    Pearl, Phillip L.

    2013-01-01

    Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondria) and large molecule disorders (including lysosomal storage disorders, peroxisomal disorders, glycosylation disorders, and leukodystrophies). Details including key clinical features, salient electrophy