WorldWideScience

Sample records for antimetabolites

  1. Outcome of trabeculectomies without adjunctive antimetabolites ...

    African Journals Online (AJOL)

    Outcome Measure: Successful intraocular pressure control defined as IOP less than 22 mmHg or a reduction of 30% if pre-operative pressure was already less than 22mmHg. Results: There were ... Lower IOP levels needed to control progressive visual field loss may require the use antimetabolites. Keywords: intraocular ...

  2. DNA methylation and sensitivity to antimetabolites in cancer cell lines.

    Science.gov (United States)

    Sasaki, Shin; Kobunai, Takashi; Kitayama, Joji; Nagawa, Hirokazu

    2008-02-01

    The prediction of the cellular direction of metabolic pathways toward either DNA synthesis or DNA methylation is crucial for determining the susceptibility of cancers to anti-metabolites such as fluorouracil (5-FU). We genotyped the methylenetetrahydrofolate reductase (MTHFR) gene in NCI-60 cancer cell lines, and identified the methylation status of 24 tumor suppressor genes using methylation-specific multiplex ligation-dependent probe amplification. The susceptibility of the cancer cell lines to seven antimetabolites was then determined. Cells homozygous for CC at MTHFR-A1298C were significantly more sensitive to cyclocytidine, cytarabine (AraC) and floxuridine than those with AA or AC (p=0.0215, p=0.0166, and p=0.0323, respectively), and carried more methylated tumor suppressor genes (p=0.0313). Among the 12 tumor suppressor genes which were methylated in >25% of cancer cell lines, the methylation status of TIMP3, APC and IGSF4 significantly correlated with sensitivity to pyrimidine synthesis inhibitors. In particular, cells with methylated TIMP3 had reduced mRNA levels and were significantly more sensitive to aphidicolin-glycinate, AraC and 5-FU than cells with unmethylated TIMP3. We speculate that MTHFR-A1298C homozygous CC might direct the methylation rather than the synthesis of DNA, and result in the methylation of several tumor suppressor genes such as TIMP3. These genes could be useful biological markers for predicting the efficacy of antimetabolites.

  3. Optimisation of cancer therapy : glucose antimetabolites as adjuvants in radiotherapy

    International Nuclear Information System (INIS)

    Jain, V.K.

    1980-01-01

    Inhibiting the repair of radiation damage in the neoplastic cells and thus differentially increasing radiation damage can be one of the ways to improve efficiency of radiotherapy of cancer. The glucose antimetabolite 2-deoxy-D-glucose (2-DG) which is known to inhibit glycolysis and ATP production in different cell systems, has been studied as to its effects on energy supply and repair of radiation damage in wild type yeast cells which are analogous to normal cells, and in respirator-deficient (RD) mutants which are analogous to hypoxic tumour cells. Results indicate that : (1) 2-DG/glucose in molar cencentration ratio of 1 completely inhibits the repair of potentially lethal X-radiation damage in RD mutants, (2) 2-DG enhances repair of sublethal radiation damage in wild-type yeast cells, (3) 2-DG induces a sharp fall in ATP level in RD-mutants as compared to that in wild type cells, (4) 2-DG inhibits repair of potentially lethal X-radiation damage in Ehrlich ascites tumour cells, (5) 2-DG induces greater cell loss from the hypoxic as well as euoxic tumour cell population of sarcoma tumour-180 in mice, and (6) 2-DG increases the survival of normal mice when given whole-body gamma irradiaition. These results, therefore, show that 2-DG may differentially inhibit the repair process in tumours while enhancing repair in normal tissues. (M.G.B.)

  4. Mechanism of purine antimetabolites and purine nucleodise imbalance

    International Nuclear Information System (INIS)

    Duan, D.S.

    1989-01-01

    Purine starvation is responsible for the cytotoxic effects of many purine antimetabolites. Guanine nucleotide depletion leads to a drastic DNA synthesis inhibition while adenine nucleotide depletion interferes with other vital functions before inhibiting DNA synthesis. To investigate the mechanism of these distinct effects, kinetics studies of adenine and guanine tracer incorporation into nucleotide pools and DNA were performed in S-49 cells. To address the question whether the cellular dGTP pool is compartmentalized, [ 14 C]Gua and [ 3 H]Guo tracer experiments were performed in a double mutant S-49 cell line, dGuo-L, with purine nucleoside phosphorylase (PNP) deficiency and dGTP feedback resistant ribonucleotide reductase (RR). While RR inhibition by dGTP was proposed as the cytotoxic mechanism in PNP immunodeficiency, additional effects of dGuo were studied in S-49 cells and human peripheral blood T lymphocytes (PBTL). RNA synthesis but not DNA synthesis was among the earliest targets of dGuo toxicity, and dGuo exerted cytotoxicity in resting PBTL before DNA synthesis. Three transformed T cells lines, PEER, HPB-ALL and HPB-MLT, were selected and characterized for cell surface markers and their sensitivities to dAdo and deoxycoformycin, an ADA inhibitor

  5. Antimetabolites in cataract surgery to prevent failure of a previous trabeculectomy.

    Science.gov (United States)

    Thomas, Roger E; Crichton, Andrew; Thomas, Bennett C

    2014-07-28

    Patients having cataract surgery have often earlier undergone a trabeculectomy for glaucoma. However, cataract surgery may be associated with failure of the previous glaucoma surgery and antimetabolites may be used with cataract surgery to prevent such failure. There is no systematic review on whether antimetabolites with cataract surgery prevent failure of a previous trabeculectomy. To assess the effects of antimetabolites with cataract surgery on functioning of a previous trabeculectomy. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 10 June 2014. We also searched the Science Citation Index database (July 2013) and reference lists of potentially relevant studies. Randomised controlled trials (RCTs) of antimetabolites with cataract surgery in people with a functioning trabeculectomy. Two review authors independently reviewed the titles and abstracts from the electronic searches. Two review authors independently assessed relevant full-text articles and entered data. We identified no RCTs to test the effectiveness of antimetabolites with cataract surgery in individuals with the intention of preventing failure of a previous trabeculectomy. There are no RCTs of antimetabolites with cataract surgery in people with a functioning trabeculectomy. Appropriately powered RCTs

  6. Modulation of cytochrome biosynthesis in yeast by antimetabolite action of levulinic acid.

    Science.gov (United States)

    Malamud, D R; Borralho, L M; Panek, A D; Mattoon, J R

    1979-01-01

    Levulinic acid, a competitive inhibitor of delta-aminolevulinic acid dehydratase, was used to inhibit cytochrome biosynthesis in growing yeast cells. In Saccharomyces cerevisiae the antimetabolite acts by inhibiting delta-aminolevulinic acid dehydratase in vivo, causing an accumulation of intracellular delta-aminolevulinic acid and simultaneous decreases in all classes of mitochondrial cytochromes. Changes in cellular cytochrome content with increasing levulinic acid concentration suggested the existence of different regulatory patterns in S. cerevisiae and Candida utilis. In C. utilis, cytochrome a.a3 formation is very resistant to the antimetabolite action of levulinic acid. In this aerobic yeast, cytochrome c+c1 is the most sensitive to levulinic acid, and cytochrome b exhibits intermediate sensitivity. PMID:378939

  7. Influence of methylene tetrahydrofolate reductase polymorphisms and coadministration of antimetabolites on toxicity after high dose methotrexate

    DEFF Research Database (Denmark)

    Niekerk, P.B. van Kooten; Schmiegelow, K.; Schroeder, H.

    2008-01-01

    .006-0.027), fever (OR = 2.65; P = 0.037) and interruption of maintenance treatment (OR = 3.04; P = 0.032). No convincing associations were found between the MTHFR C677T or A1298C polymorphisms and toxicity. CONCLUSION: Our findings demonstrate that toxicity after HDMTX is influenced by coadministrated...... in the methylene tetrahydrofolate reductase (MTHFR) gene and coadministration of antimetabolites on post-HDMTX toxicity. METHODS: Toxicity was retrospectively analysed after 656 HDMTX courses administered to 88 paediatric ALL patients at a single treatment centre. RESULTS: High-dose methotrexate with high...

  8. Chemical and Metabolic Aspects of Antimetabolite Toxins Produced by Pseudomonas syringae Pathovars

    Directory of Open Access Journals (Sweden)

    Eva Arrebola

    2011-08-01

    Full Text Available Pseudomonas syringae is a phytopathogenic bacterium present in a wide variety of host plants where it causes diseases with economic impact. The symptoms produced by Pseudomonas syringae include chlorosis and necrosis of plant tissues, which are caused, in part, by antimetabolite toxins. This category of toxins, which includes tabtoxin, phaseolotoxin and mangotoxin, is produced by different pathovars of Pseudomonas syringae. These toxins are small peptidic molecules that target enzymes of amino acids’ biosynthetic pathways, inhibiting their activity and interfering in the general nitrogen metabolism. A general overview of the toxins’ chemistry, biosynthesis, activity, virulence and potential applications will be reviewed in this work.

  9. Modern Methods of Controlling Wound Healing after Fistulizing Glaucoma Surgery. Risk Factors and Antimetabolites

    Directory of Open Access Journals (Sweden)

    S. Yu. Petrov

    2017-01-01

    Full Text Available The article describes modern approaches to controlling wound healing after fistulizing glaucoma surgery. It provides a classification of refractory glaucoma degrees and summarizes risk factors for excessive scarring. Author describes various applications of widely administered in clinical practice antimetabolites (5 fluorouracil, mitomycin C in patients with different degrees of excessive wound healing risk. The review also recounts international experience of steroidal and nonsteroidal anti-inflammatory drug use and their efficacy research study results. Much attention is given to new strategies of wound healing regulation after fistulizing glaucoma surgery, aimed at enhancing its results. The article describes characteristics and modes of action of medicinal agents effecting the cytoskeleton, such as Rho-kinase inhibitors and taxane anticancer agents. A detailed account of modes of effecting wound healing through regulating the process growth factors, proteinases and cytokines is also given. Possible strategies include antifibrotic cytokine interferon-α application and inhibiting the following agents: transforming growth factor β; connective tissue growth factor (CTGF, that controls extracellular matrix components production and cicatrical tissue formation; vascular endothelial growth factor (VEGF, that indirectly influences fibrotic activity through its angiogenic effect and also has a supposed direct effect on fibroblast activity; proinflammatory placental growth factor (PIGF, that increases bleb area size and its survival time, and decreases postoperative angiogenesis, inflammation and fibrosis intensity. The last part of the article gives a brief report on less widespread and researched methods of wound healing regulation, such as suppressing the activity of matrix metalloproteinases and amniotic membrane application.

  10. Structure and Function of Neisseria gonorrhoeae MtrF Illuminates a Class of Antimetabolite Efflux Pumps

    Directory of Open Access Journals (Sweden)

    Chih-Chia Su

    2015-04-01

    Full Text Available Neisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually transmitted disease gonorrhea. The control of this disease has been compromised by the increasing proportion of infections due to antibiotic-resistant strains, which are growing at an alarming rate. N. gonorrhoeae MtrF is an integral membrane protein that belongs to the AbgT family of transporters for which no structural information is available. Here, we describe the crystal structure of MtrF, revealing a dimeric molecule with architecture distinct from all other families of transporters. MtrF is a bowl-shaped dimer with a solvent-filled basin extending from the cytoplasm to halfway across the membrane bilayer. Each subunit of the transporter contains nine transmembrane helices and two hairpins, posing a plausible pathway for substrate transport. A combination of the crystal structure and biochemical functional assays suggests that MtrF is an antibiotic efflux pump mediating bacterial resistance to sulfonamide antimetabolite drugs.

  11. Development of new promising antimetabolite, DFP-11207 with self-controlled toxicity in rodents

    Directory of Open Access Journals (Sweden)

    Fukushima M

    2017-06-01

    -FU-related toxicities, such as a decrease in body weights, GI injury, and myelosuppression, especially thrombocytopenia. Taken together, the preclinical evaluation of DFP-11207 strongly indicates that DFP-11207 be a potential new version of the oral fluoropyrimidine prodrug for further clinical development. Keywords: antimetabolite, 5-FU, citrazinic acid, 5-chloro-2,4-dihydroxypyridine, antitumor activity, myelo-toxicity

  12. Effect of Moderate UVC Irradiation on Bovine Serum Albumin and Complex with Antimetabolite 5-Fluorouracil: Fluorescence Spectroscopic and Molecular Modelling Studies

    Directory of Open Access Journals (Sweden)

    Shanmugavel Chinnathambi

    2015-01-01

    Full Text Available The interaction of antimetabolite 5-fluorouracil (5FU with bovine serum albumin (BSA under UVC (253.7 nm irradiation was investigated in the present study using UV-Vis spectroscopy, steady state/time resolved fluorescence spectroscopic techniques. The stability of protein was found to be very strong when BSA gets bind to 5FU and moreover it is compared with the free BSA under UVC irradiation. From the fluorescence spectroscopic study, the stability of the complex was found to acquire 2-fold stronger than free protein. From the molecular modelling studies, we came to know the hydrogen bonds between BSA and antimetabolite 5FU are strong, up to 70.4 J/m2 under UVC irradiation.

  13. Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug.

    Science.gov (United States)

    Wang, Jin; Yin, Hailin; Panandikar, Ashwini; Gandhi, Varsha; Sen, Subrata

    2015-08-01

    Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells.

  14. Physiologic Aging of Mature Porcine Erythrocytes: Effects of Various Metabolites, Antimetabolites, and Physical Stressors

    Science.gov (United States)

    1986-10-01

    antioxidative biochemical pathways in- trols. The method of heating or the presence of pyruvate, crease the inherent sensitivity of erythrocytes to mem...irradiation (the mean specific absorp- Percentage tion rate was 91 = 4 Wkg). Hemolvsis’ difference 1410 nm absorbanceI from the corrected Actual...column of dex- nitrate or polypropylene centrifuge tubes. Two concentrations tran gel-filtration beads equilibrated with PBSS IpH 6.9). The of cells were

  15. Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Nersting, Jacob; Borst, Louise; Schmiegelow, Kjeld

    2011-01-01

    , but also multiplied the complex interaction of genetic and other laboratory parameters that can be used for therapy adjustments. Thus, with the advances in the laboratory techniques, post laboratory issues have become major obstacles for treatment individualization. Many of these challenges have been...

  16. Is mytomicyn better than 5-fluorouracil as antimetabolite in trabeculectomy for glaucoma?

    Directory of Open Access Journals (Sweden)

    Eduardo Pimentel

    2018-01-01

    Full Text Available Resumen INTRODUCCIÓN La trabeculectomía es considerada la intervención de elección en pacientes con glaucoma con indicación de manejo quirúrgico. Dentro de los factores asociados al fracaso de este tratamiento se encuentra la cicatrización postoperatoria. Para disminuir este factor se han usado distintos antimetabolitos, en particular el 5-fluorouracilo y la mitomicina C. Si bien ambos se consideran efectivos, no está claro si existen diferencias entre ambos en relación al éxito de la trabeculectomía y los efectos adversos. MÉTODOS Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis, preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos cuatro revisiones sistemáticas que en conjunto incluyen 17 estudios primarios, de los cuales, 12 corresponden a ensayos aleatorizados. Concluimos que el uso de mitomicina C podría lograr una mayor disminución de la presión intraocular e incrementar la tasa de éxito calificado en comparación con el 5-fluorouracilo. Sin embargo, su uso podría asociarse a una mayor incidencia de complicaciones.

  17. Role of diamine oxidase during the treatment of tumour-bearing mice with combinations of polyamine anti-metabolites.

    Science.gov (United States)

    Kallio, A; Jänne, J

    1983-01-01

    Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 1.4.3.6), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone. PMID:6411077

  18. Transfer of intestine-derived diamines into tumour cells during treatment of Ehrlich-ascites--carcinoma-bearing mice with polyamine anti-metabolites.

    Science.gov (United States)

    Kallio, A; Nikula, P; Jänne, J

    1984-01-01

    Treatment of Ehrlich-ascites-carcinoma-bearing mice with methylglyoxal bis(guanylhydrazone) alone or in combination with 2-difluoromethylornithine greatly enhanced the transfer of intragastrically administered radioactive putrescine and cadaverine into the carcinoma cells. Difluoromethylornithine alone did not have any effect on the accumulation of intestine-derived diamines in the tumour cells. The frequently reported restoration of difluoromethylornithine-induced polyamine depletion on administration of methylglyoxal bis(guanylhydrazone) is in all likelihood attributable to a profound inhibition of intestinal diamine oxidase (EC 1.4.3.6), resulting in an enhanced entry of intestinal (bacterial) diamines into general circulation and finally into tumour cells. PMID:6424664

  19. Dgroup: DG00687 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 974 ... Fluorouracil sodium salt Antineoplastic ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineopla...stic ... DG01935 ... Fluoropyrimidine antineoplastic Unclassified ... DG02018 ... Antimetabolit...e ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic... ATC code: L01BC02 Antineoplastics, Antimetabolite TYMS [HSA:7298] [KO:K00560] Enzyme: DPYD [HSA:1806] ...

  20. Dgroup: DG00686 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available Cytarabine ocfosphate hydrate (JAN) ... D03637 ... Cytarabine hydrochloride (USAN) Antineoplastic ... DG01958 ... Nuc...leic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic...acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ATC code: L01BC01 Antineoplastics, Antimetabolite DNA polymerase ... ... Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic

  1. Dgroup: DG00684 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00684 Chemical ... DGroup Tioguanine ... D08603 ... Tioguanine (INN) D06109 ... Thioguanine (USP) ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic Unclassified ... DG02018 ... Antimetabo...lite ... DG01958 ... Nucleic acid derivative, antineoplastic ATC code: L01BB03 Antineoplastics, Antimetabolite ...

  2. Dgroup: DG00685 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ne phosphate (JAN/USP) ... Antineoplastic ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabin...ofuranosyl type antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimet...abolite ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplasti...c ATC code: L01BB05 Antineoplastics, Antimetabolite RRM [HSA:6240 6241 50484] [KO:K10807 K10808] DNA polymerase RNA polymerase ...

  3. Dgroup: DG00688 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available itabine hydrochloride (JAN/USAN) ... D10222 ... Gemcitabine elaidate (USAN/INN) Antineoplastic ... DG01958 ... Nucleic... acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic...ic ... DG01439 ... Arabinofuranosyl type antineoplastic ATC code: L01BC05 Antineoplastics, Antimetabolite RRM1 [HSA:6240] [KO:K10807] ... ... Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplast

  4. Riboflavin analogs as antiinfectives: occurrence, mode of action, metabolism and resistance.

    Science.gov (United States)

    Pedrolli, Danielle Biscaro; Jankowitsch, Frank; Schwarz, Julia; Langer, Simone; Nakanishi, Shinobu; Frei, Eva; Mack, Matthias

    2013-01-01

    Antimetabolites are molecules, which are structurally similar to molecules needed to carry out primary metabolic reactions.The inhibitory activity of an antimetabolite depends on its successful competition with the natural substrate, ligand, modulator or cofactor of a given biomolecule. Antimetabolites are indispensable as molecular tools in order to understand biological processes. Beyond that,antimetabolites have a large variety of applications in the pharmaceutical and food industries. The identification of the structural riboflavin(vitamin B2) analog roseoflavin in Streptomyces davawensis demonstrates that anti-vitamins/cofactor analogs may serve as lead structures for the development of novel antibiotics. The latter is supported by the recent finding that roseoflavin had a profound inhibiting effect on the growth and infectivity of the human bacterial pathogen Listeria monocytogenes at very low concentrations. Roseoflavin is studied in our laboratory as a model compound. We investigate the biosynthesis, the possible large-scale production, the metabolization,the mechanism of action and the resistance mechanism of the producer organism in order to pave the way for the structured analysis of other vitamin analogs yet to be discovered. These compounds hopefully will help to replenish the arsenal of antimicrobials urgently needed to fight multiresistant bacterial pathogens.

  5. Design, synthesis and cytotoxic activity of some novel compounds ...

    Indian Academy of Sciences (India)

    Insight into different biological activities of pyrazolo. [3,4-d]pyrimidines as antimetabolites in purine bioche- mical reactions, were gained and several mechanisms were described for their cytotoxic activities as EGFR inhibitors,3 GSK-3 inhibitors,4,5 xanthine oxidase inhi- bitors,6 Mer receptor tyrosine kinase inhibitors,7 tyro-.

  6. Fluorouracil Topical

    Science.gov (United States)

    ... are also used to treat a type of skin cancer called superficial basal cell carcinoma if usual types of treatment cannot be used. Fluorouracil is in a class of medications called antimetabolites. It ... such as the abnormal cells in actinic keratoses and basal cell carcinoma.

  7. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial

    NARCIS (Netherlands)

    Khanna, Reena; Bressler, Brian; Levesque, Barrett G.; Zou, Guangyong; Stitt, Larry W.; Greenberg, Gordon R.; Panaccione, Remo; Bitton, Alain; Paré, Pierre; Vermeire, Séverine; D'Haens, Geert; MacIntosh, Donald; Sandborn, William J.; Donner, Allan; Vandervoort, Margaret K.; Morris, Joan C.; Feagan, Brian G.; Anderson, Frank; Atkinson, Kenneth; Bacchus, Rahman; Berezny, Gary; Borthistle, Bruce; Buckley, Alan; Chiba, Naoki; Cockeram, Alan; Elkashab, Magdy; Fashir, Baroudi; Gray, James; Hemphill, Douglas; Hoare, Connie; Holland, Stephen; Hurowitz, Eric; Kaal, Nuri; Laflamme, Pierre; Borromee, Saint-Charles; Lau, Helena; McMullen, William; Memiche, Reshat; Menon, Krishna; Miller, D. Alexander; O'Hara, William; Oravec, Michael; Penner, Robert; Petrunia, Denis; Pluta, Henryk; Prabhu, Umesh; Prest, Marcia; Shaaban, Hani; Sheppard, Duane; Shulman, Scott

    2015-01-01

    Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of

  8. Drug: D07966 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07966 Drug Fludarabine (INN); Fluradosa (TN) ... C10H12FN5O4 D07966.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG0...1439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic Same as:

  9. Drug: D10222 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10222 Drug Gemcitabine elaidate (USAN/INN) ... C27H43F2N3O5 D10222.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01...439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ATC code:

  10. Drug: D04197 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D04197 Drug Floxuridine (USP/INN); FUDR (TN) ... C9H11FN2O5 D04197.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic ... DG01935 ... F...luoropyrimidine antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01935 ... Fluoropyrimidine antineoplastic Same as: C11736 ... TYMS [

  11. Drug: D03637 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D03637 Drug Cytarabine hydrochloride (USAN) ... C9H13N3O5. HCl D03637.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG...01439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ATC cod

  12. Drug: D05134 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 5 D05134.gif ... Antineoplastic ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... ...DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic... D05134 Drug Nelarabine (JAN/USAN/INN); Nelzarabine (USAN); Arranon (TN) ... C11H15N5O

  13. Drug: D09712 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09712 Drug Elacytarabine (USAN/INN) ... C27H45N3O6 D09712.gif ... Antineoplastic ... DG0...1958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arab...inofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ... Elacytarabine i

  14. Drug: D01651 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01651 Drug Ancitabine hydrochloride (JAN) ... C9H11N3O4. HCl D01651.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG0...1439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic Same as:

  15. Drug: D07974 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07974 Drug Fluorouracil sodium salt; Fluorouracil (TN) ... C4H3FN2O2. xNa D07974.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic... ... DG01935 ... Fluoropyrimidine antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplasti...c ... DG01935 ... Fluoropyrimidine antineoplastic ATC code:

  16. Drug: D02368 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02368 Drug Gemcitabine (USAN/INN) ... C9H11F2N3O4 D02368.gif ... Antineoplastic ... DG01...958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arabi...nofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic Same as: C07650 ATC

  17. Drug: D06100 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06100 Drug Tezacitabine (USAN); Tezacitabine monohydrate ... C10H12FN3O4. H2O D06100.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic

  18. Drug: D01309 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01309 Drug Doxifluridine (JP17/INN); Furtulon (TN) ... C9H11FN2O5 D01309.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic ... DG0...1935 ... Fluoropyrimidine antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01935 ... Fluoropyrimidine antineoplastic Same as: C12739 Th

  19. Drug: D04233 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D04233 Drug Flurocitabine (USAN/INN) ... C9H10FN3O4 D04233.gif ... Antineoplastic ... DG0...1958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arab...inofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ... CAS: 37717-

  20. Drug: D04134 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D04134 Drug Fazarabine (USAN/INN) ... C8H12N4O5 D04134.gif ... Antineoplastic ... DG01958... ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplas...tic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ... arabinofuranosyl de

  1. Drug: D09722 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09722 Drug Sapacitabine (USAN/INN) ... C26H42N4O5 D09722.gif ... Antineoplastic ... DG01...958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arabi...nofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ... nucleoside analo

  2. Drug: D01633 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01633 Drug Enocitabine (JAN/INN); Sunrabin (TN) ... C31H55N3O6 D01633.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... D...G01439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic Therap

  3. Drug: D06221 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06221 Drug Triciribine phosphate (USAN) ... C13H17N6O7P D06221.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ... CAS: 6

  4. Drug: D01784 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01784 Drug Carmofur (JP17/INN); Mifurol (TN) ... C11H16FN3O3 D01784.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic Unclassified ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01935 ... Fluoropyrimidine antineoplastic ATC code: L01BC04 ... Act

  5. Deoxyribonucleotide pool analysis: functional association of thymidylate synthase with the other enzymes of DNA biosynthesis in mammalian cells

    International Nuclear Information System (INIS)

    Reddy, G.P.V.; Christiansen, E.

    1986-01-01

    Allosteric interaction between thymidylate synthase (TS) and the other enzymes of DNA biosynthesis was suggested from the authors observation that inhibitors of ribonucleotide reductase, topoisomerase of DNA polymerase-α inhibit TS in intact S phase CHEF/18 cells, but not in their soluble extracts. In addition the authors observed that 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA), a poison of topoisomerase II, had similar effects on TS activity in mammalian cells. They have examined if the inhibitory effects of these antimetabolites on TS is due to the accumulation of thymidine nucleotide(s) in intact cells, rather than to an allosteric interaction in the replitase complex. A novel method of nucleotide pool analysis revealed that in the presence of these antimetabolites the incorporation of radioactivity from 3 H-deoxyuridine (dUrd) into thymidine nucleotide pools inside the cell did not increase as compared to the control. Furthermore, TS activity as measured in-vitro was not inhibited by supraphysiological concentrations (50μM) of thymidine mono- or tri-phosphates. None of these antimetabolites dramatically influenced the uptake of dUrd and its subsequent phosphorylation to deoxyuridine monophosphate. Therefore, they suggest that the inhibitory effect of these antimetabolites is due to the functional association of their target enzymes with TS

  6. Comparative studies on the effect of radiation-sensitizing agents used in radiating VX2 Carcinoma

    International Nuclear Information System (INIS)

    Migita, Hidenobu

    1975-01-01

    The effects of 5-Fu and BUdR as radiation-sensitizing agents macroscopically were investigated in 122 VX2 Carcinomas transplanted into the calves of the hind legs of rabbits. Experimental groups and contrast groups are divided into six as follows: A: No treatment, B: 5-Fu infusion, C: BUdR+Antimetabolite infusion, D: Radiation, E: 5-Fu infusion and radiation, and F: BUdR+Antimetabolite infusion and radiation. The amount of agent given to each was 5 mg/kg/day of 5-Fu and 50 mg/kg/day of BUdR, and the amount of radiation was 300 rad/day. 5-Fu was used as the Antimetabolite, and its amount was one-tenth of that in the 5-Fu Infusion Group. The agent and the radiation were given for five days. 1. In the 300 rad/day Group, the radiation was not enough to result in a complete cure. 2. In the two Agent Infusion Group, 5-Fu and BUdR+Antimetabolite proved to be anti-cancer, but neither of them resulted in effective treatment. 3. The 5-Fu Infusion and Radiation Group, showed a strong degenerative change in the tumor cell and a radiosensitive effect from 5-Fu, but the tumor was not lessened. 4. In the BUdR-Antimetabolite Infusion and Radiation Group, the tumor began to reduce on the third day. On the seventh and fourteenth days, necrosis of the greater part of tumor was seen, and the rest of the tumor cells were found to be in degenerative change. On the twenty first day, no live tumor cell was found, only dead remains of tumor cells. The results were confirmed both macroscopically and histopathologically. 5. BUdR can be expected to be effective in clinical application to oral malignant tumors. (Evans, J.)

  7. Biochemical and chemical characterization of trifluoromethylglyoxal bis(guanylhydrazone), a close analog of the antileukemic drug mitoguazone.

    Science.gov (United States)

    Elo, H; Mutikainen, I

    1988-01-01

    In order to study the structure-activity relationships of bis(guanylhydrazone) type polyamine antimetabolites, trifluoromethylglyoxal bis(guanylhydrazone) (CF3-GBG), a close analog of the antileukemic drug methylglyoxal bis(guanylhydrazone) (mitoguazone, MGBG) was synthesized according to a novel modification of previous methods, yielding single crystals. Single-crystal X-ray crystallography revealed the presence of an isomer different from the one detected in the case of MGBG and all other bis(guanylhydrazones) so far studied. In contrast to MGBG, CF3-GBG was shown to be a very weak inhibitor of yeast adenosylmethionine decarboxylase, being thus devoid of value as a polyamine antimetabolite. In addition, the compound did not have antiproliferative activity against mouse L1210 leukemia cells in vitro. As long as analogous isomers of the two compounds are not available, no conclusions can be drawn about the reasons lying behind the drastical differences between their biological properties.

  8. POSSIBILITY OF LEUKOGENICITY EFFECT OF LONG TERM USE OF HYDROXYUREA IN SICKLE CELL ANAEMIA

    OpenAIRE

    Archana; Bhanu P.

    2015-01-01

    Malignancy in patient with Sickle Cell Anemia has been reported by many researchers, but the type of malignancy and its incidence remain undefined. Before this case report; the association of chronic myeloid leukemia in sickle cell patients, 5 cases were reported in 200 5, 9 cases reported in 2008 and then 10 cases in the year of 2011. Hydroxyurea is an antimetabolite that minimizes pain and prolongs survival in patient with Sickle Cell Anemia. This drug is more widely pr...

  9. Relation of arginine-lysine antagonism to herpes simplex growth in tissue culture.

    Science.gov (United States)

    Griffith, R S; DeLong, D C; Nelson, J D

    1981-01-01

    In the studies conducted, arginine deficiency suppressed herpes simplex virus replication in tissue culture. Lysine, an analog of arginine, as an antimetabolite, antagonized the viral growth-promoting action of arginine. The in vitro data may be the basis for the observation that patients prone to herpetic lesions and other related viral infections, particularly during periods of stress, should abstain from arginine excess and may also require supplemental lysine in their diet.

  10. Drug: D03046 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available arasid (TN) ... C27H49N3O8P. Na. H2O D03046.gif ... Antineoplastic ... DG01958 ... Nucleic acid derivative, antineoplastic... ... DG01439 ... Arabinofuranosyl type antineoplastic ... DG01439 ... Arabinofuranosyl type antineoplastic Unclassi...fied ... DG02018 ... Antimetabolite ... DG01958 ... Nucleic acid derivative, antineoplastic ... ... DG01439 ... Arabinofuranosyl type antineoplastic Therapeutic category: 4224 ATC code: L01BC01 Chemical group

  11. Drug: D01244 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01244 Drug Tegafur (JP17/USAN/INN); Atillon (TN) ... C8H9FN2O3 D01244.gif ... Antineoplastic... ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic ... DG0193...5 ... Fluoropyrimidine antineoplastic Cyp substrate ... DG01638 ... CYP2A6 substrate Unclassified ... DG02018 ... Antimetab...olite ... DG01958 ... Nucleic acid derivative, antineoplastic ... DG01935 ... Fluoropyrimidine antineoplastic

  12. The Acyclic 2,4-Diaminopyrimidine Nucleoside Phosphonate Acts as a Purine Mimetic in HIV-1 Reverse Transcriptase DNA Polymerization

    Czech Academy of Sciences Publication Activity Database

    Herman, B. D.; Votruba, Ivan; Holý, Antonín; Sluis-Cremer, N.; Balzarini, J.

    2010-01-01

    Roč. 285, č. 16 (2010), s. 12101-12108 ISSN 0021-9258 Grant - others:NIH(US) R01 AI81571; KU Leuven(BE) GOA Kredit 05/19 Institutional research plan: CEZ:AV0Z40550506 Keywords : acyclic nucleotide analogue * purine open ring * HIV-1 RT * antiviral * antimetabolite Subject RIV: CC - Organic Chemistry Impact factor: 5.328, year: 2010

  13. The biochemical basis for l-canavanine tolerance by the tobacco budworm Heliothis virescens (Noctuidae)

    OpenAIRE

    Melangeli, Coromoto; Rosenthal, Gerald A.; Dalman, Douglas L.

    1997-01-01

    The tobacco budworm, Heliothis virescens (Noctuidae), a destructive insect pest, is remarkably resistant to l-canavanine, l-2-amino-4-(guanidinooxy)butyric acid, an arginine antimetabolite that is a potent insecticide for nonadapted species. H. virescens employs a constitutive enzyme of the larval gut, known trivially as canavanine hydrolase (CH), to catalyze an irreversible hydrolysis of l-canavanine to l-homoserine and hydroxyguanidine. As such, it represents a new type of hydrolase, one ac...

  14. Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases.

    Science.gov (United States)

    Schem, Christian; Tower, Robert J; Kneissl, Philipp; Rambow, Anna-Christina; Campbell, Graeme M; Desel, Christine; Damm, Timo; Heilmann, Thorsten; Fuchs, Sabine; Zuhayra, Maaz; Trauzold, Anna; Glüer, Claus C; Schott, Sarah; Tiwari, Sanjay

    2017-03-01

    Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

  15. Pemetrexed-Induced Nephrogenic Diabetes Insipidus.

    Science.gov (United States)

    Fung, Enrica; Anand, Shuchi; Bhalla, Vivek

    2016-10-01

    Pemetrexed is an approved antimetabolite agent, now widely used for treating locally advanced or metastatic nonsquamous non-small cell lung cancer. Although no electrolyte abnormalities are described in the prescribing information for this drug, several case reports have noted nephrogenic diabetes insipidus with associated acute kidney injury. We present a case of nephrogenic diabetes insipidus without severely reduced kidney function and propose a mechanism for the isolated finding. Severe hypernatremia can lead to encephalopathy and osmotic demyelination, and our report highlights the importance of careful monitoring of electrolytes and kidney function in patients with lung cancer receiving pemetrexed. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  16. Purine and pyrimidine metabolism in man V

    International Nuclear Information System (INIS)

    Nyhan, W.L.; Thompson, L.F.; Watts, R.W.E.

    1986-01-01

    This book comprises the proceedings of the Fifth International Symposium on Human Purine and Pyrimidine Metabolism. Its papers are organized under the following categories: adenosine receptors; purine receptors and the central nervous system; nucleoside and base transport; studies with antimetabolites; deoxynucleotide and nucleoside toxicity and metabolism; enzymes; purine and pyrimidine metabolism during lymphocyte differentiation; purine metabolism in skeletal muscle; purine nucleotide metabolism in the heart; purine and pyrimidine metabolism in primary cell cultures and in parasites; nucleoside kinases and drug activation; phosphoribosylpyrophosphate; S-adenosylmethionine metabolism; and the metabolic effects of interferon

  17. Enzyme Promiscuity: Engine of Evolutionary Innovation*

    Science.gov (United States)

    Pandya, Chetanya; Farelli, Jeremiah D.; Dunaway-Mariano, Debra; Allen, Karen N.

    2014-01-01

    Catalytic promiscuity and substrate ambiguity are keys to evolvability, which in turn is pivotal to the successful acquisition of novel biological functions. Action on multiple substrates (substrate ambiguity) can be harnessed for performance of functions in the cell that supersede catalysis of a single metabolite. These functions include proofreading, scavenging of nutrients, removal of antimetabolites, balancing of metabolite pools, and establishing system redundancy. In this review, we present examples of enzymes that perform these cellular roles by leveraging substrate ambiguity and then present the structural features that support both specificity and ambiguity. We focus on the phosphatases of the haloalkanoate dehalogenase superfamily and the thioesterases of the hotdog fold superfamily. PMID:25210039

  18. Improving cancer treatment with cyclotron produced radionuclides. Progress report

    Energy Technology Data Exchange (ETDEWEB)

    Larson, S.M.; Finn, R.D.

    1992-08-04

    Our goal is to improve the scientific basis for tumor diagnosis, treatment and treatment follow-up based on the use of cyclotron produced radiotracers in oncology. The grant includes 3 interactive components: Radiochemistry/Cyclotron; Pharmacology; and Immunology. The radiochemistry group seeks to develop innovative cyclotron targetry, radiopharmaceuticals, and radiolabeled antibodies, which are then used to assess important unanswered questions in tumor pharmacology and immunology. Examples include selected positron emitting radionuclides, such as Iodine-124, and Ga-66; I-124, I-123, I-131 labeled iododeoxyuridine, C-11 colchicine, and antimetabolites, like C-11 methotrexate; and radiolabeled antibodies, 3F8, M195, A33, and MRK16 for application in the pharmacology and immunology projects. The pharmacology program studies tumor resistance to chemotherapy, particularly the phenomenon of multidrug resistance and the relationship between tumor uptake and retention and the tumor response for anti-metabolite drugs. The immunology program studies the physiology of antibody localization at the tissue level as the basis for novel approaches to improving tumor localization such as through the use of an artificial lymphatic system which mechanically reduces intratumoral pressures in tumors in vivo. Quantitative imaging approaches based on PET and SPECT in radioimmunotherapy are studied to give greater insight into the physiology of tumor localization and dosimetry.

  19. Improving cancer treatment with cyclotron produced radionuclides

    Energy Technology Data Exchange (ETDEWEB)

    Larson, S.M.; Finn, R.D.

    1992-08-04

    Our goal is to improve the scientific basis for tumor diagnosis, treatment and treatment follow-up based on the use of cyclotron produced radiotracers in oncology. The grant includes 3 interactive components: Radiochemistry/Cyclotron; Pharmacology; and Immunology. The radiochemistry group seeks to develop innovative cyclotron targetry, radiopharmaceuticals, and radiolabeled antibodies, which are then used to assess important unanswered questions in tumor pharmacology and immunology. Examples include selected positron emitting radionuclides, such as Iodine-124, and Ga-66; I-124, I-123, I-131 labeled iododeoxyuridine, C-11 colchicine, and antimetabolites, like C-11 methotrexate; and radiolabeled antibodies, 3F8, M195, A33, and MRK16 for application in the pharmacology and immunology projects. The pharmacology program studies tumor resistance to chemotherapy, particularly the phenomenon of multidrug resistance and the relationship between tumor uptake and retention and the tumor response for anti-metabolite drugs. The immunology program studies the physiology of antibody localization at the tissue level as the basis for novel approaches to improving tumor localization such as through the use of an artificial lymphatic system which mechanically reduces intratumoral pressures in tumors in vivo. Quantitative imaging approaches based on PET and SPECT in radioimmunotherapy are studied to give greater insight into the physiology of tumor localization and dosimetry.

  20. Improving cancer treatment with cyclotron produced radionuclides

    International Nuclear Information System (INIS)

    Larson, S.M.; Finn, R.D.

    1992-01-01

    Our goal is to improve the scientific basis for tumor diagnosis, treatment and treatment follow-up based on the use of cyclotron produced radiotracers in oncology. The grant includes 3 interactive components: Radiochemistry/Cyclotron; Pharmacology; and Immunology. The radiochemistry group seeks to develop innovative cyclotron targetry, radiopharmaceuticals, and radiolabeled antibodies, which are then used to assess important unanswered questions in tumor pharmacology and immunology. Examples include selected positron emitting radionuclides, such as Iodine-124, and Ga-66; I-124, I-123, I-131 labeled iododeoxyuridine, C-11 colchicine, and antimetabolites, like C-11 methotrexate; and radiolabeled antibodies, 3F8, M195, A33, and MRK16 for application in the pharmacology and immunology projects. The pharmacology program studies tumor resistance to chemotherapy, particularly the phenomenon of multidrug resistance and the relationship between tumor uptake and retention and the tumor response for anti-metabolite drugs. The immunology program studies the physiology of antibody localization at the tissue level as the basis for novel approaches to improving tumor localization such as through the use of an artificial lymphatic system which mechanically reduces intratumoral pressures in tumors in vivo. Quantitative imaging approaches based on PET and SPECT in radioimmunotherapy are studied to give greater insight into the physiology of tumor localization and dosimetry

  1. Drug repositioning for enzyme modulator based on human metabolite-likeness.

    Science.gov (United States)

    Lee, Yoon Hyeok; Choi, Hojae; Park, Seongyong; Lee, Boah; Yi, Gwan-Su

    2017-05-31

    Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for

  2. Disseminated cytomegalovirus infection complicating active treatment of systemic lupus erythematosus: an emerging problem.

    Science.gov (United States)

    Berman, N; Belmont, H M

    2017-04-01

    Patients with systemic lupus erythematosus (SLE) often require immunosuppression to induce remission of active disease exacerbations. Over the past two decades, treatment modalities for this condition have emerged leading to improved morbidity from disease related outcomes. However, as a result, infection risks and patterns have changed, leading to higher rates of opportunistic infections among this population. We report four cases of cytomegalovirus (CMV) in patients with SLE who received immunosuppressive therapy, including pulse steroids, antimetabolites such as mycophenolate mofetil, and alkylating agents such as cyclophosphamide. We propose that given the rise in prevalence of CMV, there is a need for appropriate screening for this opportunistic pathogen and studies to determine the risks and benefits of prophylactic or preemptive treatment for this virus.

  3. Crystal structure of the Alcanivorax borkumensis YdaH transporter reveals an unusual topology

    Science.gov (United States)

    Bolla, Jani Reddy; Su, Chih-Chia; Delmar, Jared A.; Radhakrishnan, Abhijith; Kumar, Nitin; Chou, Tsung-Han; Long, Feng; Rajashankar, Kanagalaghatta R.; Yu, Edward W.

    2015-04-01

    The potential of the folic acid biosynthesis pathway as a target for the development of antibiotics has been clinically validated. However, many pathogens have developed resistance to these antibiotics, prompting a re-evaluation of potential drug targets within the pathway. The ydaH gene of Alcanivorax borkumensis encodes an integral membrane protein of the AbgT family of transporters for which no structural information was available. Here we report the crystal structure of A. borkumensis YdaH, revealing a dimeric molecule with an architecture distinct from other families of transporters. YdaH is a bowl-shaped dimer with a solvent-filled basin extending from the cytoplasm to halfway across the membrane bilayer. Each subunit of the transporter contains nine transmembrane helices and two hairpins that suggest a plausible pathway for substrate transport. Further analyses also suggest that YdaH could act as an antibiotic efflux pump and mediate bacterial resistance to sulfonamide antimetabolite drugs.

  4. Selective small-molecule inhibition of an RNA structural element

    Energy Technology Data Exchange (ETDEWEB)

    Howe, John A.; Wang, Hao; Fischmann, Thierry O.; Balibar, Carl J.; Xiao, Li; Galgoci, Andrew M.; Malinverni, Juliana C.; Mayhood, Todd; Villafania, Artjohn; Nahvi, Ali; Murgolo, Nicholas; Barbieri, Christopher M.; Mann, Paul A.; Carr, Donna; Xia, Ellen; Zuck, Paul; Riley, Dan; Painter, Ronald E.; Walker, Scott S.; Sherborne, Brad; de Jesus, Reynalda; Pan, Weidong; Plotkin, Michael A.; Wu, Jin; Rindgen, Diane; Cummings, John; Garlisi, Charles G.; Zhang, Rumin; Sheth, Payal R.; Gill, Charles J.; Tang, Haifeng; Roemer , Terry (Merck)

    2015-09-30

    Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

  5. The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy.

    Directory of Open Access Journals (Sweden)

    Tsutomu Iwata

    Full Text Available CBP-93872 suppresses maintenance of DNA double-stranded break-induced G2 checkpoint, by inhibiting the pathway between ataxia-telangiectasia mutated (ATM and ATM- and Rad3-related (ATR activation. To examine the potential use of CBP-93872 for clinical applications, we analyzed the synergistic effects of platinum-containing drugs, oxaliplatin and cisplatin, pyrimidine antimetabolites, gemcitabine and 5-fluorouracil (5-FU, in combination with CBP-93872, on cell lethality in colorectal and pancreatic cancer cell lines. Treatment with CBP-93872 significantly increased cancer cell sensitivities to various chemotherapeutic agents tested through suppression of checkpoint activation. Our results thus reveal that combination treatment of CBP-93872 with known chemotherapeutic agents inhibits phosphorylation of ATR and Chk1, and induces cell death.

  6. Epidemiologic and therapeutic aspects of refractory coeliac disease - a systematic review

    DEFF Research Database (Denmark)

    Rowinski, Sara Anna; Christensen, Erik

    2016-01-01

    INTRODUCTION: Refractory coeliac disease (RCD) is a rare and severe malabsorptive disease. The condition has two subtypes: RCDI and RCDII. Different treatments have been tested: and because RCD has a poor prognosis due to progress to enteropathy-associated T-cell lymphoma, the aim was to review...... the epidemiologic aspects and the therapeutic options for RCD. METHODS: A systematic literature search was performed in 18 databases, and 122 records were identified. Incidence, prevalence, treatment methods and their efficacy were evaluated. RESULTS: Among coeliac disease patients, the cumulative incidence of RCD...... is 1-4% per ten-year period and the prevalence is 0.31-0.38%. In the general population, the prevalence of RCD is 0.002%. Treatment of RCDI is azathioprine (effect 100%), mesalamine (effect 60%) or tioguanine (effect 83%). Treatment for RCDII is the antimetabolite cladribine (effect 81%) and autologous...

  7. Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

    Directory of Open Access Journals (Sweden)

    Chiaming Fan

    2011-01-01

    Full Text Available The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX, the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities.

  8. Strain improvement of industrially important microorganisms based on resistance to toxic metabolites and abiotic stress.

    Science.gov (United States)

    Fiedurek, Jan; Trytek, Mariusz; Szczodrak, Janusz

    2017-06-01

    Improvement of the biosynthetic capabilities of industrially relevant microbes to produce desired metabolites in higher quantities is one of the important topics of modern biotechnology. In this article, different strategies of improvement of mutated microbial strains are briefly described. This is followed by the first comprehensive review of the literature on obtaining high yielding microorganisms, that is, mutants exhibiting resistance to antimetabolites, nutritional repression, and abiotic stresses as well as tolerance to solvents and toxic substrates or products. Furthermore, the efficiency of the microbial metabolites produced by improved microbial strains, advantages, and limitations, as well as future prospects for strategies of strain development are discussed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Effects of caffeine on purine metabolism and ultraviolet light-induced lethality in cultured mammalian cells

    International Nuclear Information System (INIS)

    Waldren, C.A.; Patterson, D.

    1979-01-01

    Caffeine, at doses which enhance the killing action of ultraviolet light, inhibits both de novo synthesis and the utilization of exogenous purines in cultured CHO-K1, a Chinese hamster ovary cell line. The effect is dose dependent, with a caffeine concentration of 7.5 mM producing a 90% reduction in 15 min. Interference with utilization of exogenous purines was seen as a substantial decrease in the conversion of [14C]hypoxanthine, [14C]adenine, or [14C]guanine into their respective di- and triphosphates in the presence of caffeine. Thus, one of the ways by which antimetabolites and caffeine act to enhance ultraviolet light killing may be by interference with the supply of purine nucleotides needed for repair

  10. Punctal-canalicular stenosis related to systemic fluorouracil therapy.

    Science.gov (United States)

    Caravella, L P; Burns, J A; Zangmeister, M

    1981-02-01

    This is, to our knowledge, the first report in the ophthalmic literature of punctal-canalicular stenosis and concomitant epiphora associated with the prolonged administration of fluorouracil; to our knowledge, fluorouracil is the first systemically administered agent to cause obstruction in the lacrimal system. Each of three patients receiving this antimetabolite alone and one patient receiving it in combination with methotrexate and cyclophosphamide were studied for complaints of epiphora. All four patients exhibited stenosis or occlusion of one or more puncta, while three also had one or four of their canaliculi stenosed. Two patients exhibited recurrent epiphora, beginning one to two days after each administration of fluorouracil and resolving in two to three days. One patient experienced amelioration of her symptoms after Silastic tube intubation of her canalicular system.

  11. Glaucoma Surgery in Pregnancy: A Case Series and Literature Review

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    Mohammad Reza Razeghinejad

    2016-09-01

    Full Text Available Glaucoma management in pregnant patients is a real challenge, especially when the glaucoma is not controlled with medications. We report the results of 6 incisional glaucoma surgeries for the management of medically uncontrolled glaucoma patients during pregnancy. This retrospective, case series was conducted on the 6 eyes of 3pregnant patients with uncontrolled glaucoma using maximum tolerable medications. Details of the glaucoma surgical management of these patients as well as their postoperative care and pregnancy and clinical outcomes on longitudinal follow-up are discussed. All 3 patients had juvenile open-angle glaucoma and were on various anti-glaucoma medications, including oral acetazolamide. The first case described underwent trabeculectomy without antimetabolites in both eyes because of uncontrolled intraocular pressure with topical medications. The surgery was done with topical lidocaine jelly and subconjunctival lidocaine during the second and third trimesters. The second patient had an Ahmed valve implantation in both eyes during the second and third trimesters because of uncontrolled IOP with topical medications and no response to selective laser trabeculoplasty. Surgery was done with topical tetracaine and subconjunctival and sub-Tenon’s lidocaine. The third case had a Baerveldt valve implantation under general anesthesia in the second trimester. In selected pregnant glaucoma patients with medically uncontrolled intraocular pressure threatening vision, incisional surgery may lead to good outcomes for the patient with no risk for the fetus.

  12. Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens.

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    Wei Sun

    Full Text Available A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug, tacrolimus (an immunosuppressive agent and floxuridine (an antimetabolite were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

  13. Radiotherapy combined with Tegafur (FT-207s) for brain tumors

    International Nuclear Information System (INIS)

    Aoki, Yoshiro

    1981-01-01

    5-Fluorouracil (5-FU) has anti-tumor effects as an anti-metabolite, but it cannot pass the Blood-Brain-Barrier (BBB). FT-207 a masked-compound of 5-FU, is easily lipid soluble and is able to pass the BBB. Twenty eight patients of primary brain tumor and 8 patients of metastatic brain tumor were treated with irradiation combined with 750 mg of FT-207 suppository. Twenty four patients of primary brain tumor were treated only with irradiation as control. The mean survival time was 20.4 +- 11.8 months for the combined therapy group and 17.6 +- 8.6 months for the control. The concentration of FT-207 and 5-FU in serum and in cerebrospinal fluid (CSF) was investigated after administration of 750 mg of FT-207 suppository per annum. The maximum concentration of FT-207 and of 5-FU in serum was 20.4 +- 11.8 mcg/ml and 0.06 +- 0.02 mcg/ml, respectively. There were observed several side effects, such as anorexia, nausea, exanthema and etc. These side effects were not so great as to interrupt the therapy at the dose level of 750 mg of FT-207. However, at the dose of 1500 mg, one case showed disturbance of consciousness, to which attention should be called. (author)

  14. Gemcitabine-loaded liposomes: rationale, potentialities and future perspectives

    Directory of Open Access Journals (Sweden)

    Federico C

    2012-11-01

    Full Text Available Cinzia Federico, Valeria M Morittu, Domenico Britti, Elena Trapasso, Donato CoscoDepartment of Health Sciences, Building of BioSciences, University “Magna Græcia” of Catanzaro, Campus Universitario “S Venuta”, Germaneto, ItalyAbstract: This review describes the strategies used in recent years to improve the biopharmaceutical properties of gemcitabine, a nucleoside analog deoxycytidine antimetabolite characterized by activity against many kinds of tumors, by means of liposomal devices. The main limitation of using this active compound is the rapid inactivation of deoxycytidine deaminase following administration in vivo. Consequently, different strategies based on its encapsulation/complexation in innovative vesicular colloidal carriers have been investigated, with interesting results in terms of increased pharmacological activity, plasma half-life, and tumor localization, in addition to decreased side effects. This review focuses on the specific approaches used, based on the encapsulation of gemcitabine in liposomes, with particular attention to the results obtained during the last 5 years. These approaches represent a valid starting point in the attempt to obtain a novel, commercializable drug formulation as already achieved for liposomal doxorubicin (Doxil®, Caelyx®.Keywords: gemcitabine, liposomes, multidrug, poly(ethylene glycol, tumors

  15. Gemcitabine for the treatment of advanced nonsmall cell lung cancer

    Directory of Open Access Journals (Sweden)

    Luca Toschi

    2009-08-01

    Full Text Available Luca Toschi1, Federico Cappuzzo21Dana-Farber Cancer Institute, Medical Oncology, Boston, MA, USA; 2Istituto Clinico Humanitas IRCCS, Department of Onco-Hematology, Rozzano, ItalyAbstract: Gemcitabine is a pyrimidine nucleoside antimetabolite agent which is active in several human malignancies, including nonsmall cell lung cancer (NSCLC. Because of its acceptable toxicity profile, with myelosuppression being the most common adverse event, gemcitabine can be safely combined with a number of cytotoxic agents, including platinum derivatives and new-generation anticancer compounds. In fact, the combination of gemcitabine and cisplatin is a first-line treatment for patients with advanced NSCLC, pharmacoeconomic data indicating that it represents the most cost-effective regimen among platinum-based combinations with thirdgeneration cytotoxic drugs. The drug has been investigated in the context of nonplatinum-based regimens in a number of prospective clinical trials, and might provide a suitable alternative for patients with contraindications to platinum. Recently, gemcitabine-based doublets have been successfully tested in association with novel targeted agents with encouraging results, providing further evidence for the role of the drug in the treatment of NSCLC. In the last few years several attempts have been pursued in order to identify molecular predictors of gemcitabine activity, and recent data support the feasibility of genomic-based approaches to customize treatment with the ultimate goal of improving patient outcome.Keywords: gemcitabine, chemotherapy, pharmacoeconomics, nonsmall cell lung cancer

  16. Substances with biological activity of vitamin B12 formed during cultivation of Propionibacterium freudenreichii in the presence of precursors (short communications).

    Science.gov (United States)

    Rauch, P; Králová, B

    1986-01-01

    The papers of Kolhouse et al. and Cooper et al. described the occurrence of vitamin B12 analogues of unknown origin in blood serum. Some of these analogues may be derived from slaughter cattle raised on feed supplemented with vitamins and minerals, as was observed by Allen. Herbert et al. found vitamin B12 analogues in multivitamin preparations produced in U.S.A., and Kanazawa et al. in human liver, red cells and brain. It is not clear so far, if and how do vitamin B12 analogues interfere with vitamin B12 metabolism. When P. freudenreichii was cultivated in the presence of o-phenylenediamine and 5,6-dimethylbenzimidazole, which may be considered precursors as well as antimetabolites of vitamin B12, the stimulation of biosynthesis of substances with biological activity of vitamin B12 took place. Various signs show that these substances are probably vitamin B12 analogues. During stimulated and nonstimulated production of vitamin B12 by P. freudenreichii, two substances with vitamin B12 biological activity have always been obtained. Their relation was not stable and differed according to the conditions of cultivation. Every attempt to stimulate the biosynthesis of vitamin B12 resulted in the suppression of production of the substance with higher molecular weight, even if the biosynthesis of cobalamin (lower molecular weight) was increased. In our note we want to pay attention to the character of substances arising in the stimulated biosynthesis.

  17. Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting.

    Science.gov (United States)

    Wang, Hao; Mann, Paul A; Xiao, Li; Gill, Charles; Galgoci, Andrew M; Howe, John A; Villafania, Artjohn; Barbieri, Christopher M; Malinverni, Juliana C; Sher, Xinwei; Mayhood, Todd; McCurry, Megan D; Murgolo, Nicholas; Flattery, Amy; Mack, Matthias; Roemer, Terry

    2017-05-18

    Riboswitches are bacterial-specific, broadly conserved, non-coding RNA structural elements that control gene expression of numerous metabolic pathways and transport functions essential for cell growth. As such, riboswitch inhibitors represent a new class of potential antibacterial agents. Recently, we identified ribocil-C, a highly selective inhibitor of the flavin mononucleotide (FMN) riboswitch that controls expression of de novo riboflavin (RF, vitamin B2) biosynthesis in Escherichia coli. Here, we provide a mechanistic characterization of the antibacterial effects of ribocil-C as well as of roseoflavin (RoF), an antimetabolite analog of RF, among medically significant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis. We provide genetic, biophysical, computational, biochemical, and pharmacological evidence that ribocil-C and RoF specifically inhibit dual FMN riboswitches, separately controlling RF biosynthesis and uptake processes essential for MRSA growth and pathogenesis. Such a dual-targeting mechanism is specifically required to develop broad-spectrum Gram-positive antibacterial agents targeting RF metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. S-adenosyl-L-methionine decarboxylase of Acanthamoeba castellanii (Neff): purification and properties.

    Science.gov (United States)

    Hugo, E R; Byers, T J

    1993-01-01

    S-Adenosyl-L-methionine decarboxylase (AdoMetDC) has been purified to near homogeneity from the Neff strain of Acanthamoeba castellanii. The holoenzyme molecular mass is 88.8 kDa, including two copies each of a 32.8 kDa alpha-subunit and a 10-15 kDa beta-subunit. The alpha-subunit contains the active site. It has an N-terminal pyruvoyl group, and the first 19 amino acids are 63 and 74% identical with comparable sequences from yeast and mammals, respectively. The apparent Km for S-adenosylmethionine (AdoMet) in the presence of 2 mM putrescine was 30.0 microM. The enzyme was stimulated 2-fold by putrescine, but was unaffected by spermidine. It was inhibited by the following anti-metabolites, listed with their Ki values: Berenil (0.17 microM), pentamidine (19.4 microM), propamidine (334 microM), hydroxystilbamidine (357 microM), methylglyoxal bis(guanylhydrazone) (604 microM) and ethidium bromide (1.3 mM). Activity of the enzyme fell to undetectable levels during cell differentiation (encystment). Images Figure 2 PMID:8216217

  19. Inhibition of DNA and protein synthesis in UV-irradiated mouse skin by 2-difluoromethylornithine, methylglyoxal bis(guanylhydrazone), and their combination

    International Nuclear Information System (INIS)

    Kaepyaho, K.; Lauharanta, J.; Jaenne, J.

    1983-01-01

    Exposure of mouse skin to UVB irradiation greatly enhanced the biosynthesis and accumulation of putrescine and spermidine before or concomitantly with stimulation of epidermal macromolecular (DNA and protein) synthesis. Topical treatment of UV-exposed skin with 2 inhibitors of polyamine biosynthesis, 2-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) (MGBG) prevented the enhanced epidermal accumulation of polyamines, especially spermidine, and also inhibited the incorporation of radioactive precursors into DNA and protein. When applied in combination, these 2 antimetabolites of polyamines produced an inhibition of macromolecular synthesis that was at least additive: [ 3 H]thymidine incorporation decreased by 80% and [ 14 C]leucine incorporation by 44% as compared with the UVB-irradiated control mice. A slight decrease in the ratio of [ 3 H]histidine/[ 14 C]leucine incorporation indicated that protein synthesis of the differentiating cell layers was also affected by the inhibitors. The effects of the combined DFMO and MGBG treatment were partially reversed by concomitant topical application of spermidine

  20. Diethylglyoxal bis(guanylhydrazone): a novel highly potent inhibitor of S-adenosylmethionine decarboxylase with promising properties for potential chemotherapeutic use.

    Science.gov (United States)

    Elo, H; Mutikainen, I; Alhonen-Hongisto, L; Laine, R; Jänne, J

    1988-07-01

    Diethylglyoxal bis(guanylhydrazone) (DEGBG), a novel analog of the antileukemic agent methylglyoxal bis(guanylhydrazone) (MGBG) was synthesized. It was found to be the most powerful inhibitor of yeast S-adenosylmethionine decarboxylase (AdoMetDC) so far studied (Ki approx. 9 nM). This property, together with the finding that the compound is a weaker inhibitor of intestinal diamine oxidase than are MGBG and its glyoxal, ethylglyoxal and ethylmethylglyoxal analogs, makes the compound a promising candidate as a polyamine antimetabolite for chemotherapy studies. DEGBG was also found to potentiate the antiproliferative effect of the ornithine decarboxylase inhibitor alpha-difluoromethyl ornithine against mouse L1210 leukemia cells in vitro. DEGBG increased several-fold the intracellular putrescine concentration of cultured L1210 cells, just as MGBG and its ethylglyoxal analog are known to do. The results strongly suggest that DEGBG is worth further studies. Combined with previous studies, they also made possible the construction of some empirical rules concerning the structure-activity relationships of bis(guanylhydrazone) type inhibitors of AdoMetDC. The identity of DEGBG was confirmed by a single-crystal X-ray analysis and by 1H- and 13C-NMR spectroscopy. It consisted of the same isomer as MGBG and several of its analogs are known to consist of.

  1. Inhibition of DNA and protein synthesis in UV-irradiated mouse skin by 2-difluoromethylornithine, methylglyoxal bis(guanylhydrazone), and their combination

    Energy Technology Data Exchange (ETDEWEB)

    Kaepyaho, K.; Lauharanta, J.; Jaenne, J.

    1983-08-01

    Exposure of mouse skin to UVB irradiation greatly enhanced the biosynthesis and accumulation of putrescine and spermidine before or concomitantly with stimulation of epidermal macromolecular (DNA and protein) synthesis. Topical treatment of UV-exposed skin with 2 inhibitors of polyamine biosynthesis, 2-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) (MGBG) prevented the enhanced epidermal accumulation of polyamines, especially spermidine, and also inhibited the incorporation of radioactive precursors into DNA and protein. When applied in combination, these 2 antimetabolites of polyamines produced an inhibition of macromolecular synthesis that was at least additive: (/sup 3/H)thymidine incorporation decreased by 80% and (/sup 14/C)leucine incorporation by 44% as compared with the UVB-irradiated control mice. A slight decrease in the ratio of (/sup 3/H)histidine/(/sup 14/C)leucine incorporation indicated that protein synthesis of the differentiating cell layers was also affected by the inhibitors. The effects of the combined DFMO and MGBG treatment were partially reversed by concomitant topical application of spermidine.

  2. Trabeculectomía con 5-fluorouracilo transoperatorio Trabeculectomy with transoperative 5-Fluorouracil

    Directory of Open Access Journals (Sweden)

    Juan R Alegre Núñez

    2002-12-01

    Full Text Available En un estudio sobre 70 ojos operados de glaucoma, a los que se les realizó una trabeculectomía convencional con uso de 5-fluorouracilo transoperatorio, se excluyeron los ojos con alto riesgo de cierre posoperatorio de la fistula y se les realizaron varios controles posoperatorios hasta el 1½ año. Se observaron complicaciones propias de la cirugía filtrante sin antimetabolitos, que mejoraron con el tratamiento habitual, y se logró un control adecuado de la presión intraocular sin necesidad de reoperaciones o de medicación hipotensora, lo que hace pensar en resultados prometedores con este tipo de cirugíaIn a study of 70 eyes operated on of glaucoma that underwent conventional trabeculectomy with the use of transoperative 5-Fluorouracil, those eyes at high risk for postoperative closure of the fistula were excluded and subjected to several postoperative controls during a year and a half. Complications characteristic of filtering surgery without antimetabolites that improved with the usual treatment were observed. An adequate control of the intraocular pressure was achieved without reoperations or hypotensive drugs, which makes us think about encouraging future results with this type of surgery

  3. Antifungal susceptibility profiles of 1698 yeast reference strains revealing potential emerging human pathogens.

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    Marie Desnos-Ollivier

    Full Text Available New molecular identification techniques and the increased number of patients with various immune defects or underlying conditions lead to the emergence and/or the description of novel species of human and animal fungal opportunistic pathogens. Antifungal susceptibility provides important information for ecological, epidemiological and therapeutic issues. The aim of this study was to assess the potential risk of the various species based on their antifungal drug resistance, keeping in mind the methodological limitations. Antifungal susceptibility profiles to the five classes of antifungal drugs (polyens, azoles, echinocandins, allylamines and antimetabolites were determined for 1698 yeast reference strains belonging to 992 species (634 Ascomycetes and 358 Basidiomycetes. Interestingly, geometric mean minimum inhibitory concentrations (MICs of all antifungal drugs tested were significantly higher for Basidiomycetes compared to Ascomycetes (p<0.001. Twenty four strains belonging to 23 species of which 19 were Basidiomycetes seem to be intrinsically "resistant" to all drugs. Comparison of the antifungal susceptibility profiles of the 4240 clinical isolates and the 315 reference strains belonging to 53 shared species showed similar results. Even in the absence of demonstrated in vitro/in vivo correlation, knowing the in vitro susceptibility to systemic antifungal agents and the putative intrinsic resistance of yeast species present in the environment is important because they could become opportunistic pathogens.

  4. PRISM 3: expanded prediction of natural product chemical structures from microbial genomes.

    Science.gov (United States)

    Skinnider, Michael A; Merwin, Nishanth J; Johnston, Chad W; Magarvey, Nathan A

    2017-07-03

    Microbial natural products represent a rich resource of pharmaceutically and industrially important compounds. Genome sequencing has revealed that the majority of natural products remain undiscovered, and computational methods to connect biosynthetic gene clusters to their corresponding natural products therefore have the potential to revitalize natural product discovery. Previously, we described PRediction Informatics for Secondary Metabolomes (PRISM), a combinatorial approach to chemical structure prediction for genetically encoded nonribosomal peptides and type I and II polyketides. Here, we present a ground-up rewrite of the PRISM structure prediction algorithm to derive prediction of natural products arising from non-modular biosynthetic paradigms. Within this new version, PRISM 3, natural product scaffolds are modeled as chemical graphs, permitting structure prediction for aminocoumarins, antimetabolites, bisindoles and phosphonate natural products, and building upon the addition of ribosomally synthesized and post-translationally modified peptides. Further, with the addition of cluster detection for 11 new cluster types, PRISM 3 expands to detect 22 distinct natural product cluster types. Other major modifications to PRISM include improved sequence input and ORF detection, user-friendliness and output. Distribution of PRISM 3 over a 300-core server grid improves the speed and capacity of the web application. PRISM 3 is available at http://magarveylab.ca/prism/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  5. Effects of Resveratrol Supplementation on  Methotrexate Chemotherapy-Induced Bone Loss.

    Science.gov (United States)

    Lee, Alice M C; Shandala, Tetyana; Soo, Pei Pei; Su, Yu-Wen; King, Tristan J; Chen, Ke-Ming; Howe, Peter R; Xian, Cory J

    2017-03-09

    Intensive cancer chemotherapy is known to cause bone defects, which currently lack treatments. This study investigated the effects of polyphenol resveratrol (RES) in preventing bone defects in rats caused by methotrexate (MTX), a commonly used antimetabolite in childhood oncology. Young rats received five daily MTX injections at 0.75 mg/kg/day. RES was orally gavaged daily for seven days prior to, and during, five-day MTX administration. MTX reduced growth plate thickness, primary spongiosa height, trabecular bone volume, increased marrow adipocyte density, and increased mRNA expression of the osteogenic, adipogenic, and osteoclastogenic factors in the tibial bone. RES at 10 mg/kg was found not to affect bone health in normal rats, but to aggravate the bone damage in MTX-treated rats. However, RES supplementation at 1 mg/kg preserved the growth plate, primary spongiosa, bone volume, and lowered the adipocyte density. It maintained expression of genes involved in osteogenesis and decreased expression of adipogenic and osteoclastogenic factors. RES suppressed osteoclast formation ex vivo of bone marrow cells from the treated rats. These data suggest that MTX can enhance osteoclast and adipocyte formation and cause bone loss, and that RES supplementation at 1 mg/kg may potentially prevent these bone defects.

  6. Comparative Genomic Analyses of Multiple Pseudomonas Strains Infecting Corylus avellana Trees Reveal the Occurrence of Two Genetic Clusters with Both Common and Distinctive Virulence and Fitness Traits.

    Directory of Open Access Journals (Sweden)

    Simone Marcelletti

    Full Text Available The European hazelnut (Corylus avellana is threatened in Europe by several pseudomonads which cause symptoms ranging from twig dieback to tree death. A comparison of the draft genomes of nine Pseudomonas strains isolated from symptomatic C. avellana trees was performed to identify common and distinctive genomic traits. The thorough assessment of genetic relationships among the strains revealed two clearly distinct clusters: P. avellanae and P. syringae. The latter including the pathovars avellanae, coryli and syringae. Between these two clusters, no recombination event was found. A genomic island of approximately 20 kb, containing the hrp/hrc type III secretion system gene cluster, was found to be present without any genomic difference in all nine pseudomonads. The type III secretion system effector repertoires were remarkably different in the two groups, with P. avellanae showing a higher number of effectors. Homologue genes of the antimetabolite mangotoxin and ice nucleation activity clusters were found solely in all P. syringae pathovar strains, whereas the siderophore yersiniabactin was only present in P. avellanae. All nine strains have genes coding for pectic enzymes and sucrose metabolism. By contrast, they do not have genes coding for indolacetic acid and anti-insect toxin. Collectively, this study reveals that genomically different Pseudomonas can converge on the same host plant by suppressing the host defence mechanisms with the use of different virulence weapons. The integration into their genomes of a horizontally acquired genomic island could play a fundamental role in their evolution, perhaps giving them the ability to exploit new ecological niches.

  7. Factors modifying 3-aminobenzamide cytotoxicity in normal and repair-deficient human fibroblasts

    International Nuclear Information System (INIS)

    Boorstein, R.J.; Pardee, A.B.

    1984-01-01

    3-Aminobenzamide (3-AB), an inhibitor of poly(ADP-ribosylation), is lethal to human fibroblasts with damaged DNA. Its cytotoxicity was determined relative to a number of factors including the types of lesions, the kinetics of repair, and the availability of alternative repair systems. A variety of alkylating agent, UV or gamma irradiation, or antimetabolites were used to create DNA lesions. 3-AB enhanced lethality with monofunctional alkylating agents only. Within this class of compounds, methylmethanesulfonate (MMS) treatments made cells more sensitive to 3-AB than did treatment with methylnitrosourea (MNU) or methylnitronitrosoguanidine (MNNG). 3-AB interfered with a dynamic repair process lasting several days, since human fibroblasts remained sensitive to 3-AB for 36-48 hours following MMS treatment. During this same interval 3-AB caused these cells to arrest in G 2 phase. Alkaline elution analysis also revealed that this slow repair was delayed further by 3-AB. Human mutant cell defective in DNA repair differed in their responses to 3-AB. Greater lethality with 3-AB could be dependent on inability of the mutant cells to repair damage by other processes

  8. Role of hydroxycarbamide in prevention of complications in patients with sickle cell disease

    Directory of Open Access Journals (Sweden)

    NM Wiles

    2009-09-01

    Full Text Available NM Wiles, J HowardDepartment of Haematology, St Thomas’ Hospital, Westminster, Bridge Road, London, SE1 7EH, UKAbstract: Sickle cell disease (SCD is a genetically inherited condition caused by a point mutation in the beta globin gene. This results in the production of the abnormal hemoglobin, sickle hemoglobin (HbS. Hydroxycarbamide, is an antimetabolite/cytotoxic which works by inhibiting ribonucleotide reductase, blocking the synthesis of DNA and arresting cells in the S phase. In sickle cell anemia, it promotes fetal hemoglobin (HbF synthesis, improves red cell hydration, decreases neutrophil and platelet count, modifies red cell endothelial cell interactions and acts as a nitric oxide donor. Trials have shown the clinical benefit of hydroxycarbamide in a subpopulation of adult patients with SCD, with a 44% reduction in the median annual rate of painful crises, a decrease in the incidence of acute chest syndrome and an estimated 40% reduction in overall mortality over a 9-year observational period. Its use in pediatrics has also been well established; trials have shown it is well tolerated and does not impair growth or development. In addition it decreases the number and duration of hospital attendences. A number of emerging uses of hydroxycarbamide currently are being investigated, such as stroke prevention.Keywords: sickle cell anemia, hydroxycarbamide, hydroxyurea, maximum tolerated dose, vaso-occlusive crisis

  9. The mbo operon is specific and essential for biosynthesis of mangotoxin in Pseudomonas syringae.

    Science.gov (United States)

    Carrión, Víctor J; Arrebola, Eva; Cazorla, Francisco M; Murillo, Jesús; de Vicente, Antonio

    2012-01-01

    Mangotoxin is an antimetabolite toxin produced by certain Pseudomonas syringae pv. syringae strains. This toxin is an oligopeptide that inhibits ornithine N-acetyl transferase, a key enzyme in the biosynthesis of ornithine and arginine. Previous studies have reported the involvement of the putative nonribosomal peptide synthetase MgoA in virulence and mangotoxin production. In this study, we analyse a new chromosomal region of P. syringae pv. syringae UMAF0158, which contains six coding sequences arranged as an operon (mbo operon). The mbo operon was detected in only mangotoxin-producing strains, and it was shown to be essential for the biosynthesis of this toxin. Mutants in each of the six ORFs of the mbo operon were partially or completely impaired in the production of the toxin. In addition, Pseudomonas spp. mangotoxin non-producer strains transformed with the mbo operon gained the ability to produce mangotoxin, indicating that this operon contains all the genetic information necessary for mangotoxin biosynthesis. The generation of a single transcript for the mbo operon was confirmed and supported by the allocation of a unique promoter and Rho-independent terminator. The phylogenetic analysis of the P. syringae strains harbouring the mbo operon revealed that these strains clustered together.

  10. Chemiclearance of food irradiation process: Its scientific basis

    International Nuclear Information System (INIS)

    Brynjolfsson, A.

    1981-01-01

    Irradiation can facilitate preservation and distribution of food; it can reduce the need for chemical additives and pesticides; and it can reduce the overall use of energy. Often, industry must make changes because of seasonal variation in supply. Application of food irradiation will be difficult, therefore, unless industry can adjust to these changes, which require a broad clearance, or that food irradiation be cleared as a process. Basic to such broad clearance is a thorough understanding of the changes that take place so that the results of animal feeding studies can be extrapolated to foods similar to those used in the animal feeding studies. Such extrapolation is sometimes called chemiclearance. The extensive research on the safety of irradiated foods is summarized and the following major categories discussed: (a) theory of interaction of radiation with food; (b) chemical analysis of the radiolytic products and measurements of their yields as a function of the chemical composition of the food, temperature, dose, and dose-rates; (c) toxicological evaluation of the radiolytic compounds; and (d) toxicological evaluation of short-term and long-term animal feeding studies, mutagenicity studies, teratogenicity studies, and anti-metabolite studies. (author)

  11. Elevated Levels of DNA Strand Breaks Induced by a Base Analog in the Human Cell Line with the P32T ITPA Variant

    Science.gov (United States)

    Waisertreiger, Irina S.-R.; Menezes, Miriam R.; Randazzo, James; Pavlov, Youri I.

    2010-01-01

    Base analogs are powerful antimetabolites and dangerous mutagens generated endogenously by oxidative stress, inflammation, and aberrant nucleotide biosynthesis. Human inosine triphosphate pyrophosphatase (ITPA) hydrolyzes triphosphates of noncanonical purine bases (i.e., ITP, dITP, XTP, dXTP, or their mimic: 6-hydroxyaminopurine (HAP) deoxynucleoside triphosphate) and thus regulates nucleotide pools and protects cells from DNA damage. We demonstrate that the model purine base analog HAP induces DNA breaks in human cells and leads to elevation of levels of ITPA. A human polymorphic allele of the ITPA, 94C->A encodes for the enzyme with a P32T amino-acid change and leads to accumulation of nonhydrolyzed ITP. The polymorphism has been associated with adverse reaction to purine base-analog drugs. The level of both spontaneous and HAP-induced DNA breaks is elevated in the cell line with the ITPA P32T variant. The results suggested that human ITPA plays a pivotal role in the protection of DNA from noncanonical purine base analogs. PMID:20936128

  12. Glucose-mediated repression of autolysis and conidiogenesis in Emericella nidulans.

    Science.gov (United States)

    Emri, Tamás; Molnár, Zsolt; Veres, Tünde; Pusztahelyi, Tünde; Dudás, Gábor; Pócsi, István

    2006-10-01

    Glucose-mediated repression of autolysis and sporulation was studied in submerged Emericellanidulans (anam. Aspergillus nidulans) cultures. Null mutation of the creA gene, which encodes the major carbon catabolite repressor CreA in E. nidulans, resulted in a hyperautolytic phenotype characterized by increased extracellular hydrolase production and dry cell mass declination. Interestingly, glucose, as well as the glucose antimetabolite 2-deoxy-d-glucose, repressed autolysis and sporulation in both the control and the creA null mutant strains suggesting that these processes were also subjected to CreA-independent carbon regulation. For example, the glucose-mediated, but CreA-independent, repression of the sporulation transcription factor BrlA was likely to contribute to the negative regulation of conidiogenesis by glucose. Although CreA played a prominent role in the regulation of autolysis via the repression of genes encoding important autolytic hydrolases like ChiB chitinase and PrtA protease the age-related production of the chitinase activity was also negatively affected by the down-regulation of brlA expression. However, neither CreA-dependent nor CreA-independent elements of carbon regulation affected the initiation and regulation of cell death in E. nidulans under carbon starvation.

  13. Assessment of laser-induced release of drugs from liposomes: An in vitro study

    International Nuclear Information System (INIS)

    Khoobehi, B.; Char, C.A.; Peyman, G.A.

    1990-01-01

    We evaluated the characteristics of laser-induced release of an antimetabolite (cytosine arabinoside) from temperature-sensitive liposomes. Previous work had shown that a laser would induce breakdown of liposomes when a dye was encapsulated within the liposomes. The present investigation was performed to determine if release could be induced from liposomes that did not contain dye. In vitro, dynamic studies of the release of the drug from liposomes diluted in blood (flowing in a capillary tube at 40 microns/min) were conducted using an argon dye laser operating either in the blue-green mode (488/514 nm) or in the dye mode (577 nm). A radio-labeled marker was used to monitor the drug release. The results showed that the drug could indeed be released from liposomes that did not contain dye, at energy levels that are not likely to be harmful to the tissue. At identical power levels, the release of the drug was greater at 577 nm than at 488/514 nm, probably owing to the greater light absorbance of hemoglobin at the longer wavelength. The results indicate the potential for the site-specific release of a variety of molecules in the ocular vasculature

  14. Role of oxidative stress mediated by glutathione-s-transferase in thiopurines' toxic effects.

    Science.gov (United States)

    Pelin, Marco; De Iudicibus, Sara; Fusco, Laura; Taboga, Eleonora; Pellizzari, Giulia; Lagatolla, Cristina; Martelossi, Stefano; Ventura, Alessandro; Decorti, Giuliana; Stocco, Gabriele

    2015-06-15

    Azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) are antimetabolite drugs, widely used as immunosuppressants and anticancer agents. Despite their proven efficacy, a high incidence of toxic effects in patients during standard-dose therapy is recorded. The aim of this study is to explain, from a mechanistic point of view, the clinical evidence showing a significant role of glutathione-S-transferase (GST)-M1 genotype on AZA toxicity in inflammatory bowel disease patients. To this aim, the human nontumor IHH and HCEC cell lines were chosen as predictive models of the hepatic and intestinal tissues, respectively. AZA, but not 6-MP and 6-TG, induced a concentration-dependent superoxide anion production that seemed dependent on GSH depletion. N-Acetylcysteine reduced the AZA antiproliferative effect in both cell lines, and GST-M1 overexpression increased both superoxide anion production and cytotoxicity, especially in transfected HCEC cells. In this study, an in vitro model to study thiopurines' metabolism has been set up and helped us to demonstrate, for the first time, a clear role of GST-M1 in modulating AZA cytotoxicity, with a close dependency on superoxide anion production. These results provide the molecular basis to shed light on the clinical evidence suggesting a role of GST-M1 genotype in influencing the toxic effects of AZA treatment.

  15. An inhibitor of potentially lethal damage (PLD) repair reduces the frequency of γ-ray mutations in cultured Chinese hamster V79 cells

    International Nuclear Information System (INIS)

    Yokoiyama, A.; Kada, T.; Kuroda, Y.

    1992-01-01

    Cordycepin (3'-deoxyadenosine, 3 - dA) is an RNA antimetabolite and a radiosensitizer in cultured mammalian cells. In the present paper, the effects of 3'-dA on γ-ray-induced lethality and 6-thioguanine (6TG)-resistant mutations in cultured Chinese hamster V79 cells were examined. 3'-dA had the effect of sensitizing the lethality induced by γ-rays. The potentially lethal damage (PLD) repair produced by post-incubation cells in Hanks' solution after γ-irradiation was almost completely suppressed by 5x10 -5 M 3'-dA. When cells were irradiated with 10 Gy γ-rays and incubated with 3'-dA for 5 h, the frequency of 6TG-resistant mutations induced by γ-rays decreased to 1/6 of that of the irradiated cells incubated without 3'-dA. The decrease in the frequency of γ-ray-induced mutations was dependent on the length of incubation time with 3'-dA. It is suggested that the inhibition of PLD repair by 3'-dA may be that of error-prone repair. (author). 26 refs.; 5 figs

  16. A phase II study of biweekly pemetrexed and gemcitabine in patients with metastatic breast cancer.

    Science.gov (United States)

    Dent, Susan F; Gertler, Stan; Verma, Shailendra; Segal, Roanne; Young, Vince; Goel, Rakesh; Keller, Oliver; Canil, Christina; Iscoe, Neill

    2010-02-01

    Pemetrexed (PEM) is a novel folate antimetabolite which inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. This phase II study was designed to assess the efficacy of Gemcitabine (GEM) and PEM given in a novel schedule in metastatic breast cancer (MBC) patients. Eligible patients had MBC and received one prior chemotherapy regimen for metastatic disease; Performance status (PS) 0-2; measurable disease (RECIST criteria). PEM(500 mg/m2) was administered intravenously (IV) over 10 min prior to GEM(1,500 mg/m2) IV given over 30 min on day 1 every 14 days. Median age of the 16 patients in the study was 54 years (range 33-77). Fourteen patients had a PS of 0/1 and were evaluable for response. There were no reported complete or partial responses, seven patients with stable disease, six patients with disease progression and one patient with unknown response. Most common toxicities were skin rash: Grade 1/2(8) and Grade 3/4(1). Grade 3/4 non-hematological toxicities were fatigue(1); anorexia(1); pneumonia(1); peripheral ischemia(1) and elevation of liver transaminases(1). Three patients experienced febrile neutropenia (FN). This study did not meet the predefined criteria to proceed with additional accrual. This regimen of PEM and GEM showed no clinical activity in the dose and schedule tested.

  17. Increasing the radiosensitivity of tumours in an hypoxic environment using inhibitors of the pentose phosphate pathway

    International Nuclear Information System (INIS)

    Sahasrabudhe, M.B.; Bhonsle, S.R.; Krishnamurti, K.; Tilak, B.D.

    1977-01-01

    Rapidly growing tumours contain few blood vessels in the tumour mass. Cells in such tumours obtain nutrients and oxygen from the periphery by diffusion, resulting in a diminishing oxygen and nutrient gradient from the periphery to centre of the tumour mass. In normal tissues, oxygen is utilized via a tricarboxylic acid (TCA) cycle; in tumour cells oxygen is utilized via a hexose monophosphate (HMP) pathway and through the TCA cycle at a 30% reduced level. Interference with the HMP pathway selectively inhibits the utilization of oxygen by tumour cells, thus increasing the availability of oxygen to hypoxic cells situated deeper in the tumour mass. This effect has been exploited for increasing the radiosensitivity of tumour cells situated in an hypoxic environment. The influence of sixteen potential antimetabolites on the HMP pathway has been studied. Of these, six compounds, namely, (1) 2-carboxy 5-hydroxymethyl thiophene, (2) the sodium salt of 2:5 dicarbethoxy 3:4 dihydroxy thiophene, (3) the dihydrazide of 2:5 dicarboxy thiophene, (4) the dihydrazide of 3:4 dimethoxy 2:5 dicarboxy thiophene, (5) trithiocyanuric acid, and (6) cyanuric trithioglycollic acid showed an inhibiting effect on the HMP pathway without any influence on the TCA cycle. Influence of administration of compounds (1), (2) and (4) prior to radiation on the growth of transplanted fibrosarcomas in mice has been studied and is reported here. These three compounds showed marked potentiation of radiosensitivity of tumours. (author)

  18. Cellular mechanisms in drug - radiation interaction

    International Nuclear Information System (INIS)

    Trott, K.R.

    1979-01-01

    Some cytotoxic drugs, especially those belonging to the group of antibiotics and antimetabolites, sensitize the cells having survived drug treatment to the subsequent irradiation by either increasing the slope of the radiation dose response curves or by decreasing extrapolation number. Bleomycin was found to interact with radiation in L-cells and FM3A cells, but not in HeLa-cells. The data with EMT-6 cells suggest that the interaction depends on drug dose: no interaction occurred after the exposure to bleomycin which killed only 20 - 40% of the cells; yet the exposure to bleomycin which killed 90% of the cells in addition sensitized the surviving cells by the DMF of 1.3. The sensitization found 24 hr after the exposure of HeLa cells to methotrexate was due to cell synchronization. Other cytostatic drugs were found to synchronize proliferating cells even better. Therefore, the fluctuation of radiosensitivity has been commonly observed after the termination of exposure to these drugs. Preirradiation may lead to the change in drug dose response curves. The recruitment of resting cells into cycle occurs hours or days later, in some irradiated normal and malignant tissues. Since many cytostatic drugs are far more active in proliferating cells than in resting cells, the recruitment after irradiation may lead to the sudden increase in drug sensitivity, days after the irradiation. No single, simple theory seems to exist to classify and predict the cellular response to combined modality treatment. (Yamashita, S.)

  19. Comparative Genomic Analyses of Multiple Pseudomonas Strains Infecting Corylus avellana Trees Reveal the Occurrence of Two Genetic Clusters with Both Common and Distinctive Virulence and Fitness Traits

    Science.gov (United States)

    Marcelletti, Simone; Scortichini, Marco

    2015-01-01

    The European hazelnut (Corylus avellana) is threatened in Europe by several pseudomonads which cause symptoms ranging from twig dieback to tree death. A comparison of the draft genomes of nine Pseudomonas strains isolated from symptomatic C. avellana trees was performed to identify common and distinctive genomic traits. The thorough assessment of genetic relationships among the strains revealed two clearly distinct clusters: P. avellanae and P. syringae. The latter including the pathovars avellanae, coryli and syringae. Between these two clusters, no recombination event was found. A genomic island of approximately 20 kb, containing the hrp/hrc type III secretion system gene cluster, was found to be present without any genomic difference in all nine pseudomonads. The type III secretion system effector repertoires were remarkably different in the two groups, with P. avellanae showing a higher number of effectors. Homologue genes of the antimetabolite mangotoxin and ice nucleation activity clusters were found solely in all P. syringae pathovar strains, whereas the siderophore yersiniabactin was only present in P. avellanae. All nine strains have genes coding for pectic enzymes and sucrose metabolism. By contrast, they do not have genes coding for indolacetic acid and anti-insect toxin. Collectively, this study reveals that genomically different Pseudomonas can converge on the same host plant by suppressing the host defence mechanisms with the use of different virulence weapons. The integration into their genomes of a horizontally acquired genomic island could play a fundamental role in their evolution, perhaps giving them the ability to exploit new ecological niches. PMID:26147218

  20. Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies

    International Nuclear Information System (INIS)

    Postiglione, Ilaria; Chiaviello, Angela; Palumbo, Giuseppe

    2011-01-01

    Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors

  1. Management of glaucoma in pregnancy: risks or choices, a dilemma?

    Directory of Open Access Journals (Sweden)

    Harinder Singh Sethi

    2016-12-01

    Full Text Available The treatment of glaucoma in and around pregnancy offers the unique challenge of balancing the risk of vision loss to the mother as against the potential harm to the fetus or newborn. Most anti-glaucoma drugs (i.e. beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors topical and systemic, cholinergics, anticholinesterases, and apraclonidine are considered category C agents and ophthalmologists are usually limited to treating patients with the category B drugs of brimonidine and dipivefrin. Brimonidine is generally the preferred first-line drug in the first, second and early third trimester. Late in the third trimester, brimonidine should be discontinued because it can induce central nervous system depression in newborns wherein topical carbonic anhydrase inhibitors may be the optimal choice. Glaucoma surgery can be performed with caution in second and third trimester if the patients have a strong indication for the procedure. However, anesthetics, sedative agents, and antimetabolites still have potential risk for the fetus. Argon laser trabeculoplasty (ALT or selective laser trabeculoplasty (SLT is an alternative treatment that can be performed in all trimesters. Carbonic anhydrase inhibitors and β-blockers are certified by the American Academy of Pediatrics for use during nursing. However, low doses of these medications should be considered when used in the breast feeding period. Optimum treatment for glaucoma in pregnancy must not be withheld so as to prevent any further deterioration in progressive vision loss and quality of life.

  2. 5-Fluorouracil-induced exacerbation of rosacea.

    Science.gov (United States)

    Haddock, Ellen S; Cohen, Philip R

    2016-11-15

    Background Topical 5-fluorouracil (5-FU) is an antineoplastic antimetabolite used for the treatment of actinic keratosis.Purpose A 66-year-old man with erythematotelangiectatic rosacea and biopsy-confirmed actinic keratoses who experienced a rosacea exacerbation after initiating topical 5-FU treatment of his actinic keratoses is described and this adverse event associated with 5-FU is reviewed.Materials and methods Using PubMed.gov the following terms were searched and relevant citations were assessed: rosacea and 5-fluorouracil. 5-FU drug label information and data sheets also were reviewed.ResultsErythematous facial papules developed within a week of starting topical treatment of his actinic keratoses with 5-FU. The lesions resolved within two weeks of discontinuing the medication. Albeit rarely, exacerbation of rosacea by topical 5-FU treatment has been described when 5-FU was introduced as a topical treatment for actinic keratosis.Conclusion Topical 5-FU has been associated with several adverse cutaneous events, including accentuation of rosacea. Although rosacea flares due to topical 5-FU may be uncommon, the incidence may be greater than reflected in the literature. Physicians should be aware of this potential adverse effect in patients in whom they plan to initiate 5-FU therapy.

  3. 5-FU-induced cardiac toxicity - an underestimated problem in radiooncology?

    Directory of Open Access Journals (Sweden)

    Steger Felix

    2012-12-01

    Full Text Available Abstract Background 5-Fluorouracil (5-FU is an antimetabolite, which is frequently used as chemotherapeutic agent for combined chemoradiotherapy. The purpose of this study was to present the clinical course of three patients who developed severe cardiac toxicity by 5-FU and to give a review of the literature on the cardiotoxic potential of 5-FU. Results Cardiotoxicity is a rare, but relevant side effect of fluoropyrimidines. It comprehends a wide spectrum of side effects, from electrocardiogram changes (69% of cardiac events to myocardial infarction (22% and cardiogenic shock (1%. In this case series three patients with cardiotoxic events during chemoradiotherapy including 5-FU, the reaction's characteristics and their influence on further therapy are described. Two of the patients could not be treated with 5-FU any more because they had developed a myocardial ischemia, which was most likely caused by fluorouracil. Another patient, who complained about typical angina pectoris during 5-FU-infusion and had a new left anterior hemiblock, was reexposed with prophylactic administration of nitrendipine. Conclusion Cardiotoxicity caused by 5-FU is an underestimated problem in radiooncology. Especially patients without history of cardiac disease are often treated as out-patients and therefore without cardiac monitoring. Consequently asymptomatic and symptomatic cardiac events may be overlooked. The benefit of prophylactic agents remains unclear, so close cardiac monitoring is the most established method to prevent manifest cardiotoxic events.

  4. 5-FU-induced cardiac toxicity - an underestimated problem in radiooncology?

    International Nuclear Information System (INIS)

    Steger, Felix; Hautmann, Matthias G; Kölbl, Oliver

    2012-01-01

    5-Fluorouracil (5-FU) is an antimetabolite, which is frequently used as chemotherapeutic agent for combined chemoradiotherapy. The purpose of this study was to present the clinical course of three patients who developed severe cardiac toxicity by 5-FU and to give a review of the literature on the cardiotoxic potential of 5-FU. Cardiotoxicity is a rare, but relevant side effect of fluoropyrimidines. It comprehends a wide spectrum of side effects, from electrocardiogram changes (69% of cardiac events) to myocardial infarction (22%) and cardiogenic shock (1%). In this case series three patients with cardiotoxic events during chemoradiotherapy including 5-FU, the reaction's characteristics and their influence on further therapy are described. Two of the patients could not be treated with 5-FU any more because they had developed a myocardial ischemia, which was most likely caused by fluorouracil. Another patient, who complained about typical angina pectoris during 5-FU-infusion and had a new left anterior hemiblock, was reexposed with prophylactic administration of nitrendipine. Cardiotoxicity caused by 5-FU is an underestimated problem in radiooncology. Especially patients without history of cardiac disease are often treated as out-patients and therefore without cardiac monitoring. Consequently asymptomatic and symptomatic cardiac events may be overlooked. The benefit of prophylactic agents remains unclear, so close cardiac monitoring is the most established method to prevent manifest cardiotoxic events

  5. Myeloproliferative disorders in patients with rheumatoid arthritis treated with total body irradiation

    International Nuclear Information System (INIS)

    Urowitz, M.B.; Rider, W.D.

    1985-01-01

    Four patients with refractory rheumatoid arthritis were treated with total body irradiation administered in two sittings, 300 to 400 rads to each half of the body. All four patients had taken antimetabolites prior to receiving total body irradiation, and two continued to use them after total body irradiation. Two patients had taken alkylating agents before, and one had used them after total body irradiation. All patients showed clinical improvement. However, in two patients myeloproliferative disorders developed: a myelodysplastic preleukemia at 40 months after total body irradiation in one and acute myelogenous leukemia at 25 months in the other. Total body irradiation differs from total nodal irradiation in the total dose of irradiation (300 to 400 rads versus 2,000 to 3,000), and in the duration of the therapy (two sittings versus treatment over several weeks to months). Furthermore, the patients in the total body irradiation study frequently used cytotoxic drugs before and/or after irradiation, whereas in one total nodal irradiation study, azathioprine (2 mg/kg per day or less) was permitted, but no other cytotoxic agents were allowed. Rheumatologists may therefore face a binding decision when deciding to treat a patient with rheumatoid arthritis with either a cytotoxic drug or irradiation

  6. Metabolic profiling using HPLC allows classification of drugs according to their mechanisms of action in HL-1 cardiomyocytes

    International Nuclear Information System (INIS)

    Strigun, Alexander; Wahrheit, Judith; Beckers, Simone; Heinzle, Elmar; Noor, Fozia

    2011-01-01

    Along with hepatotoxicity, cardiotoxic side effects remain one of the major reasons for drug withdrawals and boxed warnings. Prediction methods for cardiotoxicity are insufficient. High content screening comprising of not only electrophysiological characterization but also cellular molecular alterations are expected to improve the cardiotoxicity prediction potential. Metabolomic approaches recently have become an important focus of research in pharmacological testing and prediction. In this study, the culture medium supernatants from HL-1 cardiomyocytes after exposure to drugs from different classes (analgesics, antimetabolites, anthracyclines, antihistamines, channel blockers) were analyzed to determine specific metabolic footprints in response to the tested drugs. Since most drugs influence energy metabolism in cardiac cells, the metabolite 'sub-profile' consisting of glucose, lactate, pyruvate and amino acids was considered. These metabolites were quantified using HPLC in samples after exposure of cells to test compounds of the respective drug groups. The studied drug concentrations were selected from concentration response curves for each drug. The metabolite profiles were randomly split into training/validation and test set; and then analysed using multivariate statistics (principal component analysis and discriminant analysis). Discriminant analysis resulted in clustering of drugs according to their modes of action. After cross validation and cross model validation, the underlying training data were able to predict 50%-80% of conditions to the correct classification group. We show that HPLC based characterisation of known cell culture medium components is sufficient to predict a drug's potential classification according to its mode of action.

  7. Vitamin D in combination cancer treatment

    Directory of Open Access Journals (Sweden)

    Yingyu Ma, Donald L. Trump, Candace S. Johnson

    2010-01-01

    Full Text Available As a steroid hormone that regulates mineral homeostasis and bone metabolism, 1α, 25-dihydroxycholecalciferol (calcitriol also has broad spectrum anti-tumor activities as supported by numerous epidemiological and experimental studies. Calcitriol potentiates the anti-tumor activities of multiple chemotherapeutics agents including DNA-damaging agents cisplatin, carboplatin and doxorubicin; antimetabolites 5-fluorouracil, cytarabine, hydroxyurea, cytarabine and gemcitabine; and microtubule-disturbing agents paclitaxel and docetaxel. Calcitriol elicits anti-tumor effects mainly through the induction of cancer cell apoptosis, cell cycle arrest, differentiation, angiogenesis and the inhibition of cell invasiveness by a number of mechanisms. Calcitriol enhances the cytotoxic effects of gamma irradiation and certain antioxidants and naturally derived compounds. Inhibition of calcitriol metabolism by 24-hydroxylase promotes growth inhibition effect of calcitriol. Calcitriol has been used in a number of clinical trials and it is important to note that sufficient dose and exposure to calcitriol is critical to achieve anti-tumor effect. Several trials have demonstrated that safe and feasible to administer high doses of calcitriol through intermittent regimen. Further well designed clinical trials should be conducted to better understand the role of calcitriol in cancer therapy.

  8. Efficacy of total lymphoid irradiation in intractable rheumatoid arthritis. A double-blind, randomized trial

    International Nuclear Information System (INIS)

    Strober, S.; Tanay, A.; Field, E.; Hoppe, R.T.; Calin, A.; Engleman, E.G.; Kotzin, B.; Brown, B.W.; Kaplan, H.S.

    1985-01-01

    Twenty-six patients participated in a randomized, double-blind study of the efficacy of total lymphoid irradiation in the treatment of intractable rheumatoid arthritis. All 26 patients, for whom therapy with gold compounds and penicillamine had failed, would ordinarily have been considered candidates for cytotoxic or antimetabolite drug therapy. Thirteen patients randomly assigned to receive full-dose total lymphoid irradiation (2000 rad) and 11 patients assigned to receive control low-dose total lymphoid irradiation (200 rad) completed radiotherapy. Alleviation of joint disease activity was significantly greater in the high-dose group as judged by morning stiffness, joint tenderness, and functional assessment (global composite score) at 3 and 6 months after radiotherapy. The high-dose group had a marked reduction in both T-lymphocyte function and numbers, but this finding was not observed in the low-dose group. Complications seen in the high-dose but not low-dose group included transient neutropenia, thrombocytopenia, pericarditis, and pleurisy

  9. In Silico Screening, Synthesis and In Vitro Evaluation of Some Quinazolinone and Pyridine Derivatives as Dihydrofolate Reductase Inhibitors for Anticancer Activity

    Directory of Open Access Journals (Sweden)

    A. G. Nerkar

    2009-01-01

    Full Text Available Dihydrofolate reductase (DHFR is the important target for anticancer drugs belonging to the class of antimetabolites as the enzyme plays important role in the de novo purine synthesis. We here report the in silico screening to obtain best fit molecules as DHFR inhibitors, synthesis of some ʻbest fitʼ quinazolinone from 2-phenyl-3-(substituted-benzilidine-amino quinazolinones (Quinazolinone Shiff's bases QSB1-5 and pyridine-4-carbohydrazide Shiff's bases (ISB1-5 derivatives and their in vitro anticancer assay. Synthesis of the molecules was performed using microwave assisted synthesis. The structures of these molecules were elucidated by IR and 1H-NMR. These compounds were then subjected for in vitro anticancer evaluation against five human cancer cell-lines for anticancer cyto-toxicity assay. Methotrexate (MTX was used as standard for this evaluation to give a comparable inhibition of the cell proliferation by DHFR inhibition. Placlitaxel, adriamycin and 5-fluoro-uracil were also used as standard to give a comparable activity of these compounds with other mechanism of anticancer activity. ISB3 (4-(N, N-dimethyl-amino-phenyl Schiff''s base derivative of pyridine carbohydrazide showed equipotent activity with the standards used in in vitro anticancer assay as per the NCI (National Cancer Institute guidelines.

  10. Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK) and FOXO1.

    Science.gov (United States)

    Fodor, Tamás; Szántó, Magdolna; Abdul-Rahman, Omar; Nagy, Lilla; Dér, Ádám; Kiss, Borbála; Bai, Peter

    2016-01-01

    Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK) jointly with methotrexate (MTX), a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.

  11. Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside.

    Science.gov (United States)

    Beckers, Annelies; Organe, Sophie; Timmermans, Leen; Vanderhoydonc, Frank; Deboel, Ludo; Derua, Rita; Waelkens, Etienne; Brusselmans, Koen; Verhoeven, Guido; Swinnen, Johannes V

    2006-09-01

    Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA riboside-induced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of compounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention.

  12. The biochemical basis for l-canavanine tolerance by the tobacco budworm Heliothis virescens (Noctuidae)

    Science.gov (United States)

    Melangeli, Coromoto; Rosenthal, Gerald A.; Dalman, Douglas L.

    1997-01-01

    The tobacco budworm, Heliothis virescens (Noctuidae), a destructive insect pest, is remarkably resistant to l-canavanine, l-2-amino-4-(guanidinooxy)butyric acid, an arginine antimetabolite that is a potent insecticide for nonadapted species. H. virescens employs a constitutive enzyme of the larval gut, known trivially as canavanine hydrolase (CH), to catalyze an irreversible hydrolysis of l-canavanine to l-homoserine and hydroxyguanidine. As such, it represents a new type of hydrolase, one acting on oxygen–nitrogen bonds (EC 3.13.1.1). This enzyme has been isolated from the excised gut of H. virescens and purified to homogeneity; it exhibits an apparent Km value for l-canavanine of 1.1 mM and a turnover number of 21.1 μmol·min−1·μmol−1. This enzyme has a mass of 285 kDa and is composed of two subunits with a mass of 50 kDa or 47.5 kDa. CH has a high degree of specificity for l-canavanine as it cannot function effectively with either l-2-amino-5-(guanidinooxy)pentanoate or l-2-amino-3-(guanidinooxy)propionate, the higher or lower homolog of l-canavanine, respectively. l-Canavanine derivatives such as methyl-l-canavanine, or l-canaline and O-ureido-l-homoserine, are not metabolized significantly by CH. PMID:9122181

  13. [Molecular-kinetic parameters of thiamine enzymes and the mechanism of antivitamin action of hydroxythiamine in animal organisms].

    Science.gov (United States)

    Ostrovskiĭ KuM; Voskoboev, A I; Gorenshtenĭn, B I; Dosta, G A

    1979-09-01

    The molecula-kinetic parameters (Km, Ki) of three thiamine enzymes, e. g. thiamine pyrophosphokinase (EC 2.7.6.2), pyruvate dehydrogenase (EC 1.2.4.1) and transketolase (EC 2.2.1.1) with respect to the effects of the thiamine antimetabolite hydroxythiamine in the whole animal organism have been compared. It has been shown that only the first two enzymes, which interact competitively with the vitamin, antivitamin or their pyrophosphate ethers, obey the kinetic parameters obtained for the purified enzymes in vitro. The anticoenzymic effect of hydroxythiamine pyrophosphate with respect to transketolase is not observed in vivo at maximal concentration of the anticoenzyme in tissues due to the absence of competitive interactions with thiamine pyrophosphate. The incorporation of the true and false coenzymes into transketolase occurs only during de novo transketolase synthesis (the apoform is absent in tissues, with the exception of erythrocytes) and proceeds slowly with a half-life time equal to 24--30 hrs. After a single injection of hydroxythiamine at a large dose (70--400 mg/kg) the maximal inhibition of the transketolase activity in tissues (liver, heart, kidney, muscle, spleen, lungs adrenal grands) manifests itself by the 48th--72nd hour, when the concentration of free hydroxythiamine and its pyrophosphate is minimal and the whole anticoenzyme is tightly bound to the protein, forming the false holoenzyme. The use of hydroxythiamine for inhibition of pyruvate dehydrogenase or transketolase in animal organism is discussed.

  14. TUG1 mediates methotrexate resistance in colorectal cancer via miR-186/CPEB2 axis.

    Science.gov (United States)

    Li, Changfeng; Gao, Yongjian; Li, Yongchao; Ding, Dayong

    2017-09-16

    Colorectal cancer (CRC) is a common malignancy, most of which remain unresponsive to chemotherapy. Methotrexate (MTX) is one of the earliest cytotoxic drugs and serves as an anti-metabolite and anti-folate chemotherapy for various types of cancer. However, MTX resistance prevents its clinical application in cancer therapy. Thereby, overcoming the drug resistance is an alternative strategy to maximize the efficacy of MTX therapies in clinics. Long non-coding RNAs (lncRNAs) have gained widespread attention in recent years. More and more evidences have shown that lncRNAs play regulatory roles in various biological activities and disease progression including drug resistance in cancer cells. Here, we observed lncRNA TUG1 was associated to the MTX resistant in colorectal cancer cells. Firstly, quantitative analysis indicated that TUG1 was significantly increased in tumors which were resistant to MTX treatment. TUG1 knockdown re-sensitized the MTX resistance in colorectal cancer cells, which were MTX-resistant colorectal cell line. Furthermore, bioinformatics analysis showed that miR-186 could directly bind to TUG1, suggesting TUG1 might worked as a ceRNA to sponge miR-186. Extensively, our study also showed that CPEB2 was the direct target of miR-186 in colorectal cancer cells. Taken together, our study suggests that lncRNA TUG1 mediates MTX resistance in colorectal cancer via miR-186/CPEB2 axis. Copyright © 2017. Published by Elsevier Inc.

  15. Chain-modified radioiodinated fatty acids

    International Nuclear Information System (INIS)

    Otto, C.A.

    1987-01-01

    Several carbon chain manipulations have been studied in terms of their effects on myocardial activity levels and residence time. The manipulations examined included: chain length, chain branching, chain unsaturation, and carbon-iodine bond stabilization. It was found that chain length affects myocardial activity levels for both straight-chain alkyl acids and branched chain alkyl and aryl acids. Similar results have been reported for the straight-chain aryl acids. Generally, the longer chain lengths correlated with higher myocardial activity levels and longer residence times. This behavior is attributed to storage as triglycerides. Branched chain acids are designed to be anti-metabolites but only the aryl β-methyl acids possessed the expected time course of constant or very slowly decreasing activity levels. The alkyl β-methyl acids underwent rapid deiodination - a process apparently independent of β-oxidation. Inhibition of β-oxidation by incorporation of carbon-carbon double and triple bonds was studied. Deiodination of ω-iodo alkyl fatty acids prevented an assessment of suicide inhibition using an unsaturated alkynoic acid. Stabilization of the carbon-iodine bond by attachment of iodine to a vinylic or aryl carbon was studied. The low myocardial values and high blood values observed for an eleven carbon ω-iodo vinylic fatty acid were not encouraging but ω-iodo aryl fatty acids appear to avoid the problems of rapid deiodination. (Auth.)

  16. Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK and FOXO1.

    Directory of Open Access Journals (Sweden)

    Tamás Fodor

    Full Text Available Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK jointly with methotrexate (MTX, a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.

  17. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5).

    Science.gov (United States)

    Kim, Hee-Jin; Sohn, Kwang-Min; Shy, Michael E; Krajewski, Karen M; Hwang, Miok; Park, June-Hee; Jang, Sue-Yon; Won, Hong-Hee; Choi, Byung-Ok; Hong, Sung Hwa; Kim, Byoung-Joon; Suh, Yeon-Lim; Ki, Chang-Seok; Lee, Soo-Youn; Kim, Sun-Hee; Kim, Jong-Won

    2007-09-01

    We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.

  18. Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs.

    Science.gov (United States)

    Fouquet, Grégory; Debuysscher, Véronique; Ouled-Haddou, Hakim; Eugenio, Mélanie Simoes; Demey, Baptiste; Singh, Amrathlal Rabbind; Ossart, Christèle; Al Bagami, Mohammed; Regimbeau, Jean-Marc; Nguyen-Khac, Eric; Naassila, Mickael; Marcq, Ingrid; Bouhlal, Hicham

    2016-05-31

    Multidrug resistance MDR proteins (MRPs) are members of the C family of a group of proteins named ATP binding cassette (ABC) transporters. MRPs can transport drugs including anticancer drugs, nucleoside analogs, antimetabolites and tyrosine kinase inhibitors. Drugs used in HCC therapy, such as tyrosine kinase inhibitor sorafenib, are substrates of uptake and/or efflux transporters. Variable expression of MRPs at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. Recently, we reported that the hepatocyte SLAMF3 expression (Signaling Lymphocytic Activation Molecule Family member 3) was reduced in tumor cells from hepatocellular carcinoma (HCC) compared to its high expression in adjacent tissues. In the present study, we make a strong correlation between induced SLAMF3 overexpression and the specific loss of MRP-1 expression and its functionalities as a drugs resistance transporter. No changes were observed on expression of ABCG2 and MDR. More importantly, we highlight a strong inverse correlation between MRP-1 and SLAMF3 expression in patients with HCC. We propose that the SLAMF3 overexpression in cancerous cells could represent a potential therapeutic strategy to improve the drugs sensibility of resistant cells and thus control the therapeutic failure in HCC patients.

  19. Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats

    International Nuclear Information System (INIS)

    Chiang, H.-M.; Fang, S.-H.; Wen, K.-C.; Hsiu, S.-L.; Tsai, Shang-Yuan; Hou, Y.-C.; Chi, Y.-C.; Lee Chao, Pei-Dawn

    2005-01-01

    Isoflavone supplements are nowadays widely used as alternative for hormone replacement therapy. However, the safety remains unanswered. This study attempted to investigate the effect of Pueraria lobata root decoction (PLRD), an isoflavone-rich herb, on the pharmacokinetics of methotrexate (MTX), a bicarboxylate antimetabolite with narrow therapeutic window. Rats were orally and intravenously given methotrexate alone and coadministered with PLRD. Blood samples were withdrawn via cardiopuncture at specific time points after drug administration. Serum methotrexate concentrations were assayed by specific monoclonal fluorescence polarization immunoassay method. Pharmacokinetic parameters were calculated using noncompartment model of WINNONLIN for both oral and intravenous data of MTX. Our results showed that coadministration of 4.0 g/kg and 2.0 g/kg of PLRD significantly increased the AUC 0-t by 207.8% and 127.9%, prolonged the mean residence time (MRT) by 237.8 and 155.2%, respectively, finally resulted in surprisingly high mortalities of 57.1% and 14.3% in rats. When MTX was given intravenously, the coadministration of PLRD at 4.0 g/kg significantly increased the half-life by 53.9% and decreased the clearance by 47.9%. In conclusion, the coadministration of PLRD significantly decreased the elimination and resulted in markedly increased exposure of MTX in rats

  20. Novel agents in the management of lung cancer.

    LENUS (Irish Health Repository)

    Kennedy, B

    2012-01-31

    Lung cancer is the leading cause of cancer death worldwide. Survival remains poor as approximately 80% of cases present with advanced stage disease. However, new treatments are emerging which offer hope to patients with advanced disease. Insights into cell biology have identified numerous intracellular and extracellular peptides that are pivotal in cancer cell signalling. Disrupting the function of these peptides inhibits intracellular signal transduction and diminishes uncontrolled proliferation, resistance to apoptosis and tumour angiogenesis. The most widely studied signalling pathway is the Epidermal Growth Factor (EGF) pathway. EGF signalling can be disrupted at numerous points. Blockade of the cell surface receptor is achieved by the monoclonal antibody cetuximab; intracellular tyrosine kinase activity is inhibited by erlotinib. Vascular Endothelial Growth Factor (VEGF) regulates another pathway important for tumour growth. Inhibition of VEGF impairs angiogenesis and disrupts metastatic spread. Bevacizumab is a monoclonal antibody that binds to VEGF and blocks interaction with its cell surface receptor. Clinical trials have demonstrated that disruption of these signalling pathways can improve survival in advanced lung cancer. New compounds including folate antimetabolites such as pemetrexed, proteasome inhibitors such as bortezomib, modified glutathione analogues such as TLK286, and other agents such as epothilones and other small molecules are currently being evaluated in patients with lung cancer. As more and more signalling peptides are targeted for manipulation, it is hoped that a new era is dawning in the treatment of advanced stage lung cancer. This review will focus on emerging new therapies in the management of lung cancer.

  1. Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis

    Directory of Open Access Journals (Sweden)

    İlknur Tuğal-Tutkun

    2016-04-01

    Full Text Available Pediatric uveitis may be a serious health problem because of the lifetime burden of vision loss due to severe complications if the problem is not adequately treated. Juvenile idiopathic arthritis (JIA-associated uveitis is characterized by insidious onset and potentially blinding chronic anterior uveitis. Periodic ophthalmologic screening is of utmost importance for early diagnosis of uveitis. Early diagnosis and proper immunomodulatory treatment are essential for good visual prognosis. The goal of treatment is to achieve enduring drug-free remission. The choice of therapeutic regimen needs to be tailored to each individual case. One must keep in mind that patients under immunomodulatory treatment should be monitored closely due to possible side effects. Local and systemic corticosteroids have long been the mainstay of therapy; however, long-term corticosteroid therapy should be avoided due to serious side effects. Steroid-sparing agents in the treatment of JIA-associated uveitis include antimetabolites and biologic agents in refractory cases. Among the various immunomodulatory agents, methotrexate is generally the first choice, as it has a well-established safety and efficacy profile in pediatric cases and does not appear to increase the risk of cancer. Other classic immunomodulators that may also be used in combination with methotrexate include azathioprine, mycophenolate mofetil, and cyclosporin A. Biologic agents, primarily tumor necrosis factor alpha inhibitors including infliximab or adalimumab, should be considered in cases of treatment failure with classic immunomodulatory agents.

  2. Elevated Levels of DNA Strand Breaks Induced by a Base Analog in the Human Cell Line with the P32T ITPA Variant

    Directory of Open Access Journals (Sweden)

    Irina S.-R. Waisertreiger

    2010-01-01

    Full Text Available Base analogs are powerful antimetabolites and dangerous mutagens generated endogenously by oxidative stress, inflammation, and aberrant nucleotide biosynthesis. Human inosine triphosphate pyrophosphatase (ITPA hydrolyzes triphosphates of noncanonical purine bases (i.e., ITP, dITP, XTP, dXTP, or their mimic: 6-hydroxyaminopurine (HAP deoxynucleoside triphosphate and thus regulates nucleotide pools and protects cells from DNA damage. We demonstrate that the model purine base analog HAP induces DNA breaks in human cells and leads to elevation of levels of ITPA. A human polymorphic allele of the ITPA, 94C->A encodes for the enzyme with a P32T amino-acid change and leads to accumulation of nonhydrolyzed ITP. The polymorphism has been associated with adverse reaction to purine base-analog drugs. The level of both spontaneous and HAP-induced DNA breaks is elevated in the cell line with the ITPA P32T variant. The results suggested that human ITPA plays a pivotal role in the protection of DNA from noncanonical purine base analogs.

  3. Characteristics of pediatric chemotherapy medication errors in a national error reporting database.

    Science.gov (United States)

    Rinke, Michael L; Shore, Andrew D; Morlock, Laura; Hicks, Rodney W; Miller, Marlene R

    2007-07-01

    Little is known regarding chemotherapy medication errors in pediatrics despite studies suggesting high rates of overall pediatric medication errors. In this study, the authors examined patterns in pediatric chemotherapy errors. The authors queried the United States Pharmacopeia MEDMARX database, a national, voluntary, Internet-accessible error reporting system, for all error reports from 1999 through 2004 that involved chemotherapy medications and patients aged error reports, 85% reached the patient, and 15.6% required additional patient monitoring or therapeutic intervention. Forty-eight percent of errors originated in the administering phase of medication delivery, and 30% originated in the drug-dispensing phase. Of the 387 medications cited, 39.5% were antimetabolites, 14.0% were alkylating agents, 9.3% were anthracyclines, and 9.3% were topoisomerase inhibitors. The most commonly involved chemotherapeutic agents were methotrexate (15.3%), cytarabine (12.1%), and etoposide (8.3%). The most common error types were improper dose/quantity (22.9% of 327 cited error types), wrong time (22.6%), omission error (14.1%), and wrong administration technique/wrong route (12.2%). The most common error causes were performance deficit (41.3% of 547 cited error causes), equipment and medication delivery devices (12.4%), communication (8.8%), knowledge deficit (6.8%), and written order errors (5.5%). Four of the 5 most serious errors occurred at community hospitals. Pediatric chemotherapy errors often reached the patient, potentially were harmful, and differed in quality between outpatient and inpatient areas. This study indicated which chemotherapeutic agents most often were involved in errors and that administering errors were common. Investigation is needed regarding targeted medication administration safeguards for these high-risk medications. Copyright (c) 2007 American Cancer Society.

  4. Synthesis of some new pyrazolo[1,5-a]pyrimidine, pyrazolo[5,1-c]triazine, 1,3,4-thiadiazole and pyridine derivatives containing 1,2,3-triazole moiety.

    Science.gov (United States)

    Abdelriheem, Nadia A; Zaki, Yasser H; Abdelhamid, Abdou O

    2017-06-12

    Pyrazolo[1,5-a]pyrimidines are purine analogues. They have beneficial properties as antimetabolites in purine biochemical reactions. This division compounds have attracted wide pharmaceutical interest because of their antitrypanosomal activity. The present work depicts an effective synthesis convention of pyrazolo[1,5-a]pyrimidines, pyrazolo[5,1-c]triazines, thieno[2,3-b]pyridines and polysubstituted pyridines containing 1,2,3,-triazole moiety from the reaction of sodium 3-(5-methyl-1-(p-toly)-1H-1,2,3-triazol-4-yl)-3-oxoprop-1-en-1-olate with the fitting heterocyclic amines and its diazonium salt, and active methylene compounds, individually. Likewise, thiazoles and, 1,3,4-thiadiazoles were obtained from 2-bromo-1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethanone and some reagent such as hydrazonoyl chlorides and halo ketones. The newly synthesized compounds were established by elemental analysis, spectral data, and alternative synthetic route whenever possible. New series of pyrazolo[1,5-a]pyrimidines, pyrazolo[5,1-c]triazines, thieno[2,3-b]pyridines and polysubstituted pyridines containing the 1,2,3,-triazole moiety were synthesized via reactions of sodium 3-(5-methyl-1-(p-toly)-1H-1,2,3-triazol-4-yl)-3-oxoprop-1-en-1-olate with the appropriate heterocyclic amines and its diazonium salt. In addition, 1,3,4-thiadiazoles and, 1,3-thiazoles were acquired in a decent yield via the reaction of substituted thiourea with the appropriate hydrazonoyl chlorides and halogenated ketenes. Graphical abstract Synthesis of some new pyrazolo[1,5-a]pyrimidines, pyrazolo[5,1-c]triazines and thieno[2,3-b]pyridines.

  5. H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/β-catenin pathway

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Ke-feng [Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong (China); Liang, Wei-Cheng [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Feng, Lu [Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Pang, Jian-xin [School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 (China); Waye, Mary Miu-Yee [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Zhang, Jin-Fang [Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Fu, Wei-Ming, E-mail: fuweiming76@smu.edu.cn [School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 (China)

    2017-01-15

    Colorectal cancer (CRC) is a common malignancy, most of which remain unresponsive to chemotherapy. As one of the earliest cytotoxic drugs, methotrexate (MTX) serves as an anti-metabolite and anti-folate chemotherapy for various cancers. Unfortunately, MTX resistance prevents its clinical application in cancer therapy. Thereby, overcoming the drug resistance is an alternative strategy to maximize the therapeutic efficacy of MTX in clinics. Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years. More and more emerging evidences have demonstrated that they play important regulatory roles in various biological activities and disease progression including drug resistance. In the present study, a MTX-resistant colorectal cell line HT-29 (HT-29-R) was developed, which displayed the active proliferation and shortened cell cycle. LncRNA H19 was found to be significantly upregulated in this resistant cell line. Further investigation showed that H19 knockdown sensitized the MTX resistance in HT-29-R cells while its overexpression improved the MTX resistance in the parental cells, suggesting that H19 mediate MTX resistance. The Wnt/β-catenin signaling was activated in HT-29-R cells, and H19 knockdown suppressed this signaling in the parental cells. In conclusion, H19 mediated MTX resistance via activating Wnt/β-catenin signaling, which help to develop H19 as a promising therapeutic target for MTX resistant CRC. - Highlights: • A methotrexate (MTX) -resistant colorectal cancer cell line HT-29 (HT-29-R) has been developed. • H19 was upregulated in HT-29-R cells. • H19 mediated MTX resistance in colorectal cancer (CRC). • Wnt/β-catenin pathway was involved in the H19-mediated MTX resistance in CRC cells.

  6. Identification of impurities in methotrexate drug substances using high-performance liquid chromatography coupled with a photodiode array detector and Fourier transform ion cyclotron resonance mass spectrometry.

    Science.gov (United States)

    Wu, Cai-Sheng; Tong, Yuan-Feng; Wang, Peng-Yuan; Wang, Dong-Mei; Wu, Song; Zhang, Jin-Lan

    2013-05-15

    Methotrexate (MTX) is an antineoplastic therapeutic medicine that acts as an antimetabolite of folic acid. In this study we identified the impurities in MTX drug substances produced by different manufacturers and in different batches using high-performance liquid chromatography coupled with a photodiode array detector and Fourier transform ion cyclotron resonance mass spectrometry (HPLC-PDA/FTICR-MS). MTX and its impurities were separated on a Restek Pinnacle II C18 column (250 × 4.6 mm, 5 µm) with a gradient elution system composed of 0.2% formic acid and acetonitrile at a flow rate of 1.0 mL/min. Ultraviolet (UV) detection was set at 305 nm. Mass detection was carried out using FTICR-MS with full-scan mass analysis at a resolving power of 100 000 coupled with multiple-stage mass analysis using a parent list of compounds. Fifteen impurities were detected in MTX drug substances, and their structures were predicted from using HPLC-PDA/FTICR-MS data, including their UV spectra, high-resolution mass spectrometry (HRMS), fragmentation patterns, and MS(n) spectra. Ten of the impurities detected in the MTX drug substances are reported for the first time. There was a high abundance of esterified impurities in some batches of MTX drug substances, over the identification threshold of International Conference on Harmonization (ICH) guidelines, which requires particular attention. This paper describes a HPLC-PDA/FTICR-MS method to profile and identify impurities in MTX drug substances. The results suggest that HPLC-PDA/FTICR-MS is a valuable analytical technique for the rapid identification of impurities. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Ubiquitin-specific Peptidase 10 (USP10) Deubiquitinates and Stabilizes MutS Homolog 2 (MSH2) to Regulate Cellular Sensitivity to DNA Damage.

    Science.gov (United States)

    Zhang, Mu; Hu, Chen; Tong, Dan; Xiang, Shengyan; Williams, Kendra; Bai, Wenlong; Li, Guo-Min; Bepler, Gerold; Zhang, Xiaohong

    2016-05-13

    MSH2 is a key DNA mismatch repair protein, which plays an important role in genomic stability. In addition to its DNA repair function, MSH2 serves as a sensor for DNA base analogs-provoked DNA replication errors and binds to various DNA damage-induced adducts to trigger cell cycle arrest or apoptosis. Loss or depletion of MSH2 from cells renders resistance to certain DNA-damaging agents. Therefore, the level of MSH2 determines DNA damage response. Previous studies showed that the level of MSH2 protein is modulated by the ubiquitin-proteasome pathway, and histone deacetylase 6 (HDAC6) serves as an ubiquitin E3 ligase. However, the deubiquitinating enzymes, which regulate MSH2 remain unknown. Here we report that ubiquitin-specific peptidase 10 (USP10) interacts with and stabilizes MSH2. USP10 deubiquitinates MSH2 in vitro and in vivo Moreover, the protein level of MSH2 is positively correlated with the USP10 protein level in a panel of lung cancer cell lines. Knockdown of USP10 in lung cancer cells exhibits increased cell survival and decreased apoptosis upon the treatment of DNA-methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and antimetabolite 6-thioguanine (6-TG). The above phenotypes can be rescued by ectopic expression of MSH2. In addition, knockdown of MSH2 decreases the cellular mismatch repair activity. Overall, our results suggest a novel USP10-MSH2 pathway regulating DNA damage response and DNA mismatch repair. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Use of radiation and radioisotopes for investigating metabolic diseases of animals in India

    International Nuclear Information System (INIS)

    Arora, S.P.

    1980-01-01

    In the last one decade, radioisotopes are being used to investigate certain metabolic diseases of animals and radiations are being utilized to produce parasitic vaccines to vaccinate animals. Some studies in which radioisotopes have been used to investigate certain metabolic disorders are reviewed. In experiments, where radioimmunoassay technique for the estimation of hormones, has been utilized, the results reveal that the animals on low plane of nutrition show greater oestrous cycle lengths or even long anoestrous periods. On the other hand, irradiation has been used as a tool to produce vaccines as well as degradation of certain dietary molecules for increased utilization. A number of studies wherein 35 S and 15 N isotopes have been used, reveal that sulphur supplementation is essential for optimum utilization of nitrogen in the ratio of 1:10. There are certain antimetabolites in feed ingredients which affect endocrine function. Evidence indicates that high nitrate forages disturb thyroid function when sup(131)I is used to elucidate its secretion rate. Similarly certain toxic substances such as tannins have been shown to affect protein metabolism and phosphorus utilization when sup(32)P isotope is used in such studies. The use of radioisotopes have also been helpful to investigate the cause of ''Degnala'' disease prevalent in village cattle in certain states of India. With the help of sup(75)Se it has been possible to trace out the metabolic disturbances which lead to the onset of this disease. Another deficiency disease, hyperkeratosis, has been shown to be caused not only because of Vitamin A deficiency, but also because of zinc deficiency. The latter helps in the mobilization of normal quantity of vitamin A from the liver into the blood vitamin A pool. There is wide scope to use radioisotopes to investigate other metabolic diseases prevalent in livestock in this country. (auth.)

  9. Cutaneous adverse reactions of chemotherapy in cancer patients: A clinicoepidemiological study

    Directory of Open Access Journals (Sweden)

    Saumita Ghosh Biswal

    2018-01-01

    Full Text Available Background: The diagnosis of cutaneous adversities in the cancer patient is especially difficult, given the complexity of their illness and combination protocols used for the treatment. The present study was undertaken to know the spectrum of cutaneous adversities in patients undergoing chemotherapy and the drug(s most commonly associated with it. Materials and Methods: A total of 1000 patients with malignancies under chemotherapy in the oncology ward and outpatient department were screened in this observational study from January 2013 to February 2015. Relevant investigations for diagnosis of malignancies under chemotherapy and dermatological disorders were carried out. Results: Three hundred and eighty-four patients presented with cutaneous adversities of chemotherapy. The most common was anagen effluvium (78.6%, followed by xerosis (4.4%, thrombophlebitis (3.1%, generalised pruritus (2.9%, melanonychia (2.9%, hand-foot syndrome (2.6%, extravasation reactions (1.8%, flagellate dermatosis (1.3%, prurigo nodularis (0.8%, exfoliation (0.5%, ichthyosis (0.5%, papulopustular rash (0.3%, bullous photodermatitis (0.3%, and Sweet's syndrome (0.3%. Chemotherapeutic drugs were mostly given in combinations. Most common drugs to cause anagen effluvium were alkylating agents in combinations, hand-foot syndrome by taxanes (docetaxel, flagellate dermatoses by antitumour antibiotics (bleomycin, and exfoliation by antimetabolites (methotrexate. The limitation of this study was to imply a specific drug as the causation of the cutaneous adversities since the chemotherapy mostly consisted of combination protocols. Therefore, we have tried to associate the drug combination itself. Conclusion: Chemotherapeutic drugs produce a range of cutaneous adversities, certain specific adversities pertaining to drugs, and their combinations have been implicated which should be looked for and managed accordingly. Knowledge of the adverse effects of anticancer drugs will help

  10. Differential effects of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the testosterone-induced growth of ventral prostate and seminal vesicles of castrated rats.

    Science.gov (United States)

    Käpyaho, K; Kallio, A; Jänne, J

    1984-05-01

    2-Difluoromethylornithine totally prevented any increases in putrescine and spermidine concentrations in the ventral prostate of castrated rats during a 6-day testosterone treatment. Prostatic ornithine decarboxylase activity was inhibited by 80%, whereas S-adenosylmethionine decarboxylase was stimulated by more than 9-fold. In seminal vesicle, the inhibition of putrescine and spermidine accumulation, as well as of ornithine decarboxylase activity, was only minimal, and no stimulation of S-adenosylmethionine decarboxylase was observed. Administration of methylglyoxal bis(guanylhydrazone) to castrated androgen-treated rats resulted in a marked increase in concentrations of all prostatic polyamines. Prostatic ornithine decarboxylase activity was nearly 2 times and adenosylmethionine decarboxylase activity 9 times higher than that of the testosterone-treated animals. In contrast with ventral prostate, methylglyoxal bis(guanylhydrazone) treatment inhibited moderately the accumulation of spermidine and spermine in seminal vesicle, although both ornithine decarboxylase and S-adenosylmethionine decarboxylase activities were stimulated. Difluoromethylornithine inhibited significantly the weight gain of ventral prostate, but methylglyoxal bis(guanylhydrazone) produced a substantial increase in prostatic weight. These changes were largely due to the fact that the volume of prostatic secretion was greatly decreased by difluoromethylornithine, whereas methylglyoxal bis(guanylhydrazone) increased the amount of secretion. Treatment with difluoromethylornithine strikingly increased the methylglyoxal bis(guanylhydrazone) content of both ventral prostate and seminal vesicle, but even under these conditions the drug concentration remained low in comparison with other tissues. The results indicate that a combined use of these two polyamine anti-metabolites does not necessarily result in a synergistic growth inhibition of the androgen-induced growth of male accessory sexual glands.

  11. H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/β-catenin pathway

    International Nuclear Information System (INIS)

    Wu, Ke-feng; Liang, Wei-Cheng; Feng, Lu; Pang, Jian-xin; Waye, Mary Miu-Yee; Zhang, Jin-Fang; Fu, Wei-Ming

    2017-01-01

    Colorectal cancer (CRC) is a common malignancy, most of which remain unresponsive to chemotherapy. As one of the earliest cytotoxic drugs, methotrexate (MTX) serves as an anti-metabolite and anti-folate chemotherapy for various cancers. Unfortunately, MTX resistance prevents its clinical application in cancer therapy. Thereby, overcoming the drug resistance is an alternative strategy to maximize the therapeutic efficacy of MTX in clinics. Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years. More and more emerging evidences have demonstrated that they play important regulatory roles in various biological activities and disease progression including drug resistance. In the present study, a MTX-resistant colorectal cell line HT-29 (HT-29-R) was developed, which displayed the active proliferation and shortened cell cycle. LncRNA H19 was found to be significantly upregulated in this resistant cell line. Further investigation showed that H19 knockdown sensitized the MTX resistance in HT-29-R cells while its overexpression improved the MTX resistance in the parental cells, suggesting that H19 mediate MTX resistance. The Wnt/β-catenin signaling was activated in HT-29-R cells, and H19 knockdown suppressed this signaling in the parental cells. In conclusion, H19 mediated MTX resistance via activating Wnt/β-catenin signaling, which help to develop H19 as a promising therapeutic target for MTX resistant CRC. - Highlights: • A methotrexate (MTX) -resistant colorectal cancer cell line HT-29 (HT-29-R) has been developed. • H19 was upregulated in HT-29-R cells. • H19 mediated MTX resistance in colorectal cancer (CRC). • Wnt/β-catenin pathway was involved in the H19-mediated MTX resistance in CRC cells.

  12. Drugs in development for prophylaxis of rejection in kidney-transplant recipients

    Directory of Open Access Journals (Sweden)

    Sanders ML

    2015-08-01

    Full Text Available Marion Lee Sanders,1 Anthony James Langone2 1Department of Medicine, Division of Nephrology and Hypertension, University of Iowa, Iowa City, IA, 2Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: Transplantation is the preferred treatment option for individuals with end-stage renal disease. Individuals who undergo transplantation must chronically be maintained on an immunosuppression regimen for rejection prophylaxis to help ensure graft survival. Current rejection prophylaxis consists of using a combination of calcineurin inhibitors, mTOR inhibitors, antimetabolite agents, and/or corticosteroids. These agents have collectively improved the short-term outcomes of renal transplantation, but improvements in late/chronic graft loss and recipient survival have lagged significantly behind challenging the field of transplantation to develop novel prophylactic agents. There have been several clinical trials conducted within the last 5 years in an attempt to bring such novel agents to the commercial market. These trials have resulted in the US Food and Drug Administration (FDA approval of extended-release tacrolimus, as well as belatacept, which has the potential to replace calcineurin inhibitors for rejection prophylaxis. Other trials have focused on the development of novel calcineurin inhibitors (voclosporin, costimulation blockade (ASKP1240 and alefacept, kinase inhibitors (tofacitinib and sotrastaurin, and inhibitors of leukocyte migration (efalizumab. While these later agents have not been FDA-approved for use in transplantation, they remain noteworthy, as these agents explore pathways not previously targeted for allograft-rejection prophylaxis. The purpose of this review was to consolidate available clinical trial data with regard to the recent developments in rejection prophylaxis in kidney transplantation. Keywords: rejection, prophylaxis, immunosuppression

  13. Attenuated Wnt/β-catenin signalling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats.

    Science.gov (United States)

    Georgiou, Kristen R; King, Tristan J; Scherer, Michaela A; Zhou, Hong; Foster, Bruce K; Xian, Cory J

    2012-06-01

    Cancer chemotherapy often causes significant bone loss, marrow adiposity and haematopoietic defects, yet the underlying mechanisms and recovery potential remain unclear. Wnt/β-catenin signalling is integral to the regulation of osteogenesis, adipogenesis and haematopoiesis; using a rat model, the current study investigated roles of this signalling pathway in changes to bone marrow stromal and haematopoietic cell differentiation after chemotherapy with methotrexate (MTX), a commonly used antimetabolite. MTX treatment in rats (5 daily administrations at 0.75 mg/kg) has previously been found to decrease bone volume and increase marrow fat, which was associated with increased osteoclastogenesis in haematopoietic cells and with an osteogenesis to adipogenesis switch in bone marrow stromal cells of treated rats. In the current study, on day 6 after the first MTX dose we found that accompanying these changes as well as a suppressed haematopoietic cellularity but increased granulocyte/macrophage differentiation potential, there was an increase in mRNA expression of Wnt antagonists sFRP-1 and Dkk-1 in bone, a reduction in nuclear β-catenin protein in bone marrow stromal cells, and decreased mRNA levels of β-catenin target genes lef-1, cyclin D1 and survivin, suggesting reduced activation of Wnt/β-catenin signalling in the bone during MTX-induced damage. Concurrent administration of BIO, a GSK-3β inhibitor that stabilises β-catenin, partially abrogated the MTX-induced transient changes in osteogenic/adipogenic commitment, granulocyte/macrophage lineage differentiation and osteoclast number. These findings demonstrate a potentially important role of Wnt/β-catenin signalling in MTX chemotherapy-induced cellular changes to the bone marrow microenvironment. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. A kinome screen identifies checkpoint kinase 1 (CHK1 as a sensitizer for RRM1-dependent gemcitabine efficacy.

    Directory of Open Access Journals (Sweden)

    Jun Zhou

    Full Text Available Gemcitabine is among the most efficacious and widely used antimetabolite agents. Its molecular targets are ribonucleotide reductase M1 (RRM1 and elongating DNA. Acquired and de novo resistance as a result of RRM1 overexpression are major obstacles to therapeutic efficacy. We deployed a synthetic lethality screen to investigate if knockdown of 87 selected protein kinases by siRNA could overcome RRM1-dependent gemcitabine resistance in high and low RRM1-expressing model systems. The models included genetically RRM1-modified lung and breast cancer cell lines, cell lines with gemcitabine-induced RRM1 overexpression, and a series of naturally gemcitabine-resistant cell lines. Lead molecular targets were validated by determination of differential gemcitabine activity using cell lines with and without target knock down, and by assessing synergistic activity between gemcitabine and an inhibitor of the lead target. CHK1 was identified has the kinase with the most significant and robust interaction, and it was validated using AZD7762, a small-molecule ATP-competitive inhibitor of CHK1 activation. Synergism between CHK1 inhibition and RRM1-dependent gemcitabine efficacy was observed in cells with high RRM1 levels, while antagonism was observed in cells with low RRM1 levels. In addition, four cell lines with natural gemcitabine resistance demonstrated improved gemcitabine efficacy after CHK1 inhibition. In tumor specimens from 187 patients with non-small-cell lung cancer, total CHK1 and RRM1 in situ protein levels were significantly (p = 0.003 and inversely correlated. We conclude that inhibition of CHK1 may have its greatest clinical utility in malignancies where gemcitabine resistance is a result of elevated RRM1 levels. We also conclude that CHK1 inhibition in tumors with low RRM1 levels may be detrimental to gemcitabine efficacy.

  15. Characterisation of the mgo operon in Pseudomonas syringae pv. syringae UMAF0158 that is required for mangotoxin production

    Science.gov (United States)

    2012-01-01

    Background Mangotoxin is an antimetabolite toxin that is produced by strains of Pseudomonas syringae pv. syringae; mangotoxin-producing strains are primarily isolated from mango tissues with symptoms of bacterial apical necrosis. The toxin is an oligopeptide that inhibits ornithine N-acetyl transferase (OAT), a key enzyme in the biosynthetic pathway of the essential amino acids ornithine and arginine. The involvement of a putative nonribosomal peptide synthetase gene (mgoA) in mangotoxin production and virulence has been reported. Results In the present study, we performed a RT-PCR analysis, insertional inactivation mutagenesis, a promoter expression analysis and terminator localisation to study the gene cluster containing the mgoA gene. Additionally, we evaluated the importance of mgoC, mgoA and mgoD in mangotoxin production. A sequence analysis revealed an operon-like organisation. A promoter sequence was located upstream of the mgoB gene and was found to drive lacZ transcription. Two terminators were located downstream of the mgoD gene. RT-PCR experiments indicated that the four genes (mgoBCAD) constitute a transcriptional unit. This operon is similar in genetic organisation to those in the three other P. syringae pathovars for which complete genomes are available (P. syringae pv. syringae B728a, P. syringae pv. tomato DC3000 and P. syringae pv. phaseolicola 1448A). Interestingly, none of these three reference strains is capable of producing mangotoxin. Additionally, extract complementation resulted in a recovery of mangotoxin production when the defective mutant was complemented with wild-type extracts. Conclusions The results of this study confirm that mgoB, mgoC, mgoA and mgoD function as a transcriptional unit and operon. While this operon is composed of four genes, only the last three are directly involved in mangotoxin production. PMID:22251433

  16. Cytostatic drugs and metabolites in municipal and hospital wastewaters in Spain: filtration, occurrence, and environmental risk.

    Science.gov (United States)

    Negreira, Noelia; de Alda, Miren López; Barceló, Damià

    2014-11-01

    Concerns about cytostatic anticancer drugs in the environment are increasing, mainly due to the lack of knowledge about the fate and impact of these cytotoxic compounds in the water cycle. In this context, the present work investigated the occurrence of 13 cytostatics and 4 metabolites in wastewater samples from various wastewater treatment plants (WWTPs) and from a large hospital from Spain. The target compounds belong to five different classes according to the Anatomical Therapeutic Classification (ATC), namely, alkylating agents, antimetabolites, plant alkaloids and other natural products, cytotoxic antibiotics and related substances, and other antineoplastic agents. Some of them have been classified as carcinogens in humans by the International Agency for Research on Cancer (IARC). These compounds were determined by an automated on line solid-phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method. Results showed the presence of methotrexate (MET), ifosfamide (IF), cyclophosphamide (CP), irinotecan (IRI), doxorubicin (DOX), capecitabine (CAP), tamoxifen (TAM) and the metabolites endoxifen (OH-D-TAM), hydroxytamoxifen (OH-TAM) and hydroxypaclitaxel (OH-PAC) at levels ranging from 2 ng L(-1) (for MET) to 180 ng L(-1) (for TAM). Some of these compounds were found to be efficiently removed after wastewater treatment, e.g. MET, DOX and IRI, whereas other compounds, such as TAM, CP and IF remained largely unaltered. The behaviour of the target compounds during the common filtration step of the water samples was also investigated with the finding that some compounds are strongly adsorbed to nylon filters, while cellulose acetate appears as the best choice for the filter material. The aquatic environmental risk associated to the detected compounds was also assessed. To the best of the authors' knowledge, this is the first report of the presence of the metabolites OH-D-TAM and OH-TAM in the water cycle. Copyright © 2014 Elsevier B.V. All

  17. Relationships among cell survival, O6-alkylguanine-DNA alkyltransferase activity, and reactivation of methylated adenovirus 5 and herpes simplex virus type 1 in human melanoma cell lines

    International Nuclear Information System (INIS)

    Maynard, K.; Parsons, P.G.; Cerny, T.; Margison, G.P.

    1989-01-01

    O6-Alkylguanine-DNA alkyltransferase (ATase) activity and host cell reactivation (HCR) of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC)-methylated viruses were compared in human melanoma cell lines that were sensitive or resistant to killing by the antitumor DNA-methylating agent MTIC. Enhanced HCR of adenovirus 5 (defined as the Mer+ phenotype) generally showed a semiquantitative correlation with the natural or induced resistance of the host cells to the toxic effects of MTIC and to the level of ATase activity. However, one MTIC-resistant cell line was found (MM170) which had a low level of ATase and intermediate HCR of adenovirus. The HCR of herpes simplex virus type 1 (HSV-1) was enhanced in the Mer+ cells that had natural resistance to MTIC compared with Mer- cells. On the other hand, HCR of HSV-1 in Mer+ cells with induced resistance to MTIC was similar to that in Mer- cells. Neither adenovirus 5 nor HSV-1 infection induced ATase activity in Mer- cells. This indicates that resistance to the toxic effects of methylating agents is not invariably associated with high levels of ATase activity in human melanoma cells. Furthermore, while induction of the Mer+ phenotype from Mer- cells was usually accompanied by the recovery of ATase activity, induced Mer+ cells had less proficient repair than natural Mer+ cells, as judged quantitatively by slightly lower cellular resistance and qualitatively by deficient HCR response for HSV-1. These results suggest that the Mer- and induced Mer+ cells lack an ATase-independent DNA repair mechanism. No differences in MTIC-induced DNA repair synthesis or strand breaks were found between the Mer-, natural Mer+, and induced Mer+ phenotypes. However, UV-induced DNA repair synthesis was higher in the natural Mer+ than in the Mer- or induced Mer+ cells, both of which had increased cellular sensitivity to the antimetabolites methotrexate and hydroxyurea

  18. UCLA Translational Biomarker Development Program (UTBD)

    Energy Technology Data Exchange (ETDEWEB)

    Czernin, Johannes [Univ. of California, Los Angeles, CA (United States)

    2014-09-01

    The proposed UTBD program integrates the sciences of diagnostic nuclear medicine and (radio)chemistry with tumor biology and drug development. UTBD aims to translate new PET biomarkers for personalized medicine and to provide examples for the use of PET to determine pharmacokinetic (PK) and pharmacodynamic (PD) drug properties. The program builds on an existing partnership between the Ahmanson Translational Imaging Division (ATID) and the Crump Institute of Molecular Imaging (CIMI), the UCLA Department of Chemistry and the Division of Surgical Oncology. ATID provides the nuclear medicine training program, clinical and preclinical PET/CT scanners, biochemistry and biology labs for probe and drug development, radiochemistry labs, and two cyclotrons. CIMI provides DOE and NIH-funded training programs for radio-synthesis (START) and molecular imaging (SOMI). Other participating entities at UCLA are the Department of Chemistry and Biochemistry and the Division of Surgical Oncology. The first UTBD project focuses on deoxycytidine kinase, a rate-limiting enzyme in nucleotide metabolism, which is expressed in many cancers. Deoxycytidine kinase (dCK) positive tumors can be targeted uniquely by two distinct therapies: 1) nucleoside analog prodrugs such as gemcitabine (GEM) are activated by dCK to cytotoxic antimetabolites; 2) recently developed small molecule dCK inhibitors kill tumor cells by starving them of nucleotides required for DNA replication and repair. Since dCK-specific PET probes are now available, PET imaging of tumor dCK activity could improve the use of two different classes of drugs in a wide variety of cancers.

  19. Jane Cooke Wright (1919-2013): Pioneering oncologist, woman and humanitarian.

    Science.gov (United States)

    Crosby, Harriet L

    2016-02-01

    Jane Wright was a fundamental researcher in cancer chemotherapy in the 1950s-1980s and was one of the first scientists to test anti-cancer drugs on humans rather than solely on mice, discovering the use of the popular antimetabolite drug methotrexate on solid tumours. From her research she was able to conclude which specific anti-cancer agents would have the greatest lethal effect on a patient's certain cancer type and she invented a method of delivering chemotherapy agents directly to an internal cancer site. During a time when the Civil Rights in the United States of America were undergoing a transformation to reduce the discrimination and segregation imposed on African Americans and the civil rights activist Martin Luther King Jr made a speech to call for an end to racism in 1963, Jane Wright became the first African American to hold such a high position at a nationally recognised institution and the first woman to be elected President of the New York Cancer Society. US President Lyndon B Johnson appointed Jane to the President's Commission of Heart Disease, Cancer and Stroke (serving 1964-1965) and the National Cancer Advisory Board (serving 1966-1970). Jane retired in 1987 by which time she had published more than 75 scientific papers, led delegations of oncologists in China, the former Soviet Union, Africa and Europe and held key positions in various international and national organisations. Jane Wright passed away on 19 February 2013 aged 93 but her legacy lives on in the name of an award from the American Association of Cancer Research. © The Author(s) 2014.

  20. Correlation between osteoporosis and skin thickness on CT scan

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Tae An; Song, Sun Wha; Lee, Dong Hoon; Kim, Bum Jin; Kim, Yoon Hee; Shinn, Young Rock; Kim, Youn Kil; Lee, Eun Jung; Cho, Song Mee; Son, Sang Bum [The Catholic Univ. College of Medicine, Seoul (Korea, Republic of)

    1998-11-01

    The purpose of this study was to evaluate the relationship between osteoporosis and skin thickness as shown by CT scanning. Eighty-six women with osteoporosis (mean age, 52) and 51 normal controls (mean age, 50) participated in the study. For a quantitative CT examinations, a CT scanner (Somatom Plus, Siemens) was used. Osteoporosis was defined as present when spinal bone mineral density was more than 2.5 standard deviations below young normal density, as determined by quantitative CT. Patients with endocrinologic, malignant or collagen disease and undergoing antimetabolite or steroid therapy were excluded. The thickness of back skin was retrospectively measured at the third lumbar vertebra level, as seen on CT films, using a conventional magnifier. For statistical analysis, Students't test and Spearman's rank correlation were used. On the basis of CT scans, the mean thickness of back skin in the osteoporotic group (0.50{+-}0.20mm) was signigicantly less than in normal control subjects(0.80{+-}0.23mm) (p<0.001). Significant correlation was observed between skin thickness and bone mineral density(r=3D0.523, p<0.0001). Sensitivity, specificity, accuracy, and positive and negative predictive values were measured as 76, 78, 76, 88, 62% with a cut-off value of 0.6 and 84, 61, 77, 81, 66% with a cut-off value of 0.7, respectively. The present study demonstrated that the thickness of back skin, as measured by CT scanning, is predictive of osteoporosis.=20.

  1. Evaluation of a UCMK/dCK fusion enzyme for gemcitabine-mediated cytotoxicity

    International Nuclear Information System (INIS)

    Johnson, Adam J.; Brown, Melissa N.; Black, Margaret E.

    2011-01-01

    Highlights: ► Goal was to enhance dFdC cytotoxicity by the creation of a UCMK/dCK fusion enzyme. ► The UCMK/dCK fusion enzyme possesses both native activities. ► The fusion renders cells equally sensitive to dFdC relative to dCK expression alone. ► Dual activities of fusion not sufficient to augment cell dFdC sensitivity in vitro. ► Data may warrant the implementation of UCMK mutagenesis studies. -- Abstract: While gemcitabine (2′-2′-difluoro-2′-deoxycytidine, dFdC) displays wide-ranging antineoplastic activity as a single agent, variable response rates and poor intracellular metabolism often limit its clinical efficacy. In an effort to enhance dFdC cytotoxicity and help normalize response rates, we created a bifunctional fusion enzyme that combines the enzymatic activities of deoxycytidine kinase (dCK) and uridine/cytidine monophosphate kinase (UCMK) in a single polypeptide. Our goal was to evaluate whether the created fusion could induce beneficial, functional changes toward dFdC, expedite dFdC conversion to its active antimetabolites and consequently amplify cell dFdC sensitivity. While kinetic analyses revealed the UCMK/dCK fusion enzyme to possess both native activities, the fusion rendered cells sensitive to the cytotoxic effects of dFdC at the same level as dCK expression alone. These results suggest that increased wild-type UCMK expression does not provide a significant enhancement in dFdC-mediated cytotoxicity and may warrant the implementation of studies aimed at engineering UCMK variants with improved activity toward gemcitabine monophosphate.

  2. Anti-leukemic potential of methyl-cobalamin inactivation by nitrous oxide.

    Science.gov (United States)

    Abels, J; Kroes, A C; Ermens, A A; van Kapel, J; Schoester, M; Spijkers, L J; Lindemans, J

    1990-06-01

    Myelo-cytotoxicity of extended nitrous oxide (N2O) inhalation was described almost forty years ago and then incidentally applied already with temporary success for suppressing leukemia. In 1948 the accompanying megaloblastic maturation arrest was explained by inactivation of the methylcobalamin coenzyme and subsequent folate deficiency. We studied the anti-leukemic effect of N2O on a transplantable acute leukemia in B(rown) N(orway) rats. Progression of this B,N,M(yelocytic)L(eukemia) was measured as spleen and liver weights, and leukemic blood cell counts. The deoxyuridine (dU)-suppression test provided in vitro indication of the functional folate activity of leukemic cells. Breathing of N2O-oxygen considerably reduced but did not eradicate, BNML-proliferation. Addition of anti-metabolites, interfering with some enzyme in the folate metabolism beyond the methylcobalamin co-enzyme dependent methionine synthase step, acted at least synergistically. The anti-leukemic effect of cycloleucine, which reduces S-adenosyl-methionine synthesis by inactivation of methionine adenosyltransferase, was moderate but became much stronger with N2O inhalation. Methotrexate, a potent anti-leukemic agent by inhibiting tetrahydrofolate (THF) generation through inactivation of di-HF reductase, became highly anti-BNML, even in low dosage when combined with or preceded by N2O. 5-Fluorouracil, which inhibits methylene-THF dependent thymidilate synthase, itself was surprisingly anti-BNML, but also became much more potent with previous or concomitant N2O exposure. Preliminary dU-suppression test results with human acute leukemia cells, exposed to N2O and/or folate antagonists in vitro, correlated well with the in vivo BNML-experiments. Combining the anticobalamin activity of N2O with an anti-folate therefore seems to be a promising chemotherapeutic approach.

  3. Acute onset lactobacillus endophthalmitis after trabeculectomy: a case report

    Directory of Open Access Journals (Sweden)

    Droutsas Konstantinos

    2010-06-01

    Full Text Available Abstract Introduction We report a case of early lactobacillus endophthalmitis which occurred ten days after trabeculectomy. Case presentation A 76-year-old Caucasian diabetic woman underwent uncomplicated trabeculectomy with a collagen implant as an adjunct, in her left phakic eye, for the treatment of uncontrolled open-angle glaucoma. Ten days post-operatively, our patient complained of left phakic eye discharge pain and visual acuity decreased to "light-perception". The anterior chamber had 3+ cells and flare, and there was also 2 mm layered hypopyon. Vitreous involvement was present obscuring visualization of the fundus. On the same day our patient underwent vitrectomy surgery and intra-vitreal and systemic antibiotics were administered. Vitreous cultures grew Lactobacillus brevis. Our patient responded well to treatment and 30 days after vitrectomy visual acuity improved to 1/10. Six months later our patient underwent cataract surgery. Eight months after initial surgery visual acuity was 2/10 and intra-ocular pressure was 14 mmHg without any anti-glaucoma medication. Conclusions This is the first report of acute lactobacillus endophthalmitis in the phakic eye of a diabetic patient after trabeculectomy. Glaucoma surgeons should be aware of the potential for acute post-operative endophthalmitis due to rare microorganisms, such as lactobacillus, in glaucoma filtration surgery, especially in diabetic patients. The literature shows an increased risk of endophthalmitis when anti-metabolites are used in conjunction with trabeculectomy. Perhaps, any type of wound healing modulation, such as collagen or mitomycin-C may increase this risk. However, it is unclear at this time and more studies need to be done. In this single case, vitrectomy combined with intra-vitreal and systemic antibiotics were efficient in limiting the devastating sequels of this complication.

  4. Sulfonamides as Inhibitors ofLeishmania- Potential New Treatments for Leishmaniasis.

    Science.gov (United States)

    Katinas, Jade; Epplin, Rachel; Hamaker, Christopher; Jones, Marjorie A

    2017-04-01

    Leishmaniasis is an endemic disease caused by the protozoan parasite Leishmania. Current treatments for the parasite are limited by cost, availability and drug resistance as the occurrence of leishmaniasis continues to be more prevalent. Sulfonamides are a class of compounds with medicinal properties which have been used to treat bacterial and parasitic disease via various pathways especially as antimetabolites for folic acid. New derivatives of sulfonamide compounds were assessed for their impact on Leishmania cell viability and potential pathways for inhibition were evaluated. Leishmania tarentolae (ATCC Strain 30143) axenic promastigote cells were grown in brain heart infusion (BHI) medium and treated with varying concentrations of the new sulfonamide compounds. Light microscopy and viability tests were used to assess the cells with and without treatment. A non-water soluble sulfonamide was determined to have 90-96% viability inhibition 24 hours after treatment with 100 µM final concentration. Because Leishmania are also autotrophs for folate precursors, the folic acid pathway was identified as a target for sulfonamide inhibition. When folic acid was added to untreated Leishmania, cell proliferation increased. A water soluble derivative of the inhibitory sulfonamide was synthesized and evaluated, resulting in less viability inhibition with a single dose (approximately 70% viability inhibition after 24 hours with 100 µM final concentration), but additive inhibition with multiple doses of the compound. However, the potential mechanism of inhibition was different between the water-soluble and non-water soluble sulfonamides. The inhibitory effects and potential pathways of inhibition indicate that these compounds may be new treatments for this disease.

  5. Second-line immunosuppressive treatment of childhood nephrotic syndrome: a single-center experience.

    Science.gov (United States)

    Kim, J; Patnaik, N; Chorny, N; Frank, R; Infante, L; Sethna, C

    2014-01-01

    Most cases of idiopathic nephrotic syndrome in childhood are responsive to corticosteroids. However, there is a small group of children that demonstrate steroid resistance (steroid-resistant nephrotic syndrome; SRNS), steroid dependence, or that frequently relapse (frequent-relapse steroid-sensitive nephrotic syndrome; FR-SSNS) which are more clinically difficult to treat. Therefore, second-line immunosuppressants, such as alkylating agents, calcineurin inhibitors, antimetabolites and, more recently, rituximab, have been used with varying success. The objective was to evaluate the response rates of various second-line therapies in the treatment of childhood nephrotic syndrome. A retrospective chart review of pediatric subjects with idiopathic nephrotic syndrome was conducted at a single tertiary care center (2007-2012). Drug responses were classified as complete response, partial response, and no response. Of the 188 charts reviewed, 121 children were classified as SSNS and 67 children as SRNS; 58% were classified as FR-SSNS. Sixty-five subjects were diagnosed with focal segmental glomerulosclerosis via biopsy. Follow-up ranged from 6 months to 21 years. The combined rate of complete and partial response for mycophenolate mofetil (MMF) was 65% (33/51) in SSNS and 67% (6/9) in SRNS. For tacrolimus, the response rate was 96% (22/23) for SSNS and 77% (17/22) for SRNS. Eighty-three percent (5/6) of SSNS subjects treated with rituximab went into complete remission; 60% relapsed after B-cell repletion. Eight refractory subjects were treated with combined MMF/tacrolimus/corticosteroid therapy with a 75% response rate. Our experience demonstrates that older medications can be replaced with newer ones such as MMF, tacrolimus, and rituximab with good outcomes and better side effect profiles. The treatment of refractory cases with combination therapy is promising.

  6. Second-Line Immunosuppressive Treatment of Childhood Nephrotic Syndrome: A Single-Center Experience

    Directory of Open Access Journals (Sweden)

    J. Kim

    2014-01-01

    Full Text Available Objective: Most cases of idiopathic nephrotic syndrome in childhood are responsive to corticosteroids. However, there is a small group of children that demonstrate steroid resistance (steroid-resistant nephrotic syndrome; SRNS, steroid dependence, or that frequently relapse (frequent-relapse steroid-sensitive nephrotic syndrome; FR-SSNS which are more clinically difficult to treat. Therefore, second-line immunosuppressants, such as alkylating agents, calcineurin inhibitors, antimetabolites and, more recently, rituximab, have been used with varying success. The objective was to evaluate the response rates of various second-line therapies in the treatment of childhood nephrotic syndrome. Study Design: A retrospective chart review of pediatric subjects with idiopathic nephrotic syndrome was conducted at a single tertiary care center (2007-2012. Drug responses were classified as complete response, partial response, and no response. Results: Of the 188 charts reviewed, 121 children were classified as SSNS and 67 children as SRNS; 58% were classified as FR-SSNS. Sixty-five subjects were diagnosed with focal segmental glomerulosclerosis via biopsy. Follow-up ranged from 6 months to 21 years. The combined rate of complete and partial response for mycophenolate mofetil (MMF was 65% (33/51 in SSNS and 67% (6/9 in SRNS. For tacrolimus, the response rate was 96% (22/23 for SSNS and 77% (17/22 for SRNS. Eighty-three percent (5/6 of SSNS subjects treated with rituximab went into complete remission; 60% relapsed after B-cell repletion. Eight refractory subjects were treated with combined MMF/tacrolimus/corticosteroid therapy with a 75% response rate. Conclusion: Our experience demonstrates that older medications can be replaced with newer ones such as MMF, tacrolimus, and rituximab with good outcomes and better side effect profiles. The treatment of refractory cases with combination therapy is promising.

  7. Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells

    Science.gov (United States)

    Sakata, Ichiro; Park, Won-Mee; Walker, Angela K.; Piper, Paul K.; Chuang, Jen-Chieh; Osborne-Lawrence, Sherri

    2012-01-01

    The peptide hormone ghrelin is released from a distinct group of gastrointestinal cells in response to caloric restriction, whereas its levels fall after eating. The mechanisms by which ghrelin secretion is regulated remain largely unknown. Here, we have used primary cultures of mouse gastric mucosal cells to investigate ghrelin secretion, with an emphasis on the role of glucose. Ghrelin secretion from these cells upon exposure to different d-glucose concentrations, the glucose antimetabolite 2-deoxy-d-glucose, and other potential secretagogues was assessed. The expression profile of proteins involved in glucose transport, metabolism, and utilization within highly enriched pools of mouse ghrelin cells and within cultured ghrelinoma cells was also determined. Ghrelin release negatively correlated with d-glucose concentration. Insulin blocked ghrelin release, but only in a low d-glucose environment. 2-Deoxy-d-glucose prevented the inhibitory effect of high d-glucose exposure on ghrelin release. mRNAs encoding several facilitative glucose transporters, hexokinases, the ATP-sensitive potassium channel subunit Kir6.2, and sulfonylurea type 1 receptor were expressed highly within ghrelin cells, although neither tolbutamide nor diazoxide exerted direct effects on ghrelin secretion. These findings suggest that direct exposure of ghrelin cells to low ambient d-glucose stimulates ghrelin release, whereas high d-glucose and glucose metabolism within ghrelin cells block ghrelin release. Also, low d-glucose sensitizes ghrelin cells to insulin. Various glucose transporters, channels, and enzymes that mediate glucose responsiveness in other cell types may contribute to the ghrelin cell machinery involved in regulating ghrelin secretion under these different glucose environments, although their exact roles in ghrelin release remain uncertain. PMID:22414807

  8. The frequency of secondary glaucoma in patients with iridocorneal endothelial syndrome in correlation to the presence of uveal ectropion

    Directory of Open Access Journals (Sweden)

    Marković Vujica

    2017-01-01

    Full Text Available Introduction/Objective. Iridocorneal endothelial (ICE syndrome incudes 3 clinical forms: progressive iris atrophy, Chandler’s syndrome, and Cogan–Reese syndrome. It is characterized by various degrees of iris atrophy, corneal endothelial changes, uveal ectropion, corectopia, peripheral anterior synechiae (PAS and secondary glaucoma. The aim of the study was to illustrate forms of ICE syndrome, determine frequency of secondary glaucoma with emphasis on cases with uveal ectropion, analyze response to medicament treatment and the need for surgical treatment in intraocular pressure (IOP control. Methods. Patients underwent slit lamp examination, applanation tonometry, gonioscopy, ophthalmoscopy, Humphrey visual field testing and Heidelberg retina tomography. Patients were divided into two groups: group I, without uveal ectropion (22 patients and group II, with uveal ectropion (14 patients. Results. A total of 36 patients were examined in a 10-year period. The average age was 38 years, male to female ratio 1:2. Secondary glaucoma was confirmed in 26 (72.2% patients, out of which 12 (54.5% in group I and 14 (100% in group II. PAS were more frequent in group II. In group I, mean initial IOP was 37 mmHg, and after medicament treatment 26 mmHg. Secondary glaucoma was controlled in 50% and remaining 50% underwent surgical treatment. In group II, mean initial IOP was 49 mmHg, and after medicament treatment 32 mmHg. All 14 patients (100% underwent surgical treatment in order to achieve IOP control. Conclusion. ICE syndrome is a rare, progressive disease, with high incidence of secondary glaucoma, which is more frequent in cases with uveal ectropion. In these cases, medicament treatment is not effective and trabeculectomy with antimetabolite application is necessary.

  9. Current trends in the management of ocular symptoms in Adamantiades-Behçet’s disease

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    Fouad R Zakka

    2009-10-01

    Full Text Available Fouad R Zakka,1 Peter Y Chang,1 Gian P Giuliari,1 C Stephen Foster1,21Massachusetts Eye Research and Surgery institution (MERSI, Cambridge, Massachusetts, USA; 2Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USAAbstract: Adamantiades-Behçet’s disease (ABD is a multisystemic vasculitic disease. It is most prevalent in the Eastern Mediterranean countries and the Eastern region of Asia. Its effect on the eye can range from mild to debilitating, resulting in total blindness. A necrotizing and obliterative vasculitis affects both arteries and veins of organs. Recurrent attacks of uveitis, oral aphthous ulcers, skin lesions, and genital ulcers are common. Topical and systemic corticosteroids have been the mainstay in the treatment of ocular inflammation for many years; however, due to the several known side effects of corticosteroids and thanks to scientific advances, more novel approaches to ABD treatment have been emerging. Antimetabolites such as methotrexate and azathioprine have been utilized with the latter showing positive results. Chlorambucil has been utilized effectively for ocular manifestations of ABD. Interferon alpha has shown encouraging results in the management of refractory ocular inflammation associated with ABD, either alone or in combination with other immunosuppressive agents. Surgical interventions to deal with complications from ABD can be safely done if adequate control of inflammation is achieved peri-operatively. Early detection and aggressive treatment, when needed, have proven to be essential in the management of this relentlessly explosive disease.Keywords: Adamantiades-Behçet’s disease, Behçet’s disease, ocular inflammation, uveitis, immunomodulatory therapy, immunosuppressive therapy

  10. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models

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    María Virtudes Céspedes

    2016-12-01

    Full Text Available We explored whether the combination of lurbinectedin (PM01183 with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii specific depletion of tumor-associated macrophages (TAMs. We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR. Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI=0.66] and SW-1990 (CI=0.80 tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX, cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop ‘molecularly targeted’ combination strategies.

  11. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models

    Science.gov (United States)

    Céspedes, María Virtudes; Guillén, María José; López-Casas, Pedro Pablo; Sarno, Francesca; Gallardo, Alberto; Álamo, Patricia; Cuevas, Carmen; Hidalgo, Manuel; Galmarini, Carlos María; Allavena, Paola; Avilés, Pablo; Mangues, Ramón

    2016-01-01

    ABSTRACT We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA) mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs). We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR). Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI)=0.66] and SW-1990 (CI=0.80) tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX), cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA) downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop ‘molecularly targeted’ combination strategies. PMID:27780828

  12. Cytotoxicity of new duplex drugs linking 3'-C-ethynylcytidine and 5-fluor-2'-deoxyuridine against human melanoma cells.

    Science.gov (United States)

    Schott, Sarah; Niessner, Heike; Sinnberg, Tobias; Venturelli, Sascha; Berger, Alexander; Ikenberg, Kristian; Villanueva, Jessie; Meier, Friedegund; Garbe, Claus; Busch, Christian

    2012-11-01

    Melanoma is an increasingly common and potentially fatal malignancy of the skin and some mucous membranes. As no cure exists for metastatic disease, there is an urgent need for novel drugs. 2'-Deoxy-5-fluorouridylyl-(3'-5')-3'-C-ethynylcytidine [5-FdU(3'-5')ECyd] and 3'-C-ethynylcytidinylyl-(5' → 1-O)-2-O-octadecyl-sn-glycerylyl-(3-O → 5')-2'-deoxy-5-fluorouridine [ECyd-lipid-5-FdU] represent cytostatic active duplex drugs, which can be metabolized into various active antimetabolites. We evaluated the cytotoxicity of these heterodinucleoside phosphate analogs, their corresponding monomers ECyd and 5-FdU and combinations thereof on six metastatic melanoma cell lines and six ex vivo patient-derived melanoma cells in comparison to current standard cytostatic agents and the BRAF V600E inhibitor Vemurafenib. In vitro (real-time)-proliferation assays demonstrated that 5-FdU(3'-5')ECyd and ECyd-lipid-5-FdU had a high cytotoxic efficacy causing 75% melanoma cell death at concentrations in the nanomolar and micromolar range. Cytotoxicity was conducted by induction of DNA cleavage indicating apoptotic cells. Chicken embryotoxicity demonstrated that the duplex drugs were less toxic than 5-FdU at 0.01 μM. In vivo the duplex drug 5-FdU(3'-5')ECyd was efficacious in the murine LOX IMVI melanoma xenograph model on administration of 11.2 mg/kg/injection every fourth day. Both duplex drugs are promising novel cytostatic agents for the treatment of malignant melanoma meriting clinical evaluation. Copyright © 2012 UICC.

  13. Radiation recall gastritis secondary to erlotinib in a patient with pancreatic cancer.

    Science.gov (United States)

    Graziani, Casey; Hegde, Sanjay; Saif, Muhammad Wasif

    2014-12-01

    Radiation recall refers to chemotherapy-triggered inflammation in healthy areas previously exposed to irradiation. Chemotherapeutics known to be associated with radiation recall phenomenon include anthracyclines, taxanes and antimetabolites, such as gemcitabine and capecitabine. Case reports detailing radiation recall dermatitis and pneumonitis associated with erlotinib have been previously described in the literature, however, there are no reported cases describing radiation gastritis associated with erlotinib. We report a patient with pancreatic cancer who developed gastrointestinal bleeding secondary to radiation recall gastritis related to erlotinib exposure. A 57-year-old Hispanic male with pancreatic cancer initially received 7 cycles of FOLFIRINOX followed by capecitabine with radiation therapy for 28 fractions for a total of 5,040 cGy. Re-staging with computed tomography demonstrated stable disease. The patient was then treated with erlotinib and capecitabine for approximately two months before restaging demonstrated progressive disease. Shortly after discontinuing erlotinib and capecitabine, the patient reported maroon colored stools. Laboratory studies demonstrated a precipitous drop in hemoglobin and hematocrit from pre-treatment baseline, ultimately requiring transfusion with packed red blood cells. Subsequent esophagogastroduodenoscopy demonstrated findings consistent with radiation gastritis, with oozing in the gastric body and antrum, which was treated therapeutically with argon plasma coagulation. The patient's gastrointestinal bleed was difficult to control. Over the course of a two-month period - the patient required multiple admissions, repeat therapeutic esophagogastroduodenoscopies and transfusions. Radiation recall from erlotinib is rare but can potentially arise in any site that has been previously irradiated. There may be an association between the pathogenesis of radiation recall and erlotinib's up-regulation of the angiogenic growth factor

  14. Modulation of the ribonucleotide reductase M1-gemcitabine interaction in vivo by N-ethylmaleimide

    International Nuclear Information System (INIS)

    Chen, Zhengming; Zhou, Jun; Zhang, Yingtao; Bepler, Gerold

    2011-01-01

    Highlights: → Gemcitabine induces a RRM1 conformational change in tumor cell lines and xenografts. → The 110 kDa RRM1 is unique to gemcitabine interaction among 12 cytotoxic agents. → The 110 kDa RRM1 can be stabilized by the thiol alkylator N-ethylmaleimide. → C218A, C429A, and E431A mutations in RRM1 abolished the conformational change. → The 110 kDa RRM1 may be a specific biomarker of gemcitabine's therapeutic efficacy. -- Abstract: Ribonucleotide reductase M1 (RRM1) is the regulatory subunit of the holoenzyme that catalyzes the conversion of ribonucleotides to 2'-deoxyribonucleotides. Its function is indispensible in cell proliferation and DNA repair. It also serves as a biomarker of therapeutic efficacy of the antimetabolite drug gemcitabine (2',2'-difluoro-2'-deoxycytidine) in various malignancies. However, a mechanistic explanation remains to be determined. This study investigated how the alkylating agent N-ethylmaleimide (NEM) interacts with the inhibitory activity of gemcitabine on its target protein RRM1 in vivo. We found, when cells were treated with gemcitabine in the presence of NEM, a novel 110 kDa band, along with the 90 kDa native RRM1 band, appeared in immunoblots. This 110 kDa band was identified as RRM1 by mass spectrometry (LC-MS/MS) and represented a conformational change resulting from covalent labeling by gemcitabine. It is specific to gemcitabine/NEM, among 11 other chemotherapy drugs tested. It was also detectable in human tumor xenografts in mice treated with gemcitabine. Among mutations of seven residues essential for RRM1 function, C218A, C429A, and E431A abolished the conformational change, while N427A, C787A, and C790A diminished it. C444A was unique since it was able to alter the conformation even in absence of gemcitabine treatment. We conclude that the thiol alkylator NEM can stabilize the gemcitabine-induced conformational change of RRM1, and this stabilized RRM1 conformation has the potential to serve as a specific

  15. Surgical outcomes of the Ex-PRESS glaucoma filtration device in African American and white glaucoma patients

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    Salim S

    2012-06-01

    postoperative complications, and overall reduced inflammation. Keywords: glaucoma, trabeculectomy, Ex-PRESS glaucoma filtration device, antimetabolites, African American, White

  16. Applications of Fluorine-18 in Biological Studies with Special Reference to Bone and Thyroid Physiology

    International Nuclear Information System (INIS)

    Anbar, M.

    1963-01-01

    diminish the overall iodine uptake. Next, it was demonstrated that the trapping stage is much less radiosensitive than the stages of thyroxine formation and release. A quite different application of F 16 -labelled fluoroborate ions was in the localization of brain tumours, by directional coincidence scanning owing to the limited permeability of these ions via the intact blood- brain barrier. Fluorine-18 labelled fluoraromatic chelating agents were prepared and applied to problems in bone physiology. Fluorine-18 labelled aromatic vital dyes were used in investigating problems of permeability through biological membranes. Fluorine-18 labelled fluorine containing antimetabolites including 5-fluorouracyl and fluoro-orotic acid, have been prepared and applied to physiological problems, including cancer research. (author) [fr

  17. Formulación de metotrexato 50 mg solución inyectable Formulation of metotrexate 50 mg injectable solution

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    Armando Gato del Monte

    2006-08-01

    Full Text Available El metotrexato es un antimetabolito que se agrupa entre los antagonistas del ácido fólico, para el tratamiento de cariocarcinoma gestacional, cariocarcinoma destructivo y lunar hidatiforme, leucemia linfocítica aguda, profilaxis y tratamiento de leucemias meníngeas y terapia de mantenimiento en combinación con otros agentes quimioterapéuticos en diferentes tumores sólidos y linfomas no Hogkin, así como en artritis y psoriasis. Para desarrollar este producto se elaboraron los ensayos preliminares en la etapa de preformulación, se determinaron las características organolépticas, el pH y la concentración del principio activo. Mediante estos estudios se logró obtener una formulación de metotrexato 50 mg solución inyectable con características adecuadas, estable física, química, biológica y microbiológicamente. La formulación que se obtuvo se escaló industrialmente, la cual se envasó en bulbos que cumplen satisfactoriamente con los parámetros de calidad establecidos. Mediante el estudio de estabilidad realizado a estos lotes se comprobaron los parámetros de calidad al producto terminado, que aparecen en la Farmacopea de los Estados Unidos 26 (USP. Se le estableció al medicamento una fecha de vencimiento de 2 años bajo las condiciones de temperatura controlada de 2-8 °C y protegido de la luzMetotrexate is an antimetabolite that groups itslef among the folic acid antagonists for the treatment of gestational choriocarcinoma, destructive choriocarcinoma, lunar hydatidiform choriocarcinoma, acute lymphocytic leukemia, prophylaxis and treatment of meningeal leukemias and maintenance therapy combined with other chemotherapeutic agents in different solid tumors and non-Hodgkin lymphomas, as well as in arthritis and psoriasis. To develop this product, preliminary trials were made in the preformulation stage, and the organoleptic characteristics, pH, and the active principle concentration were determined. By these studies, it was

  18. Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo

    International Nuclear Information System (INIS)

    Montano, Ryan; Thompson, Ruth; Chung, Injae; Hou, Huagang; Khan, Nadeem; Eastman, Alan

    2013-01-01

    Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence. Growth inhibition induced by gemcitabine plus MK-8776 was assessed across multiple cancer cell lines. Experiments used clinically relevant “bolus” administration of both drugs rather than continuous drug exposures. We assessed the effect of different treatment schedules on cell cycle perturbation and tumor cell growth in vitro and in xenograft tumor models. MK-8776 induced an average 7-fold sensitization to gemcitabine in 16 cancer cell lines. The time of MK-8776 administration significantly affected the response of tumor cells to gemcitabine. Although gemcitabine induced rapid cell cycle arrest, the stalled replication forks were not initially dependent on Chk1 for stability. By 18 h, RAD51 was loaded onto DNA indicative of homologous recombination. Inhibition of Chk1 at 18 h rapidly dissociated RAD51 leading to the collapse of replication forks and cell death. Addition of MK-8776 from 18–24 h after a 6-h incubation with gemcitabine induced much greater sensitization than if the two drugs were incubated concurrently for 6 h. The ability of this short incubation with MK-8776 to sensitize cells is critical because of the short half-life of MK-8776 in patients’ plasma. Cell cycle perturbation was also assessed in human pancreas tumor xenografts in mice. There was a dramatic accumulation of cells in S/G 2 phase 18 h after gemcitabine administration, but cells had started to recover by 42 h. Administration of MK-8776 18 h after gemcitabine caused significantly delayed tumor growth compared to either drug alone, or when the two drugs were administered with only a 30 min interval. There are two reasons why delayed

  19. Tendiendo puentes: la utilidad de la historia de la ciencia para comprender el proceso de investigación y desarrollo de medicamentos Filling the gap: the usefulness of history of science to understand the process of drug research and development

    Directory of Open Access Journals (Sweden)

    F. Bosch

    2010-12-01

    use of two cases is outlined that were successfully completed and awarded the Nobel Prize: the modification of neurotransmitters´ structure to obtain new drugs (emasculated hormones by James Black, and the application of the antimetabolite concept to design drugs for infectious, cancer and endocrine diseases. Conclusion. A teaching approach is remarkably successful in helping students understand the complexities of research and drug development.

  20. Syntheses and antifolate activity of 5-methyl-5-deaza analogues of aminopterin, methotrexate, folic acid, and N10-methylfolic acid.

    Science.gov (United States)

    Piper, J R; McCaleb, G S; Montgomery, J A; Kisliuk, R L; Gaumont, Y; Sirotnak, F M

    1986-06-01

    Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepared by hydrogenolysis of its known 6-chloro precursor, was treated with guanidine to give 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile which was converted via the corresponding aldehyde and hydroxymethyl compound to 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine. Reductive condensation of the nitrile 8 with diethyl N-(4-amino-benzoyl)-L-glutamate followed by ester hydrolysis gave 5-methyl-5-deazaaminopterin. Treatment of 12 with formaldehyde and Na(CN)BH3 afforded 5-methyl-5-deazamethotrexate, which was also prepared from 15 and dimethyl N-[(4-methylamino)benzoyl]-L-glutamate followed by ester hydrolysis. 5-Methyl-10-ethyl-5-deazaaminopterin was similarly prepared from 15. Biological evaluation of the 5-methyl-5-deaza analogues together with previously reported 5-deazaaminopterin and 5-deazamethotrexate for inhibition of dihydrofolate reductase (DHFR) isolated from L1210 cells and for their effect on cell growth inhibition, transport characteristics, and net accumulation of polyglutamate forms in L1210 cells revealed the analogues to have essentially the same properties as the appropriate parent compound, aminopterin or methotrexate (MTX), except that 20 and 21 were approximately 10 times more growth inhibitory than MTX. In in vivo tests against P388/0 and P388/MTX leukemia in mice, the analogues showed activity comparable to that of MTX, with the more potent 20 producing the same response in the P388/0 test as MTX but at one-fourth the dose; none showed activity against P388/MTX. Hydrolytic deamination of 12 and 20 produced 5-methyl-5-deazafolic acid and 5,10-dimethyl-5-deazafolic acid, respectively. In bacterial studies on

  1. Degradation of 5-FU by means of advanced (photo)oxidation processes: UV/H{sub 2}O{sub 2}, UV/Fe{sup 2+}/H{sub 2}O{sub 2} and UV/TiO{sub 2} — Comparison of transformation products, ready biodegradability and toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Lutterbeck, Carlos Alexandre, E-mail: lutterbeck@leuphana.de [Sustainable Chemistry and Material Resources, Institute of Sustainable and Environmental Chemistry, Faculty of Sustainability, Leuphana University of Lüneburg, Scharnhorststraße 1/C13, DE-21335 Lüneburg (Germany); Graduate Program in Environmental Technology, Universidade de Santa Cruz do Sul — UNISC, Av. Independência, 2293, CEP 96815-900 Santa Cruz do Sul, Rio Grande do Sul (Brazil); Wilde, Marcelo Luís, E-mail: wilde@leuphana.de [Sustainable Chemistry and Material Resources, Institute of Sustainable and Environmental Chemistry, Faculty of Sustainability, Leuphana University of Lüneburg, Scharnhorststraße 1/C13, DE-21335 Lüneburg (Germany); Baginska, Ewelina, E-mail: ewelina.baginska@leuphana.de [Sustainable Chemistry and Material Resources, Institute of Sustainable and Environmental Chemistry, Faculty of Sustainability, Leuphana University of Lüneburg, Scharnhorststraße 1/C13, DE-21335 Lüneburg (Germany); Leder, Christoph, E-mail: cleder@leuphana.de [Sustainable Chemistry and Material Resources, Institute of Sustainable and Environmental Chemistry, Faculty of Sustainability, Leuphana University of Lüneburg, Scharnhorststraße 1/C13, DE-21335 Lüneburg (Germany); Machado, Ênio Leandro, E-mail: enio@unisc.br [Graduate Program in Environmental Technology, Universidade de Santa Cruz do Sul — UNISC, Av. Independência, 2293, CEP 96815-900 Santa Cruz do Sul, Rio Grande do Sul (Brazil); and others

    2015-09-15

    The present study investigates the degradation of the antimetabolite 5-fluorouracil (5-FU) by three different advanced photo oxidation processes: UV/H{sub 2}O{sub 2}, UV/Fe{sup 2+}/H{sub 2}O{sub 2} and UV/TiO{sub 2}. Prescreening experiments varying the H{sub 2}O{sub 2} and TiO{sub 2} concentrations were performed in order to set the best catalyst concentrations in the UV/H{sub 2}O{sub 2} and UV/TiO{sub 2} experiments, whereas the UV/Fe{sup 2+}/H{sub 2}O{sub 2} process was optimized varying the pH, Fe{sup 2+} and H{sub 2}O{sub 2} concentrations by means of the Box–Behnken design (BBD). 5-FU was quickly removed in all the irradiation experiments. The UV/Fe{sup 2+}/H{sub 2}O{sub 2} and UV/TiO{sub 2} processes achieved the highest degree of mineralization, whereas the lowest one resulted from the UV/H{sub 2}O{sub 2} treatment. Six transformation products were formed during the advanced (photo)oxidation processes and identified using low and high resolution mass spectrometry. Most of them were formed and further eliminated during the reactions. The parent compound of 5-FU was not biodegraded, whereas the photolytic mixture formed in the UV/H{sub 2}O{sub 2} treatment after 256 min showed a noticeable improvement of the biodegradability in the closed bottle test (CBT) and was nontoxic towards Vibrio fischeri. In silico predictions showed positive alerts for mutagenic and genotoxic effects of 5-FU. In contrast, several of the transformation products (TPs) generated along the processes did not provide indications for mutagenic or genotoxic activity. One exception was TP with m/z 146 with positive alerts in several models of bacterial mutagenicity which could demand further experimental testing. Results demonstrate that advanced treatment can eliminate parent compounds and its toxicity. However, transformation products formed can still be toxic. Therefore toxicity screening after advanced treatment is recommendable. - Highlights: • Full primary elimination of 5-FU was

  2. Outcomes of liver transplantation in simultaneously hepatitis B surface antigen and hepatitis C virus RNA positive recipients: the deleterious effect of donor hepatitis B core antibody positivity.

    Science.gov (United States)

    Tandoi, F; Romagnoli, R; Martini, S; Mazza, E; Nada, E; Cocchis, D; Lupo, F; Salizzoni, M

    2012-09-01

    Recent data from Italian studies have shown excellent results of liver transplantation (LT) in hepatitis B virus (HBV)-infected patients with grafts from hepatitis B core antibody (HBcAb)-positive donors, whereas such grafts in hepatitis C virus (HCV)-infected recipients have displayed poorer outcomes. We investigated the results of LT with HBcAb-positive grafts in patients with ongoing HBV and HCV coinfections. From August 1999 to December 2009, we performed 27 adult primary LTs from deceased heart-beating donors into recipients showing hepatitis B surface antigen (HBsAg)- and HCV-RNA-positivity simultaneously: 12 patients received a graft from an HBsAg-negative HBcAb-positive donor (core+D group) and 15 from an HBcAb-negative donor (core-D group). Immunosuppression included a calcineurin inhibitor, antimetabolite and steroids which were suspended at 6 months. Anti-HBV prophylaxis was always perfomed with anti-HBs immunoglobulins and nucleos(t)idic analogues. The groups were similar regarding variables of donor, recipient, donor-recipient match, LT procedure, and acute rejection treatment. Median follow-up for surviving grafts was 67 months (range, 16-141). Among all patients, HCV-RNA remained positive after LT. The prevalence of histologically proven recurrent HCV hepatitis was similar in the 2 groups: 83% core+D vs 73% core-D. No recurrent HBV hepatitis occurred during the follow-up. Graft survival at 5 years was significantly lower in the core+D group (core+D 48% vs core-D 87%; P = .018), in which a significantly higher prevalence of graft loss was caused by HCV recurrence (core+D 5/12, 42% vs core-D 1/15, 7%; P = .03). All of the 5 core+D patients who lost their grafts due to HCV recurrence did not receive anti-HCV therapy (4 owing to an aggressive disease and 1 because of patient refusal). Outcomes of LT in patients with ongoing HBV and HCV coinfection are adversely affected by donor HBcAb positivity, an effect that is mainly mediated by the dismal course of

  3. ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

    International Nuclear Information System (INIS)

    Stewart, F.A.; Akleyev, A.V.; Hauer-Jensen, M.; Hendry, J.H.; Kleiman, N.J.; MacVittie, T.J.; Aleman, B.M.; Edgar, A.B.; Mabuchi, K.; Muirhead, C.R.; Shore, R.E.; Wallace, W.H.

    2012-01-01

    This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of ‘practical’ threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40–50 years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1–1.2, and in a few cases 1.5–2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating

  4. MODERN OPPORTUNITIES IN UVEITIS TREATMENT

    Directory of Open Access Journals (Sweden)

    D. A. Krakhmaleva

    2017-01-01

    Full Text Available Uveitis is a heterogeneous group  of inflammatory  diseases of the  choroid  and  adjacent structures. The pathophysiology of uveitis may be different. The treatment approach of infectious and non-infectious uveitis or masquerade syndrome is also different, but the correction of immune  disorders of any uveitis should play a leading role.  Infectious etiology requires the  pathogen eradication with adequate antimicrobial therapy. Therapy of noninfectious  uveitis based on the suppression of the local immune response. Depending on the activit y of the inflammatory process it may require  system or topical anti-inflammatory and/or immunosuppressive treatment with corticosteroids or immunomodulatory therapeutic agents. The main groups  of drugs are presented with the immunosuppressive alkylating agents,  corticosteroids, antimetabolites, T-cell inhibitors  and  biological modulators of the  immune  response. They can reduce the amount  and intensit y of recurrence, the number of complications, decrease  the dose  of corticosteroids or even replace them  in the  case of the  development of side effects and resistance. An alternative uveitis treatment is extracorporal efferent-quantum hemocorrection methods. The most  commonly used  is plasmapheresis based on the removal of plasma  with dissolved mediators of inflammation,  immune complexes, antibodies, exoand endotoxins.  Treatment should  be  pathogenetically oriented  and  localized to  the  affected tissue in order  to  maximize the  ratio  of efficacy / side effect. Often, however, this can’t be achieved.  So the  search continues to develop new therapies for use  in uveitis that  aim  to  suppress inflammatory  activit y,  prevent  accumulation of damage, and  preserve  visual function  for  patients with the minimum possible  side effects.

  5. Malignancy risk in patients with inflammatory eye disease treated with systemic immunosuppressive therapy: a tertiary referral cohort study.

    Science.gov (United States)

    Yates, William B; Vajdic, Claire M; Na, Renhua; McCluskey, Peter J; Wakefield, Denis

    2015-02-01

    To ascertain whether patients on long-term systemic immunosuppressive therapy for inflammatory eye disease (IED) are at increased risk of malignancy. A single-center, retrospective cohort study. We included 190 adults with IED treated with corticosteroids only (n = 58) or systemic immunosuppression (n = 132) for ≥6 months between 1985 and 2007. Immunosuppressed patients were treated with antimetabolites, T-cell inhibitors, and/or alkylating agents. Incident malignancies were ascertained by self-report and confirmed by medical record review. Multiple malignancies in a single patient were counted, except for nonmelanoma skin cancer (NMSC), where only the first was counted. Standardized incidence ratios (SIRs) were calculated by malignancy type. Cox regression models were used to compare malignancy incidence by treatment type. Risk of malignancy relative to the general population and within the cohort. During a median 7.34 years of follow-up, 25 malignancies were observed in 17 patients, namely, 2.10 per 100 person-years and 0.43 per 100 person-years in the immunosuppressed and corticosteroid only groups, respectively. In the immunosuppressed group, the most common malignancies were NMSC (n = 11) and non-Hodgkin's lymphoma (NHL; n = 4) and malignancy risk was significantly increased compared with the general population for any malignancy (SIR, 4.39; 95% CI, 2.78-6.59) and for any malignancy excluding NMSC (SIR, 4.16; 95% CI, 1.67-8.57). Significantly elevated SIRs were observed for NMSC and NHL in those treated with immunosuppressive agents. Compared with the corticosteroid treatment-only group, the immunosuppressed group was at an increased risk of any malignancy (adjusted hazard ratio, 4.36; 95% CI, 1.02-18.7), but not first malignancy (n = 17; adjusted hazard ratio, 2.56; 95% CI, 0.57-11.5). No cancer-related deaths were observed. Our findings suggest that patients with IED treated with systemic immunosuppressive therapy are at increased risk of malignancy

  6. Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery.

    Science.gov (United States)

    Cabourne, Emily; Clarke, Jonathan C K; Schlottmann, Patricio G; Evans, Jennifer R

    2015-11-06

    Raised intraocular pressure is a risk factor for glaucoma. One treatment option is glaucoma drainage surgery (trabeculectomy). Antimetabolites are used during surgery to reduce postoperative scarring during wound healing. Two agents in common use are mitomycin C (MMC) and 5-Fluorouracil (5-FU). To assess the effects of MMC compared to 5-FU as an antimetabolite adjunct in trabeculectomy surgery. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2015), EMBASE (January 1980 to October 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 October 2015. We included randomised controlled trials where wound healing had been modified with MMC compared to 5-FU. Two review authors independently selected trials and collected data. The primary outcome was failure of a functioning trabeculectomy one year after surgery. Secondary outcomes included mean intraocular pressure at one year. We considered three subgroups: high risk of trabeculectomy failure (people with previous glaucoma surgery, extracapsular cataract surgery, African origin and people with secondary glaucoma or congenital glaucoma); medium risk of trabeculectomy failure (people undergoing trabeculectomy with extracapsular cataract surgery) and low risk of trabeculectomy failure (people who have received no previous surgical eye intervention). We identified 11 trials that enrolled 687 eyes of 679 participants. The

  7. Closing Remarks.

    Science.gov (United States)

    Reed

    1996-01-01

    -related conditions were developed. * The only three drugs to date that have been specifically approved for the treatment of AIDS-AZT, DDI, and DDC-were developed under the guidance of the DCT, with Bruce Chabner as Scientific Director. * The first clinical trials conducted with each of these agents-AZT, DDI, and DDC-were performed in the Intramural Program of the DCT. * Concurrently, many of the exciting findings reported by the National Surgical Adjuvant Breast and Bowel Project over the past 10 years (as well as other cooperative groups) were a direct result of the strong support shown by Bruce Chabner during his tenure as Director of the Division of Cancer Treatment. Further, the list above does not include his personal labortory and clinical accomplishments, some of which are: * Development of the principles of use of important antimetabolites, such as methotrexate. * Elucidation of biochemical pathways affected, and the mechanisms of action, of antifols and other antimetabolites. * The conduct of seminal studies in the clinical staging of non-Hodgkin's lymphomas, using laparoscopy as a primary tool. * Important contributions to the development of multiagent regimens in the clinical treatment of lymphomas, and of Hodgkin's disease. * Developed and is editor of the textbook which is considered to be the primary reference source for anticancer chemotherapeutic agents [1]. With all of these accomplishments, his career is long from over. Having just become the Medical Director of the Cancer Center at the Massachusetts General Hospital, Bruce Chabner is uniquely poised to have an even more far-reaching impact on a discipline in which he has played such a strong seminal role. This author was never a postdoctoral fellow in Bruce Chabner's laboratory. However, more than any other single person, he has played a central role in my professional development. I know of many others for whom the same statement would be true. It is a pleasure for me to witness the launching of the second phase

  8. Polymorphism in the Methylenetetrahydrofolate Reductase and Thymidylate Synthase Gene Predicts for Response to Fluorouracil-based Chemotherapy in Advanced Gastric Cancer Patients

    Directory of Open Access Journals (Sweden)

    Jianwei Lu

    2013-03-01

    Full Text Available Objective: Fluorouracil (5-FU is widely used in the treatment of gastric cancer. Methylenetetrahydrofolate reductase (MTHFR and thymidylate synthetase (TS are important targets of many antimetabolites, including 5-FU. The relationship between polymorphism in the MTHFR (C677T, A1298C and TS (5`-TUR, 3`-UTR genotypes and sensitivity of gastric cancer to 5-FU-based chemotherapy is investigated in the present study. Methods: 173 patients with advanced gastric cancer were analyzed. All patients were treated with 5-FU-based chemotherapy (FOLFOX, FP and DCF regimen. DNA from peripheral blood leukocytes was obtained before the treatment. All genotypes were detected by PCR-RFLP. 12 germline polymorphisms within 2 genes were analyzed. The genotypes of MTHFR C677T, A1298C and TS 3`-TUR were analyzed in 173 patients while TS 5`-TUR in 135 patients. Results: The overall response rate (RR was 35.8%. The RR of the DCF regimen group was significantly higher than that of the FP and FOLFOX regimen groups (55.8% vs. 27.1%, 31.1%; P=0.006. The RR of the MTHFR C677T T/T genotype was significantly higher than that of the C/ C and C/T genotypes (73.3% vs. 28.0%; P=0.000. In MTHFR A1298C, a higher RR was observed in A/A genotype compared with the C/C and A/C genotypes (41.8% vs. 21.6%, P=0.011. The RR of -6/-6 bp and -6/+6 bp genotypes in TS 3`UTR was significantly higher than that of +6/+6 bp genotype (40.3% vs. 17.6%, P=0.014. There was no difference in RR according to TS 5`UTR polymorphism (2R/2R and 2R/3R: 41.7% vs. 3R/3R: 36.8%, P=0.487. The RR of MTHFR C677T T/T genotypes in FOLFOX or FP regimens was significantly higher than that of C/C and C/T genotypes (P=0.008, P=0.000 while no difference in DCF regimen. The RR of DCF regimen wassignificantly higher than that of FOLFOX and FP regimens in C/T and C/C genotypes (P=0.000. The MTHFR C677T T/T genotypes had a significantly higher incidence of grade 3/4 emesis (66.7% and stomatitis (30.0% than patients with C/T or

  9. Risk-directed therapy for childhood acute lymphoblastic leukemia. Results of the Associazione Italiana Ematologia Oncologia Pediatrica '82 studies.

    Science.gov (United States)

    Vecchi, V; Aricò, M; Basso, G; Ceci, A; Madon, E; Mandelli, F; Masera, G; Massimo, L; Pession, A; Zanesco, L

    1993-10-15

    patients, a successor study (8503) was developed that yielded a 5-year EFS of 46.1% (SE, 5.1). Site-specific relapse rates were 18.5% (LR), 13.4% (AR), 35.1% (HR on 8303), and 18.3% (HR in Study 8503) for bone marrow and 9.2%, 7.9%, 17.5%, and 19.3%, respectively, for the CNS (isolated). Isolated testicular relapse was observed in 3.9% of male patients. This risk-directed therapy cured at least 50% of patients with ALL with relatively nonintensive therapy. The 80% overall survival rate for LR and AR patients at 7 years suggested that the total cure rate may be higher than 50% because of the significant salvage rate for patients who received antimetabolite-based therapy initially.

  10. Biochemical criteria of toxicity of therapy with high doses of methotrexate in children with osteosarcoma

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    A. M. Strizhevskaya

    2015-01-01

    Full Text Available Methotrexate (Mtx is a cytotoxic drug from the group of antimetabolites, folic acid antagonists. High-dose (HD Mtx in pediatric oncology are used for the treatment of osteosarcoma (OS, and other types of tumors. This therapy has allowed to achieve a five-year relapse-free survival rates up to 80 % in patients with OS. However, the high toxicity of Mtx is a serious constraint in achieving the maximum therapeutic effect, which in most cases poses the occurrence of side effects in patients on various organs and systems. Treatment should be under strict laboratory monitoring, primarily therapeutic drug monitoring the concentration of Mtx in serum.246 children (boys – 125, girls – 121 aged 5 to 16 years with osteosarcoma (mean age 12.2 years who were treated in N.N. Blokhin Russian Cancer Research Center from 2006 to 2013. Patients were conducted from 1 to 8 courses HD Mtx at a dose of 8 or 12 g/m2 , administered within 4 h of infusion on the background of alkaline prehydrate. Leucovorin was administered intravenously, every 6 hours, starting 24 h from the start of the Mtx infusion. 1137 courses of HD Mtx were conducted with FPIA method (analyzer TDx/Flx, Abbott, USA. The technique of monitoring of homocysteine (Hcy in the blood serum by analyzer Vitros 5/1FS (Johnson & Johnson, USA during the entire course of high-dose Mtx was tested. In groups calculated pharmacokinetic parameters Mtx were tested: area under the pharmacokinetic curve (MtxAUC, clearance of methotrexate (ClMtx, the elimination half-life (T1/2 and the total time of excretion (Ttotal. Normal excretion of Mtx was revealed at 1050 courses Mtx, corresponding to the following values: 4 h – 1109 ± 283 μmol/l; 24 h – 4,67 ± 0,95 μmol/l; 42 h – 0,38 ± 0.16 µmol/l; 48 h – less than 0,23 ± 0.04 µmol/l; 72 h of 0.07 ± 0,03 µmol/l; 96 h of 0.03 ± 0.01 µmol/l. At 87 courses identified delayed Mtx excretion, accounting for 7.6 % of all courses. In all measured parameters

  11. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial.

    Science.gov (United States)

    Khanna, Reena; Bressler, Brian; Levesque, Barrett G; Zou, Guangyong; Stitt, Larry W; Greenberg, Gordon R; Panaccione, Remo; Bitton, Alain; Paré, Pierre; Vermeire, Séverine; D'Haens, Geert; MacIntosh, Donald; Sandborn, William J; Donner, Allan; Vandervoort, Margaret K; Morris, Joan C; Feagan, Brian G

    2015-11-07

    Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95

  12. Distinct Paths for Basic Amino Acid Export in Escherichia coli: YbjE (LysO) Mediates Export of L-Lysine.

    Science.gov (United States)

    Pathania, Amit; Sardesai, Abhijit A

    2015-06-15

    In Escherichia coli, argO encodes an exporter for L-arginine (Arg) and its toxic analogue canavanine (CAN), and its transcriptional activation and repression, by Arg and L-lysine (Lys), respectively, are mediated by the regulator ArgP. Accordingly argO and argP mutants are CAN supersensitive (CAN(ss)). We report the identification of ybjE as a gene encoding a predicted inner membrane protein that mediates export of Lys, and our results confirm the previous identification with a different approach of YbjE as a Lys exporter, reported by Ueda and coworkers (T. Ueda, Y. Nakai, Y. Gunji, R. Takikawa, and Y. Joe, U.S. patents 7,629,142 B2 [December 2009] and 8,383,363 B1 [February 2013] and European patent 1,664,318 B1 [September 2009]). ybjE was isolated as a multicopy suppressor of the CAN(ss) phenotype of a strain lacking ArgO. The absence of YbjE did not confer a CAN(ss) phenotype but instead conferred hypersensitivity to the lysine antimetabolite thialysine and led to growth inhibition by the dipeptide lysylalanine, which is associated with elevated cellular Lys content. YbjE overproduction resulted in Lys excretion and syntrophic cross-feeding of a Lys auxotroph. Constitutive overexpression of argO promoted Lys cross-feeding that is indicative of a latent Lys export potential of ArgO. Arg modestly repressed ybjE transcription in an ArgR-dependent manner, and ArgR displayed Arg-sensitive binding to the ybjE promoter region in vitro. Our studies suggest that the reciprocal repression of argO and ybjE, respectively, by Lys and Arg confers the specificity for basic amino acid export by distinct paths and that such cross-repression contributes to maintenance of cytoplasmic Arg/Lys balance. We propose that YbjE be redesignated LysO. This work ascribes a lysine export function to the product of the ybjE gene of Escherichia coli, leading to a physiological scenario wherein two proteins, ArgO and YbjE, perform the task of separately exporting arginine and lysine

  13. Análisis del tratamiento quirúrgico del glaucoma en Ciudad de La Habana durante el año 2000 Analysis of the surgical treatment of Glaucoma the City of Havana in 2000

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    Beatriz Zozaya Aldana

    2008-12-01

    techniques were reviewed. No difference was found in terms of sex, but Caucasians and 51-70 y age group were predominant. The main type of glaucoma in these surgeries was Simple Chronic Glaucoma; there was less non-serious cases at the time of surgery than at the time of diagnosis. The most frequent cause to decide upon the surgical treatment was lack of control of ocular pressure in spite of the medical treatment, the most used technique was Trabeculectomy and a percentage of surgeries used anti-metabolites. The main complication found was the bule closing. The percentage of re-operated cases was low.

  14. Genetical Studies On Haploid Production In Some Ornamental Plants

    International Nuclear Information System (INIS)

    MOSTAFA, M.A.M.

    2013-01-01

    growth, (2) resistant, which resist specific drugs, antimetabolites, or abnormal environmental or nutritional condition and (3) autotrophic mutants, that grow in deficient media and are capable of synthesizing some substances normally required for wild lines. The use of mutagenesis and in vitro induce mutation should provide a new input to the solution if breeding problems in crop plant (Ancora and Sonnino, 1987). The aim of the present investigation is production of haploid plants through anther culture in N. alata and study the effect of gamma rays, salt stress and combined effect between them on it. Morever, determining the changes in the internal composition of the cell as proline and protein. Also, to study the molecure diversity as revealed by; Protein Acrylamid Gel Electrophoresis - SDS (PAGE-SDS), Random Amplified Polymorphic DNA (RAPD) .

  15. Flavor vs Energy Sensing in Brain Reward Circuits

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    Ivan E De Araujo

    2014-07-01

    intake produces significantly greater levels of dopamine efflux compared to artificial sweetener intake in dorsal striatum, whereas disrupting glucose oxidation suppresses dorsal striatum dopamine efflux; conversely, inhibiting striatal dopamine receptor signalling during glucose intake in sweet-naïve animals resulted in reduced, artificial sweetener-like intake of glucose during subsequent glucoprivation [1]. This is consistent with data using physiological preparations demonstrating that intravenous administration of the glucose anti-metabolite 2-deoxy-D-glucose robustly suppresses dopamine efflux in dorsal striatum, an effect annulled by subsequent infusions of glucose via the same route [2]. Of note is the fact that the same study demonstrates that glucose utilization rates control both nutrient choice in tasteless mutant mice. Overall, these results point to the notion that glucose oxidation controls intake levels of sweet tastants by regulating the midbrain dopaminergic nigro-striatal pathway, and suggest that glucose utilization is one critical physiological signal involved in the control of goal-directed sweetener intake [1]. It is equally striking, on the other hand, that the other major midbrain dopaminergic system, the mesolimbic pathway, is considerably less selective in their responses to sweeteners: sweetness and energy appear to independently stimulate dopamine release into the nucleus accumbens of ventral striatum, in the absence of any apparent additive effects; in fact, while artificial sweeteners cause dopamine to be released in ventral striatum of wild-type mice, sugar (bot not sweeteners induces similar effluxes in ventral striatum of tasteless mutant mice [3]. Such nigro-striatal selectivity to energy-containing sweeteners may have a deeper behavioral meaning: dopamine release into dorsal striatum is not only critical for motivation to eat [4], but also for the formation of compulsive behavioral habits (whereas the nucleus accumbens seem to play a

  16. Device-modified trabeculectomy for glaucoma.

    Science.gov (United States)

    Wang, Xue; Khan, Rabeea; Coleman, Anne

    2015-12-01

    Glaucoma is an optic neuropathy that leads to vision loss and blindness. It is the second most common cause of irreversible blindness worldwide. The main treatment for glaucoma aims to reduce intraocular pressure (IOP) in order to slow or prevent further vision loss. IOP can be lowered with medications, and laser or incisional surgeries. Trabeculectomy is the most common incisional surgical procedure to treat glaucoma. Device-modified trabeculectomy is intended to improve drainage of the aqueous humor to lower IOP. Trabeculectomy-modifying devices include Ex-PRESS, Ologen, amniotic membrane, expanded polytetrafluoroethylene (E-PTFE) membrane, Gelfilm and others. However, the effectiveness and safety of these devices are uncertain. To assess the relative effectiveness, primarily with respect to IOP control and safety, of the use of different devices as adjuncts to trabeculectomy compared with standard trabeculectomy in eyes with glaucoma. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to December 2014), EMBASE (January 1980 to December 2014), PubMed (1948 to December 2014), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 22 December 2014. We included randomized controlled trials comparing devices used during trabeculectomy with trabeculectomy alone. We also included studies where antimetabolites were used in either or both treatment groups. We used standard procedures