WorldWideScience

Sample records for antimetabolites

  1. Antimetabolite Treatment for Pancreatic Cancer

    OpenAIRE

    Valenzuela, Malyn May Asuncion; Neidigh, Jonathan W.; Wall, Nathan R.

    2014-01-01

    Pancreatic cancer is a deadly and aggressive disease. Less than 1% of diagnosed patients survive 5 years with an average survival time of only 4–8 months. The only option for metastatic pancreatic cancer is chemotherapy where only the antimetabolites gemcitabine and 5-fluorouracil are used clinically. Unfortunately, efforts to improve chemotherapy regimens by combining, 5-fluorouracil or gemcitabine with other drugs, such as cisplatin or oxaliplatin, have not increased cell killing or improve...

  2. Trypan blue identifies antimetabolite treatment area in trabeculectomy

    OpenAIRE

    Healey, P R; Crowston, J G

    2005-01-01

    Aim: Colourless solutions of mitomycin C (MMC) and 5-fluorouracil (5-FU) are widely used during trabeculectomy to inhibit postoperative scarring. The poor visibility of these agents on the eye has several drawbacks including the inability to accurately assess the area of treatment. This study examined the utility of using trypan blue dye to colour antimetabolites used during trabeculectomy and the effect of trypan blue on antimetabolite cytotoxicity in vitro.

  3. Targeting one carbon metabolism with an antimetabolite disrupts pyrimidine homeostasis and induces nucleotide overflow

    OpenAIRE

    Ser, Zheng; GAO, XIA; Johnson, Christelle; Mehrmohamadi, Mahya; Liu, Xiaojing; Li, SiQi; Locasale, Jason W.

    2016-01-01

    Anti-metabolite agents that affect nucleotide metabolism are frontline chemotherapy agents in several cancers and often successfully target one carbon metabolism. However, the precise mechanisms and resulting determinants of their therapeutic value are unknown. We show that 5-fluorouracil (5-FU), a commonly used anti-metabolite therapeutic with varying efficacy, induces specific alterations to nucleotide metabolism by disrupting pyrimidine homeostasis. An integrative metabolomics analysis of ...

  4. 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

    BACKGROUND AND OBJECTIVE: Through interruption of maintenance treatment with 6-mercaptopurine (6MP), toxicity after high-dose methotrexate (HDMTX) may compromise the efficiency of the treatment of children with acute lymphocytic leukaemia (ALL). We investigated the influence of polymorphisms 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...

  5. Mode of action of the biotin antimetabolites actithiazic acid and alpha-methyldethiobiotin.

    OpenAIRE

    Eisenberg, M. A.; Hsiung, S C

    1982-01-01

    Actithiazic acid and alpha-methyldethiobiotin inhibited the conversion of dethiobiotin to biotin resting-cell suspensions of Escherichia coli. The concentrations which effected 50% inhibition were 0.45 and 1.1 microM for actithiazic acid and alpha-methyldethiobiotin, respectively. Cells grown in low concentrations of the two biotin antimetabolites showed derepression of the biotin A operon, as evidenced by the enhanced levels of the enzymes 7,8-diaminopelargonic acid aminotransferase and deth...

  6. Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase

    Directory of Open Access Journals (Sweden)

    Asuncion Valenzuela MM

    2015-02-01

    Full Text Available Malyn M Asuncion Valenzuela, Imilce Castro, Amber Gonda, Carlos J Diaz Osterman, Jessica M Jutzy, Jonathan R Aspe, Salma Khan, Jonathan W Neidigh, Nathan R Wall Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA Abstract: New agent development, mechanistic understanding, and combinatorial partnerships with known and novel modalities continue to be important in the study of pancreatic cancer and its improved treatment. In this study, known antimetabolite drugs such as gemcitabine (ribonucleotide reductase inhibitor and 5-fluorouracil (thymidylate synthase inhibitor were compared with novel members of these two drug families in the treatment of a chemoresistant pancreatic cancer cell line PANC-1. Cellular survival data, along with protein and messenger ribonucleic acid expression for survivin, XIAP, cIAP1, and cIAP2, were compared from both the cell cytoplasm and from exosomes after single modality treatment. While all antimetabolite drugs killed PANC-1 cells in a time- and dose-dependent manner, neither family significantly altered the cytosolic protein level of the four inhibitors of apoptosis (IAPs investigated. Survivin, XIAP, cIAP1, and cIAP2 were found localized to exosomes where no significant difference in expression was recorded. This inability for significant and long-lasting expression may be a reason why pancreatic cancer lacks responsiveness to these and other cancer-killing agents. Continued investigation is required to determine the responsibilities of these IAPs in their role in chemoresistance in pancreatic adenocarcinoma. Keywords: IAPs, exosomes, pancreatic cancer, antimetabolites, gemcitabine, cladribine, hydroxyurea, 5-fluorodeoxyuridine, 5-fluorouracil

  7. Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle.

    Science.gov (United States)

    McEwan, Conor; Kamila, Sukanta; Owen, Joshua; Nesbitt, Heather; Callan, Bridgeen; Borden, Mark; Nomikou, Nikolitsa; Hamoudi, Rifat A; Taylor, Mark A; Stride, Eleanor; McHale, Anthony P; Callan, John F

    2016-02-01

    In this manuscript we describe the preparation of an oxygen-loaded microbubble (O2MB) platform for the targeted treatment of pancreatic cancer using both sonodynamic therapy (SDT) and antimetabolite therapy. O2MB were prepared with either the sensitiser Rose Bengal (O2MB-RB) or the antimetabolite 5-fluorouracil (O2MB-5FU) attached to the microbubble (MB) surface. The MB were characterised with respect to size, physical stability and oxygen retention. A statistically significant reduction in cell viability was observed when three different pancreatic cancer cell lines (BxPc-3, MIA PaCa-2 and PANC-1), cultured in an anaerobic cabinet, were treated with both SDT and antimetabolite therapy compared to either therapy alone. In addition, a statistically significant reduction in tumour growth was also observed when ectopic human xenograft BxPC-3 tumours in SCID mice were treated with the combined therapy compared to treatment with either therapy alone. These results illustrate not only the potential of combined SDT/antimetabolite therapy as a stand alone treatment option in pancreatic cancer, but also the capability of O2-loaded MBs to deliver O2 to the tumour microenvironment in order to enhance the efficacy of therapies that depend on O2 to mediate their therapeutic effect. Furthermore, the use of MBs to facilitate delivery of O2 as well as the sensitiser/antimetabolite, combined with the possibility to activate the sensitiser using externally applied ultrasound, provides a more targeted approach with improved efficacy and reduced side effects when compared with conventional systemic administration of antimetabolite drugs alone. PMID:26702983

  8. Biosynthesis of the antimetabolite 6-thioguanine in Erwinia amylovora plays a key role in fire blight pathogenesis.

    Science.gov (United States)

    Coyne, Sébastien; Chizzali, Cornelia; Khalil, Mohammed N A; Litomska, Agnieszka; Richter, Klaus; Beerhues, Ludger; Hertweck, Christian

    2013-09-27

    Sulfur for fire: The molecular basis for the biosynthesis of the antimetabolite 6-thioguanine (6TG) was unveiled in Erwinia amylovora, the causative agent of fire blight. Bioinformatics, heterologous pathway reconstitution in E. coli, and mutational analyses indicate that the protein YcfA mediates guanine thionation in analogy to 2-thiouridylase. Assays in planta and in cell cultures reveal for the first time a crucial role of 6TG in fire blight pathogenesis. PMID:24038828

  9. 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.

  10. The combination effects of bendamustine with antimetabolites against childhood acute lymphoblastic leukemia cells.

    Science.gov (United States)

    Goto, Shoko; Goto, Hiroaki; Yokosuka, Tomoko

    2016-05-01

    Bendamustine combined with other drugs is clinically efficacious for some adult lymphoid malignancies, but to date there are no reports of the use of such combinatorial approaches in pediatric patients. We investigated the in vitro activity of bendamustine combined with other antimetabolite drugs on B cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines established from pediatric patients with refractory or relapsed ALL. We also developed a mathematically drown improved isobologram method to assess the data objectively. Three BCP-ALL cell lines; YCUB-2, YCUB-5, and YCUB-6, were simultaneously exposed to various concentrations of bendamustine and cladribine, cytarabine, fludarabine, or clofarabine. Cell growth inhibition was determined using the WST-8 assay. Combinatorial effects were estimated using our improved isobologram method with IC80 (drug concentration corresponding to 80 % of maximum inhibition). Bendamustine alone inhibited ALL cell growth with mean IC80 values of 11.30-18.90 μg/ml. Combinations of bendamustine with other drugs produced the following effects: (1) cladribine; synergistic-to-additive on all cell lines; (2) cytarabine; synergistic-to-additive on YCUB-5 and YCUB-6, and synergistic-to-antagonistic on YCUB-2; (3) fludarabine; additive-to-antagonistic on YCUB-5, and synergistic-to-antagonistic on YCUB-2 and YCUB-6; (4) clofarabine; additive-to-antagonistic on all cell lines. Flow cytometric analysis also showed the combination effects of bendamustine and cladribine. Bendamustine/cladribine or bendamustine/cytarabine may thus represent a promising combination for salvage treatment in childhood ALL. PMID:26886449

  11. (64)Cu-ATSM therapy targets regions with activated DNA repair and enrichment of CD133(+) cells in an HT-29 tumor model: Sensitization with a nucleic acid antimetabolite.

    Science.gov (United States)

    Yoshii, Yukie; Furukawa, Takako; Matsumoto, Hiroki; Yoshimoto, Mitsuyoshi; Kiyono, Yasushi; Zhang, Ming-Rong; Fujibayashi, Yasuhisa; Saga, Tsuneo

    2016-06-28

    (64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a potential theranostic agent targeting the over-reduced state under hypoxia within tumors. Recent clinical Cu-ATSM positron emission tomography studies have revealed a correlation between uptake and poor prognosis; however, the reason is unclear. Here, using a human colon carcinoma HT-29 model, we demonstrated that the intratumoral (64)Cu-ATSM high-uptake regions exhibited malignant characteristics, such as upregulated DNA repair and elevated %CD133(+) cancer stem-like cells. Based on this evidence, we developed a strategy to enhance the efficacy of (64)Cu-ATSM internal radiotherapy (IRT) by inhibiting DNA repair with a nucleic acid (NA) antimetabolite. The results of the analyses showed upregulation of pathways related to DNA repair along with NA incorporation (bromodeoxyuridine uptake) and elevation of %CD133(+) cells in (64)Cu-ATSM high-uptake regions. In an in vivo(64)Cu-ATSM treatment study, co-administration of an NA antimetabolite and (64)Cu-ATSM synergistically inhibited tumor growth, with little toxicity, and effectively reduced %CD133(+) cells. (64)Cu-ATSM therapy targeted malignant tumor regions with activated DNA repair and high concentrations of CD133(+) cells in the HT-29 model. NA antimetabolite co-administration can be an effective approach to enhance the therapeutic effect of (64)Cu-ATSM IRT. PMID:26996296

  12. The Pseudomonas aeruginosa antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid inhibits growth of Erwinia amylovora and acts as a seed germination-arrest factor.

    Science.gov (United States)

    Lee, Xiaoyun; Azevedo, Mark D; Armstrong, Donald J; Banowetz, Gary M; Reimmann, Cornelia

    2013-02-01

    The Pseudomonas aeruginosa antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) shares biological activities with 4-formylaminooxyvinylglycine, a related molecule produced by Pseudomonas fluorescens WH6. We found that culture filtrates of a P. aeruginosa strain overproducing AMB weakly interfered with seed germination of the grassy weed Poa annua and strongly inhibited growth of Erwinia amylovora, the causal agent of the devastating orchard crop disease known as fire blight. AMB was active against a 4-formylaminooxyvinylglycine-resistant isolate of E. amylovora, suggesting that the molecular targets of the two oxyvinylglycines in Erwinia do not, or not entirely, overlap. The AMB biosynthesis and transport genes were shown to be organized in two separate transcriptional units, ambA and ambBCDE, which were successfully expressed from IPTG-inducible tac promoters in the heterologous host P. fluorescens CHA0. Engineered AMB production enabled this model biocontrol strain to become inhibitory against E. amylovora and to weakly interfere with the germination of several graminaceous seeds. We conclude that AMB production requires no additional genes besides ambABCDE and we speculate that their expression in marketed fire blight biocontrol strains could potentially contribute to disease control. PMID:23757135

  13. Spectral, thermal, and antimicrobial studies on the copper(II), zinc(II), cadmium(II), and mercury(II) chelates of a new antimetabolite-5-dimethylaminomethyl-2-thiouracil

    International Nuclear Information System (INIS)

    Owing to the presence of multiple donor atoms such as N(1)H, C(2)SH, N(3), C(4)O and C-N-C in the newly synthesized antimetabolite, namely 5-dimethylaminomethyl-2-thiouracil, preferences of the heteroatoms for coordination with metal ions like Cd(II) were explored. The complexes isolated were characterized by chemical analysis and spectroscopic techniques. It is shown that the ligand behaves as a bidentate/tetradentate chelating ligand in complexes CdX2·DMAMTU (X = Cl, Br) and Cd(NO3)2·DMAMTU, respectively. Invariably in all the complexes one of the donor atoms is the soft C(2)SH

  14. 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

    ABSTRACT: Predicting the response to medical therapy and subsequently individualizing the treatment to increase efficacy or reduce toxicity has been a longstanding clinical goal. Not least within oncology, where many patients fail to be cured, and others are treated to or beyond the limit...... of acceptable toxicity, an individualized therapeutic approach is indicated. The mapping of the human genome and technological developments in DNA sequencing, gene expression profiling, and proteomics have raised the expectations for implementing genotype-phenotype data into the clinical decision process......, 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...

  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

    ABSTRACT: Predicting the response to medical therapy and subsequently individualizing the treatment to increase efficacy or reduce toxicity has been a longstanding clinical goal. Not least within oncology, where many patients fail to be cured, and others are treated to or beyond the limit of...... acceptable toxicity, an individualized therapeutic approach is indicated. The mapping of the human genome and technological developments in DNA sequencing, gene expression profiling, and proteomics have raised the expectations for implementing genotype-phenotype data into the clinical decision process, 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. Comparative study between trabeculectomy with photodynamic therapy (BCECF-AM and trabeculectomy with antimetabolite (MMC in the treatment of primary open angle glaucoma

    Directory of Open Access Journals (Sweden)

    Saeed AM

    2012-10-01

    Full Text Available Ahmed M SaeedOphthalmology Department, Benha University, Benha, EgyptBackground: Various methods have been investigated to avoid postoperative scarring of the filtering bleb in modern glaucoma surgery. Most deal with the application of antimetabolic drugs such as mitomycin C (MMC. 2’,7’-bis-(2-carboxyethyl-5-(and-6-carboxyfluorescein, acetoxymethyl ester (BCECF-AM is a locally acting intracellular photosensitizer which could control and decrease postoperative fibrosis at the trabeculectomy site.Purpose: To compare the effect of photodynamic therapy in combination with trabeculectomy to the effect of MMC combined with the same procedure in controlling postoperative intraocular pressure (IOP in patients with medically uncontrolled primary open angle glaucoma (1ry OAG.Methods: A randomized controlled clinical trial was conducted on 76 eyes of 76 patients divided into three groups undergoing trabeculectomy, trabeculectomy with BCECF-AM (group A, trabeculectomy with MMC (group B, and trabeculectomy only as a control group (group C. Patients were reviewed postoperatively for clinical evaluation and photo documentation of the blebs with a fundus camera and ultrasonic biomicroscopy (UBM. The desirable effect of the adjunctive material was evaluated according to the clinical efficacy, tolerability, and safety by comparison with the control group.Setting: Benha University Hospital, Benha, Egypt.Results: After a mean follow-up of 24 months, all procedures succeeded in lowering IOP. The cumulative probability of complete success at the 24 month follow-up was 91% for group B, compared to 82% and 81.5% for group A and group C, respectively. The percentage of complete success was highest for group B, second highest for group A, and lowest for group C over the follow-up period; however, these differences were not statistically significant (P > 0.05. Regarding the bleb morphology and UBM reflectivity, the differences were not statistically significant (P > 0.05. The mean bleb height and breadth were larger in groups A and B in comparison to group C over the study period. The mean aqueous drainage route was similar in groups A and C, but less than in group B at 3 and 12 months postoperatively. Complications were generally mild and less marked in group A and C than group B.Conclusion: Cellular photoablation using BCECF-AM seems to be a feasible new method to use in combination with glaucoma filtration surgery. Although MMC might be considered a more potent adjunctive to trabeculectomy in promoting IOP reduction, photodynamic therapy carries relatively less risk of adverse effects and complications. Cellular photoablation using BCECF-AM could be considered efficient, tolerable and relatively safer in managing patients with 1ry OAG. Further studies are necessary to determine the safety and the reliability of this therapy.Keywords: photodynamic therapy, mitomycin C, trabeculectomy, open angle glaucoma, ultrasonic biomicroscopy

  17. Nab-paclitaxel and Gemcitabine vs Gemcitabine Alone as Adjuvant Therapy for Patients With Resected Pancreatic Cancer (the "Apact" Study)

    Science.gov (United States)

    2016-06-22

    Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Digestive System Diseases; Endocrine System Diseases; Gemcitabine; Antimetabolites, Antineoplastic

  18. Drug: D00584 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00584 Drug Fluorouracil (JP16/USP/INN); 5-FU ... (TN); Adrucil (TN); Carac (TN); Fluoroplex (TN) C4 ... in Japan [BR:br08301] 4 Agents affecting cellular fu nction 42 Antineoplastics 422 Antimetabolites 4223 ...

  19. Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Asplund, Anna;

    2015-01-01

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines...... 85 antimetabolites that can inhibit growth of, or even kill, any of the cell lines, while at the same time not being toxic for 83 different healthy human cell types. 60 of these antimetabolites were found to inhibit growth in all cell lines. Finally, we experimentally validated one of the predicted...... antimetabolites using two cell lines with different phenotypic origins, and found that it is effective in inhibiting the growth of these cell lines. Using immunohistochemistry, we also showed high or moderate expression levels of proteins targeted by the validated antimetabolite. Identified anti-growth factors...

  20. Cytarabine Lipid Complex Injection

    Science.gov (United States)

    Cytarabine lipid complex is used to treat lymphomatous meningitis (a type of cancer in the covering of the spinal cord and brain). Cytarabine lipid complex is in a class of medications called antimetabolites. ...

  1. Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity

    OpenAIRE

    Nagai, Shinjiro; Takenaka, Kazumasa; Nachagari, Deepa; Rose, Charles; Domoney, Kali; Sun, Daxi; Sparreboom, Alex; Schuetz, John D.

    2011-01-01

    Purine nucleoside antimetabolites, such as clofarabine, are effective antileukemic agents. However, their effectiveness depends on an initial activation step in which they are monophosphorylated by deoxycytidine kinase (dCK). Some purine nucleoside antimetabolites and their monophosphate derivatives are exported by the ABC transporter ABCG2. Because clofarabine is a dCK substrate, and we show substantial variation in dCK and ABCG2 in myeloid leukemia, we hypothesized that the activity of dCK ...

  2. Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer

    OpenAIRE

    Boulware, Stephen B.; Christensen, Laura A.; Thames, Howard; Coghlan, Lezlee; Vasquez, Karen M.; Finch, Rick A.

    2013-01-01

    Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly-proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex-forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene,...

  3. Metabolic activation and antineoplastic-selective mechanism of action of two novel fluoropyrimidines

    International Nuclear Information System (INIS)

    The coadministration of tetrahydrouridine (H4Urd) diverted the metabolism of 3H-5-fluoro-2'-deoxycytidine (FdCyd) in human epidermoid laryngeal carcinoma (HEp-2) cells through the deoxycytidine kinase-deoxycytidylate deaminase (dCK-dCMPD) pathway to the formation of 5-fluorodeoxyuridylate (FdUMP) without the incorporation of 5-fluorouridylate (FUMP) into RNA or the formation of RNA-level antimetabolite pools. Antimetabolite pool sizes, as assayed by HPLC, following treatment of BD2F1 mice bearing ascitic mammary adenocarcinoma-755 (ADC-755) or Lewis lung carcinoma (LLC) with 3H-FdCyd + H4 Urd resulted in pool sizes indicative of a tumor-selective, dual pathway metabolism of FdCyd via both the cytidine deaminase-deoxythymidine kinase (CD-dTK) and dCK-dCMPD pathways. In contrast to the high levels of all RNA- and DNA-level antimetabolites derived from FdCyd found in tumor tissue, in normal tissues (bone marrow, intestine, liver and spleen) and in serum, FdCyd was metabolized to only a small extent, all antimetabolite pools were markedly lower. 3H-FdCyd + H4Urd exposure resulted in selective incorporation of antimetabolites into tumor RNA and DNA. dCMPD and CD enzyme assays have confirmed that H4Urd administration effectively inhibited the low CD activity in normal, but not the elevated levels found in tumor tissue

  4. Liquid chromatography-tandem mass spectrometry quantification of 6-thioguanine in DNA using endogenous guanine as internal standard

    DEFF Research Database (Denmark)

    Jacobsen, Jack Hummeland; Schmiegelow, Kjeld; Nersting, Jakob

    Thiopurines are S-substituted antimetabolites that are widely used in the treatment of hematological malignancies and as immunosuppressants. Because of extensive inter-individual variation in drug disposition and the significant toxicity associated with thiopurine therapy, there is a need for imp...

  5. Predictive impact of RRM1 protein expression on vinorelbine efficacy in NSCLC patients randomly assigned in a chemotherapy phase III trial

    DEFF Research Database (Denmark)

    Vilmar, A C; Santoni-Rugiu, E; Sørensen, Jens Benn

    2013-01-01

    Platinum-based doublets (PBDs) remain the cornerstone of treatment in non-small-cell lung cancer (NSCLC) and may include gemcitabine. A biomarker predicting sensitivity to this antimetabolite would represent a major step forward. Accordingly, we explored the predictive role of ribonucleotide...

  6. Vitamin D in combination cancer treatment

    OpenAIRE

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

    2010-01-01

    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-distu...

  7. Vitamin D in combination cancer treatment

    OpenAIRE

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

    2010-01-01

    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-...

  8. Mangotoxin production of Pseudomonas syringae pv. syringae is regulated by MgoA

    NARCIS (Netherlands)

    Carrion, V.J.; Voort, van der M.; Arrebola, E.; Gutiérrez-Barranquero, J.A.; Vicente, de A.; Raaijmakers, J.M.; Cazorla, F.M.

    2014-01-01

    Background The antimetabolite mangotoxin is a key factor in virulence of Pseudomonas syringae pv. syringae strains which cause apical necrosis of mango trees. Previous studies showed that mangotoxin biosynthesis is governed by the mbo operon. Random mutagenesis led to the identification of two other

  9. Systemic Medications for Psoriasis and Psoriatic Arthritis Including Biologics

    Science.gov (United States)

    ... as antimetabolites. It was initially used to treat cancer. Methotrexate was found to be effective in clearing psoriasis ... sold as a generic. The doses administered for cancer are considerably higher than those given for psoriasis ... is prescribed for adults with severe psoriasis or ...

  10. Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer.

    Science.gov (United States)

    Boulware, Stephen B; Christensen, Laura A; Thames, Howard; Coghlan, Lezlee; Vasquez, Karen M; Finch, Rick A

    2014-09-01

    Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex-forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene, thereby inducing replication-independent, unscheduled DNA repair synthesis (UDS) preferentially in the TFO-targeted region. The TFO-directed UDS facilitated incorporation of the antimetabolite, gemcitabine (GEM), into the damaged oncogene, thereby potentiating the anti-tumor activity of GEM. Mice bearing COLO 320DM human colon cancer xenografts (containing amplified c-MYC) were treated with a TFO targeted to c-MYC in combination with GEM. Tumor growth inhibition produced by the combination was significantly greater than with either TFO or GEM alone. Specific TFO binding to the genomic c-MYC gene was demonstrated, and TFO-induced DNA damage was confirmed by NBS1 accumulation, supporting a mechanism of enhanced efficacy of GEM via TFO-targeted DNA damage-induced UDS. Thus, coupling antimetabolite chemotherapeutics with a strategy that facilitates selective targeting of cells containing amplification of cancer-relevant genes can improve their activity against solid tumors, while possibly minimizing host toxicity. PMID:23681918

  11. Base-Modified Nucleosides as Chemotherapeutic Agents: Past and Future.

    Science.gov (United States)

    Burke, Matthew P; Borland, Kayla M; Litosh, Vladislav A

    2016-01-01

    Nucleoside and nucleobase antimetabolites have substantially impacted treatment of cancer and infections. Their close resemblance to natural analogs gives them the power to interfere with a variety of intracellular targets, which on one hand gives them high potency, but on the other hand incurs severe side effects, especially of the chemotherapeutics used against malignancies. Therefore, the development of novel nucleoside analogs with widened therapeutic windows represents an attractive target to synthetic organic and medicinal chemists. This review discusses the current antimetabolite drugs: 5- fluorouracil, 6-mercaptopurine, 6-thioguanine, Cladribine, Vidaza, Decitabine, Emtricitabine, Abacavir, Sorivudine, Clofarabine, Fludarabine, and Nelarabine; gives insight into the nucleoside drug candidates that are being developed; and outlines the approaches to nucleobase modifications that may help discover novel bioactive nucleoside analogs with the mechanism of action focused on termination of DNA synthesis, which is expected to diminish the off-target toxicity in non-proliferating human cells. PMID:26369814

  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 ostatní: 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. Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress

    OpenAIRE

    Rezaei Moghadam, Adel; Tutunchi, Soheil; Namvaran-Abbas-Abad, Ali; Yazdi, Mina; Bonyadi, Fatemeh; Mohajeri, Daryoush; Mazani, Mohammad; Marzban, Hassan; Los, Marek Jan; Ghavami, Saeid

    2015-01-01

    Background: Methotrexate (MTX) is an antimetabolite broadly used in treatment of cancer and autoimmune diseases. MTX-induced hepatotoxicity limits its application. We investigated hepatoprotective effects of turmeric in MTX-induced liver toxicity. Methods: All experiments were performed on male Wistar albino rats that were randomly divided into six groups. Group one received saline orally for 30 days (control group), groups two and three received turmeric extract (100, 200 mg/kg respectively)...

  14. Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

    OpenAIRE

    LI, QIONGYU; Wang, Xiangfeng; SHEN, ALING; Zhang, Yuchen; Chen, Youqin; Sferra, Thomas J.; LIN, JIUMAO; Peng, Jun

    2015-01-01

    Previous studies have demonstrated that Hedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5-fluorouracil (5-FU); however, less is known with regard to the activity of HDW against 5-FU-resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (...

  15. Post-transplantation diabetes mellitus

    OpenAIRE

    N Zbiti; K Souly; Z Errami; L Guendouz; L Benamar; F Ezaitouni; N Ouzeddoun; R Bayahia; A Chabraoui; H Rhou

    2012-01-01

    To determine the prevalence of post-kidney transplantation diabetes (PTDM) and to assess its risk factors, we retrospectively studied 92 non-diabetic kidney transplant patients. The immunosuppressive drugs used to prevent rejection included prednisone, a calcineurin inhibitor (cyclosporine or tacrolimus) and an antimetabolite (azathioprine or mycofenolate mofetil). Diabetes was defined according to the WHO criteria and the American Diabetes Association. The mean age of our patients was 35.8 ±...

  16. Removal of antinutritional factors from bean (Phaseolus vulgaris L.) seeds

    OpenAIRE

    Bollini R.; Carnovale E.; Campion B.

    1999-01-01

    Phytohemagglutinin and the lectin-related proteins present in bean seeds are toxic to monogastric animals and lower the nutritional value of beans. Since these antimetabolites are present in substantial amounts, a breeding program aimed to the removal ofphytohemagglutinin was developed. The character ""absence of phytohemagglutinin"" was transferred into a bean cultivar by backcrossing. The lines obtained maintained the agronomic performance of the recurrent parent. Preliminary results show t...

  17. Late-Onset Glaucoma-Filtrating Bleb Leak in a Penetrating Keratoplasty Patient: A Case Report

    OpenAIRE

    Zuleyha Yalniz-Akkaya; Ayse Burcu; Firdevs Ornek

    2012-01-01

    Introduction. Late-onset bleb leaks occur more frequently after the use of adjunctive antimetabolites and require surgical management to seal and preserve filtrating bleb. Case Presentation. A 48-year-old female presented with decreased visual acuity for five days in her left eye. She had a left penetrating keratoplasty one year earlier and two trabeculectomies 7 years earlier. Visual acuity was hand motions, intraocular pressure was 3 mmHg, corneal graft was clear, mature cataract was presen...

  18. Gemcitabine-Induced Pulmonary Toxicity During Adjuvant Therapy in a Patient with Pancreatic Cancer

    OpenAIRE

    Walid Shaib; Frederick Lansigan; Daniel Cornfeld; Kostas Syrigos; Muhammad Wasif Saif

    2008-01-01

    Context Gemcitabine is a pyrimidine antimetabolite with activity in a number of cancers. Gemcitabine is the accepted standard for the adjuvant and metastatic treatment of pancreatic cancer, however, it also has indications in breast, ovarian, and non-small cell lung cancers. The most common side effect is myelosuppression. Dyspnea is reported in 23% and bronchospasm occurs in less than 2% of subjects. Acute respiratory distress syndrome is rare with single agent use or in combination. Case re...

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

    OpenAIRE

    NM Wiles; Howard, J.

    2009-01-01

    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. ...

  20. Functional thiamine deficiency in end-stage renal disease: malnutrition despite ample nutrients.

    Science.gov (United States)

    Moradi, Hamid; Said, Hamid M

    2016-08-01

    Zhang et al. found that plasma concentrations of the thiamine antimetabolite oxythiamine are significantly increased in patients with end-stage renal disease. These investigators discuss the potential sources of oxythiamine and the consequences of its plasma elevation. This commentary addresses the significance of these findings and expands on the potential role of gut microbiome in the generation of this antithiamine metabolite. PMID:27418090

  1. Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

    OpenAIRE

    Stocco, Gabriele; Pelin, Marco; Franca, Raffaella; De Iudicibus, Sara; Cuzzoni, Eva; Favretto, Diego; Martelossi, Stefano; Ventura, Alessandro; Decorti, Giuliana

    2014-01-01

    Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced s...

  2. Antineoplastic Drugs : Treatment Principles and Toxicity

    Directory of Open Access Journals (Sweden)

    Bibu John Kariyil

    Full Text Available The therapy of cancer has improved dramatically during the past half century. This improvement can be traced to a number of factors: a better understanding of cancer's cause and natural history, better technologies for early detection and diagnosis, improved control of primary tumors through surgery and radiation therapy and more effective drugs. The evolution of drug therapy for cancer has progressed rapidly from alkylating agents and antimetabolites to natural products, and most recently, molecular targeted drugs such as imatinib and gefitinib. As our understanding of the biology of cancer improves, new targets for therapy are being identified daily. [Vet. World 2011; 4(8.000: 380-382

  3. Removal of antinutritional factors from bean (Phaseolus vulgaris L. seeds

    Directory of Open Access Journals (Sweden)

    Bollini R.

    1999-01-01

    Full Text Available Phytohemagglutinin and the lectin-related proteins present in bean seeds are toxic to monogastric animals and lower the nutritional value of beans. Since these antimetabolites are present in substantial amounts, a breeding program aimed to the removal ofphytohemagglutinin was developed. The character ""absence of phytohemagglutinin"" was transferred into a bean cultivar by backcrossing. The lines obtained maintained the agronomic performance of the recurrent parent. Preliminary results show that removal of phytohemagglutinin results in a higher true protein digestibility. Further modification in the composition of the lectin-related protein family is now under way.

  4. Nucleoside and Nucleotide Analogues for the Treatment of Herpesvirus Infections: Current Stage and New Prospects in the Field of Acyclic Nucleoside Phosphonates

    Czech Academy of Sciences Publication Activity Database

    Krečmerová, Marcela

    Rijeka : InTech, 2012 - (Magel, G.; Tyring, S.), s. 245-270 ISBN 978-953-51-0186-4 R&D Projects: GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z40550506 Keywords : acyclic nucleoside phosphonates * acyclic nucleoside analogue * antimetabolite * DHPA * 5-azacytosine * cidofovir * HPMPDAP * prodrugs * animal herpesviruses Subject RIV: CC - Organic Chemistry http://www.intechopen.com/books/herpesviridae-a-look-into-this-unique-family-of-viruses/nucleoside-and-nucleotide-analogues-for-the-treatment-of-herpesvirus-infections-current-stage-and-ne

  5. S-1 induced secondary acute erythroid leukemia with a chromosome inv(12)(p13;q13)

    Institute of Scientific and Technical Information of China (English)

    Kensuke Matsumoto; Akira Kitanaka; Makiko Uemura; Fusako Waki; Tetsuya Fukumoto; Hiroaki Ohnishi; Yoshitsugu Kubota; Toshihiko Ishida

    2011-01-01

    Adjuvant chemotherapy by S-1 following gastrectomy is considered standard treatment in Japan. Analysis of follow-up data have proved the efficacy of S-1 administration,and that hematological adverse events were relatively rare. PPyrimidine anti-metabolites, including S-1, have shown relatively lower risks for secondary hematological malignancies in comparison to alkylating agents and topoisomerase-Ⅱ inhibitors. We here report a case of therapy-related leukemia after S-1 administration. A patient who had received S-1as the sole adjuvant chemotherapy was diagnosed with acute erythroid leukemia. To the best of our knowledge, our patient represents the first report of S-1 induced acute leukemia.

  6. Effects of methotrexate on rat P-450 cytochrome mono-oxygenases; Action du methotrexate sur les monooxygenases a cytochromes P-450 chez le rat

    Energy Technology Data Exchange (ETDEWEB)

    Guitton, J.; Guilluy, R.; Brazier, J.L. [Faculte de Pharmacie, 69 - Lyon (France); Souillet, G. [Hopital Debrousse, 69 - Lyon (France); Riviere, J.L. [INRA, 69 - Marcy l`Etoile (France); Gerard, F. [Institut Pasteur, 69 - Lyon (France)

    1994-12-31

    Methotrexate, an anti-cancerous agent, acts as an anti-metabolite of the nucleic acids which synthesis is then inhibited. Using aminopyrine breath test after methotrexate processing, the effects of the molecule on activities of the hepatocyte P-450 cytochrome mono-oxygenases, are studied. Breath micro-tests with carbon 13-labelled aminopyrine have been carried out to observe the metabolism evolution. Micro-test results have been compared to microsomal enzymatic activities for various substrates, and also to P-450 cytochrome ratio. Results show that methotrexate induces a reduction in the P-450 cytochrome ratio, and thus reduce the hepatic biotransformation process. 1 fig., 30 refs.

  7. Effects of methotrexate on rat P-450 cytochrome mono-oxygenases

    International Nuclear Information System (INIS)

    Methotrexate, an anti-cancerous agent, acts as an anti-metabolite of the nucleic acids which synthesis is then inhibited. Using aminopyrine breath test after methotrexate processing, the effects of the molecule on activities of the hepatocyte P-450 cytochrome mono-oxygenases, are studied. Breath micro-tests with carbon 13-labelled aminopyrine have been carried out to observe the metabolism evolution. Micro-test results have been compared to microsomal enzymatic activities for various substrates, and also to P-450 cytochrome ratio. Results show that methotrexate induces a reduction in the P-450 cytochrome ratio, and thus reduce the hepatic biotransformation process. 1 fig., 30 refs

  8. Microbial transformations in phosphonate biosynthesis and catabolism, and their importance in nutrient cycling.

    Science.gov (United States)

    Chin, Jason P; McGrath, John W; Quinn, John P

    2016-04-01

    Phosphorus cycling in the biosphere has traditionally been thought to involve almost exclusively transformations of the element in its pentavalent oxidation state. Recent evidence, however, suggests that a significant fraction of environmental phosphorus may exist in a more reduced form. Most abundant of these reduced phosphorus compounds are the phosphonates, with their direct carbon-phosphorus bonds, and striking progress has recently been made in elucidating the biochemistry of microbial phosphonate transformations. These advances are now presented in the context of their contribution to our understanding of phosphorus biogeochemistry and of such diverse fields as the productivity of the oceans, marine methanogenesis and the discovery of novel microbial antimetabolites. PMID:26836350

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

    OpenAIRE

    Nerkar, A. G.; Saxena, A. K.; S. A. Ghone; A. K. Thaker

    2009-01-01

    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 vi...

  10. A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates.

    Directory of Open Access Journals (Sweden)

    Karthikeyan Ganesan

    2008-11-01

    Full Text Available Genome sequences of Plasmodium falciparum allow for global analysis of drug responses to antimalarial agents. It was of interest to learn how DNA microarrays may be used to study drug action in malaria parasites. In one large, tightly controlled study involving 123 microarray hybridizations between cDNA from isogenic drug-sensitive and drug-resistant parasites, a lethal antifolate (WR99210 failed to over-produce RNA for the genetically proven principal target, dihydrofolate reductase-thymidylate synthase (DHFR-TS. This transcriptional rigidity carried over to metabolically related RNA encoding folate and pyrimidine biosynthesis, as well as to the rest of the parasite genome. No genes were reproducibly up-regulated by more than 2-fold until 24 h after initial drug exposure, even though clonal viability decreased by 50% within 6 h. We predicted and showed that while the parasites do not mount protective transcriptional responses to antifolates in real time, P. falciparum cells transfected with human DHFR gene, and adapted to long-term WR99210 exposure, adjusted the hard-wired transcriptome itself to thrive in the presence of the drug. A system-wide incapacity for changing RNA levels in response to specific metabolic perturbations may contribute to selective vulnerabilities of Plasmodium falciparum to lethal antimetabolites. In addition, such regulation affects how DNA microarrays are used to understand the mode of action of antimetabolites.

  11. DNA precursor compartmentation in mammalian cells: metabolic and antimetabolic studies of nuclear and mitochondrial DNA synthesis

    International Nuclear Information System (INIS)

    HeLa cells were used for the quantitation of cellular and mitochondrial deoxyribonucleoside triphosphate (dNTP) and ribonucleoside triphosphate (rNTP) pools and of changes in pools in response to treatment with the antimetabolites methotrexate (mtx) and 5-fluorodeoxyuridine (FUdR). Use of an enzymatic assay of dNTPs and of improved nucleotide extraction methods allowed quantitation of mitochondrial dNTP pools. All four mitochondrial dNTP pools expand following treatment with mtx or FUdR whereas cellular dTTP and dGTP pools are depleted. Mitochrondrial rNTP pools were also found to expand in response to these antimetabolites. Mouse L-cells were used to determine the relative contributions of an exogenously supplied precursor to nuclear and mitochrondrial DNA replication. Cells were labeled to near steady state specific activities with 32P-orthophosphate and subsequently labeled with [3H]uridine, a general pyrimidine precursor, in the continuing presence of 32P. Deoxyribonucleoside monophosphates derived from these DNAs were separated by HPLC and the 3H/32P ratio in each pyrimidine determined. The dCMP residues in mitochondrial DNA (mtDNA) were found to be derived exclusively from the exogenous supplied uridine. The dTMP residues from nuclear and mtDNA and the dCMP residues from nuclear DNA were seen to be synthesized partly from exogenous sources and partly from other sources, presumably de novo pyrimidine synthesis

  12. Long-term outcomes for children with acute lymphoblastic leukemia (ALL) treated on The Cancer Institute of New Jersey ALL trial (CINJALL).

    Science.gov (United States)

    Drachtman, Richard A; Masterson, Margaret; Shenkerman, Angela; Vijayanathan, Veena; Cole, Peter D

    2016-10-01

    The Cancer Institute of New Jersey Acute Lymphoblastic Leukemia trial (CINJALL) employed a post-induction regimen centered on intensive oral antimetabolite therapy, with no intravenous methotrexate (MTX). Fifty-eight patients enrolled between 2001 and 2005. A high rate of induction death (n = 3) or induction failure (n = 1) was observed. Among those who entered remission, five-year DFS is 80 ± 8.9% for those at standard risk of relapse and 76 ± 7.8% for high-risk patients, with median follow up over six years. The estimated cumulative incidence of testicular relapse among boys was elevated (13 ± 7.2%) compared to the rate observed on contemporary protocols. We conclude that post-induction therapy using intensive oral antimetabolites for children with acute lymphoblastic leukemia (ALL) can result in overall long-term DFS comparable to that observed among children treated with regimens including intravenous MTX. However, an increased risk of late extramedullary relapse among boys was observed, supporting the prevailing opinion that high-dose MTX improves outcome for children with ALL. PMID:26879921

  13. 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.

  14. 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.

  15. Control of plant defense mechanisms and fire blight pathogenesis through the regulation of 6-thioguanine biosynthesis in Erwinia amylovora.

    Science.gov (United States)

    Coyne, Sébastien; Litomska, Agnieszka; Chizzali, Cornelia; Khalil, Mohammed N A; Richter, Klaus; Beerhues, Ludger; Hertweck, Christian

    2014-02-10

    Fire blight is a devastating disease of Rosaceae plants, such as apple and pear trees. It is characterized by necrosis of plant tissue, caused by the phytopathogenic bacterium Erwinia amylovora. The plant pathogen produces the well-known antimetabolite 6-thioguanine (6TG), which plays a key role in fire blight pathogenesis. Here we report that YcfR, a member of the LTTR family, is a major regulator of 6TG biosynthesis in E. amylovora. Inactivation of the regulator gene (ycfR) led to dramatically decreased 6TG production. Infection assays with apple plants (Malus domestica cultivar Holsteiner Cox) and cell cultures of Sorbus aucuparia (mountain ash, rowan) revealed abortive fire blight pathogenesis and reduced plant response (biphenyl and dibenzofuran phytoalexin production). In the presence of the ΔycfR mutant, apple trees were capable of activating the abscission machinery to remove infected tissue. In addition to unveiling the regulation of 6TG biosynthesis in a major plant pathogen, we demonstrate for the first time that this antimetabolite plays a pivotal role in dysregulating the plant response to infection. PMID:24449489

  16. Immunosuppressive Medications and Squamous Cell Skin Carcinoma: Nested Case-Control Study Within the Skin Cancer after Organ Transplant (SCOT) Cohort.

    Science.gov (United States)

    Coghill, A E; Johnson, L G; Berg, D; Resler, A J; Leca, N; Madeleine, M M

    2016-02-01

    Organ transplant recipients (OTRs) have a substantially elevated risk of squamous cell skin carcinoma (SCSC), largely attributed to immunosuppressive medications used to prevent graft rejection, although data to support the role of newer drugs in SCSC risk are sparse. We investigated the association between immunosuppressive medications and SCSC risk among cardiac and renal transplant recipients in the SCOT cohort study. Incident cases were ascertained through medical record review after self-report of skin biopsy (n = 170). Controls without SCSC (n = 324) were matched to cases on sex, age, race, transplant year, hospital, donor type, organ transplanted, and time between transplantation and interview. Conditional logistic regression was used to evaluate the association between specific medications and SCSC. Users of the antimetabolite azathioprine were more than twice as likely to develop SCSC (odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.23-5.76). In contrast, the newer antimetabolite preparations (i.e., mycophenolic acid [MPA]) were associated with lower SCSC risk (OR = 0.45, 95% CI 0.29-0.69). This inverse association between MPA and SCSC persisted among OTRs with no history of azathioprine use, even after adjustment for simultaneous use of the calcineurin inhibitor tacrolimus (OR = 0.52, 95% CI 0.32-0.84). Our data suggest that the increased risk of SCSC historically associated with azathioprine is not seen in OTRs prescribed newer regimens, including MPA and tacrolimus. PMID:26824445

  17. 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.

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

    International Nuclear Information System (INIS)

    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

  19. L-canavanine incorporation into vitellogenin and macromolecular conformation.

    Science.gov (United States)

    Rosenthal, G A; Reichhart, J M; Hoffmann, J A

    1989-08-15

    L-Canavanine is a potentially deleterious arginine antimetabolite whose toxicity is expressed in canavanine-sensitive organisms ranging from viruses to humans. Canavanine, a substrate for arginyl-tRNA synthetase, is incorporated into nascent polypeptide chains in place of arginine. This substitution results in the production of structurally aberrant, canavanyl proteins. Chemical, physical, and immunological studies of native and canavanine-containing vitellogenin obtained from female migratory locusts (Locusta migratoria migratorioides (Orthoptera] provide the first experimental evidence that canavanine can disrupt the tertiary and/or quaternary structure that yields the three-dimensional conformation unique to the protein. These findings enhance our understanding of the biochemical basis for canavanine's antimetabolic and potent insecticidal properties. PMID:2760038

  20. Grade 4 oral mucositis and prolonged pancytopenia with high dose intravenous methotrexate in a patient of philadelphia positive acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Vidisha M. Shah

    2012-02-01

    Full Text Available Antimetabolite drugs are rarely associated with grade 3 or 4 mucositis. However specific side effects such as bone marrow suppression, pancytopenia, hospitalization, high cost limit the use of intravenous methotrexate. Here we report a case of 25-year-old girl patient with Acute Lymphoblastic Leukemia (ALL treated with 24 hour methotrexate in her continuous phase of chemotherapy. After 12 hours of completing the treatment she developed oral mucosal pain & she was not able to speak. After a week, her White Blood Cell (WBC count was 600/cumm with fever and she could not speak and eat or drink. So she was hospitalized for few days till she can drink something. We report high grade mucositis with methotrexate. Hematologists should be aware of this possible side effect to undertake early intervention. [Int J Basic Clin Pharmacol 2012; 1(1.000: 36-38

  1. Cerebral metastases--a therapeutic update.

    Science.gov (United States)

    Cavaliere, Robert; Schiff, David

    2006-08-01

    Cerebral metastases remain a common complication among patients with cancer. Historically, whole-brain radiotherapy has remained the standard of care, with surgery being reserved for selected cases. Recent advances have changed our practice, however. In particular, stereotactic radiosurgery has emerged as a vital treatment modality for this disease. In addition, chemotherapy, including temozolomide, topoisomerase inhibitors and antimetabolites, and treatment sensitizers, such as efaproxiral and motexafin gadolinium, are actively being assessed in clinical trials, and are likely to play an increasing role in the management of cerebral metastases in the future. Nonetheless, many uncertainties remain, such as the optimal combination and timing of therapeutics. As the arsenal of therapeutics expands, it will be increasingly important to select appropriate patients for a particular treatment paradigm. Understanding the efficacy and toxicity of treatment is essential to this task. PMID:16932601

  2. 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.

  3. Overview of immunosuppression in liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Anjana A Pillai; Josh Levitsky

    2009-01-01

    Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease. Beginning with the revolutionary discovery of cyclosporine in the 1970s, immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors, anti-metabolites, mTOR inhibitors, steroids and antibody-based therapies. These agents target different sites in the T cell activation cascade, usually by inhibiting T cell activation or via T cell depletion. They are used as induction therapy in the immediate periand post-operative period, as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon.

  4. Drug: D02115 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02115 Drug Methotrexate sodium; Trexall (TN) C20H21N8O5. Na 476.1533 476.4211 D021...p07050 Antirheumatics - DMARDs and biological agents map04976 Bile secretion Anatomical Therapeutic Chemical (ATC) classification [BR:br08303] L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS L01 ANTINEOPLASTIC AGENTS L01B ANTIMETABOLITES L01BA Folic acid analogues L01BA01 Methotrexate D02115 Methotrexate sodium L04 IMMUNOSUPPRESSANTS L04A IMMUNOSUPPRESSANTS L04AX Other immunosuppressants L04AX03 Methotrexate D02115 Methotrexate sodium USP drug classification [BR:br08302] Immunological Agents Immune Suppressants Methotrexate D02115 Methotrexate sodium Target-based classification of drugs [BR:br08310] Enzymes Oxidoredu...ase [HSA:1719 200895] [KO:K00287] Methotrexate...lites Folic acid analogues Methotrexate... [ATC:L01BA01] D02115 Methotrexate sodium CAS: 15475-56-6 PubChem: 78

  5. Docking Studies in Target Proteins Involved in Antibacterial Action Mechanisms: Extending the Knowledge on Standard Antibiotics to Antimicrobial Mushroom Compounds

    Directory of Open Access Journals (Sweden)

    Maria José Alves

    2014-01-01

    Full Text Available In the present work, the knowledge on target proteins of standard antibiotics was extended to antimicrobial mushroom compounds. Docking studies were performed for 34 compounds in order to evaluate their affinity to bacterial proteins that are known targets for some antibiotics with different mechanism of action: inhibitors of cell wall synthesis, inhibitors of protein synthesis, inhibitors of nucleic acids synthesis and antimetabolites. After validation of the molecular docking approach, virtual screening of all the compounds was performed against penicillin binding protein 1a (PBP1a, alanine racemase (Alr, d-alanyl-d-alanine synthetase (Ddl, isoleucyl-tRNA sinthetase (IARS, DNA gyrase subunit B, topoisomerase IV (TopoIV, dihydropteroate synthetase (DHPS and dihydrofolate reductase (DHFR using AutoDock4. Overall, it seems that for the selected mushroom compounds (namely, enokipodins, ganomycins and austrocortiluteins the main mechanism of the action is the inhibition of cell wall synthesis, being Alr and Ddl probable protein targets.

  6. Adjuvant chemotherapy and cancer cure

    International Nuclear Information System (INIS)

    The use of chemotherapy as an adjuvant to surgery and/or radiotherapy is well founded in experimental tumor systems and appears to be effective in patients in some circumstances. It is clear from both clinical and experimental studies that (1) the dose is important, (2) the earlier chemotherapy is started after primary therapy the better, and (3) combination chemotherapy may be more effective than single-agent treatment. The better the estimation of risk of recurrence, the better the assessment of the risk-benefit ratio with adjuvant therapy. Salvage therapy as well as relative risk of recurrence are considerations in the choice of patients to be treated. Finally, some evidence is presented to indicate that alkylating agents may not be necessary in combination regimens for adjuvant therapy if effective antimetabolite combinations are available

  7. In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile.

    Directory of Open Access Journals (Sweden)

    Michael J Sorich

    2008-04-01

    Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111; Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D; Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D.

  8. Analysis on anticancer drugs used in Guigang City People’s Hospital from 2011 to 2013%2011-2013年贵港市人民医院抗肿瘤药物的使用情况分析

    Institute of Scientific and Technical Information of China (English)

    林洪奇

    2014-01-01

    Objective To analyze the usage of anticancer drugs in Guigang City People’s Hospital from 2011 to 2013. Methods The data were drawn from the HIS system in the hospital retrospectively, and the consumption sum, sales volume, and component ratio of anticancer drugs were analyzed. Results Consumption sum of anticancer drugs increased year by year substantially during 2011-2013, especially antimetabolite and anticancer drugs from plants and their derivatives, but alkylating drugs showed a downward trend in demand. Consumption sum of top three drugs in anticancer drugs were gemcitabine, docetaxel, and pemetrexed. The largest sale of the anticancer drugs was fluorouracil, then was gemcitabine. Conclusion The growth rate of sales of anticancer drugs in Guigang City People’s Hospital closes to the national level. The antimetabolite and anticancer drugs from plants and their derivatives have a big demand in the market, therefore the varieties of production and optimization should be intensified.%目的:分析2011-2013年贵港市人民医院抗肿瘤药物的使用情况和用药趋势。方法通过回顾性检索贵港市人民医院HIS系统2011-2013年的数据,并对各类抗肿瘤药物的销售金额、销售量及构成比等进行统计。结果2011-2013年抗肿瘤药物的销售金额逐年增大,尤其抗代谢药和植物来源抗肿瘤药及其衍生物的增长幅度较大,烷化剂类药物的销售金额却呈下降趋势。销售金额前3位的抗肿瘤药分别是吉西他滨、多西他赛、培美曲塞。销量最大的抗肿瘤药是氟尿嘧啶,其次是吉西他滨。结论贵港市人民医院抗肿瘤药物的销售金额增长率接近全国水平,抗代谢药和植物来源抗肿瘤药及其衍生物的市场需求大,应加大对其品种的生产和优化力度。

  9. Vascular Complications of Cancer Chemotherapy.

    Science.gov (United States)

    Cameron, Alan C; Touyz, Rhian M; Lang, Ninian N

    2016-07-01

    Development of new anticancer drugs has resulted in improved mortality rates and 5-year survival rates in patients with cancer. However, many of the modern chemotherapies are associated with cardiovascular toxicities that increase cardiovascular risk in cancer patients, including hypertension, thrombosis, heart failure, cardiomyopathy, and arrhythmias. These limitations restrict treatment options and might negatively affect the management of cancer. The cardiotoxic effects of older chemotherapeutic drugs such as alkylating agents, antimetabolites, and anticancer antibiotics have been known for a while. The newer agents, such as the antiangiogenic drugs that inhibit vascular endothelial growth factor signalling are also associated with cardiovascular pathology, especially hypertension, thromboembolism, myocardial infarction, and proteinuria. Exact mechanisms by which vascular endothelial growth factor inhibitors cause these complications are unclear but impaired endothelial function, vascular and renal damage, oxidative stress, and thrombosis might be important. With increasing use of modern chemotherapies and prolonged survival of cancer patients, the incidence of cardiovascular disease in this patient population will continue to increase. Accordingly, careful assessment and management of cardiovascular risk factors in cancer patients by oncologists and cardiologists working together is essential for optimal care so that prolonged cancer survival is not at the expense of increased cardiovascular events. PMID:26968393

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

    International Nuclear Information System (INIS)

    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)

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

    International Nuclear Information System (INIS)

    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

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

    International Nuclear Information System (INIS)

    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.

  13. Controlled release of 6-aminonicotinamide from aligned, electrospun fibers alters astrocyte metabolism and dorsal root ganglia neurite outgrowth

    Science.gov (United States)

    Schaub, Nicholas J.; Gilbert, Ryan J.

    2011-08-01

    Following central nervous system (CNS) injury, activated astrocytes form a glial scar that inhibits the migration of axons ultimately leading to regeneration failure. Biomaterials developed for CNS repair can provide local delivery of therapeutics and/or guidance mechanisms to encourage cell migration into damaged regions of the brain or spinal cord. Electrospun fibers are a promising type of biomaterial for CNS injury since these fibers can direct cellular and axonal migration while slowly delivering therapy to the injury site. In this study, it was hypothesized that inclusion of an anti-metabolite, 6-aminonicotinamide (6AN), within poly-l-lactic acid electrospun fibers could attenuate astrocyte metabolic activity while still directing axonal outgrowth. Electrospinning parameters were varied to produce highly aligned electrospun fibers that contained 10% or 20% (w/w) 6AN. 6AN release from the fiber substrates occurred continuously over 2 weeks. Astrocytes placed onto drug-releasing fibers were less active than those cultured on scaffolds without 6AN. Dorsal root ganglia placed onto control and drug-releasing scaffolds were able to direct neurites along the aligned fibers. However, neurite outgrowth was stunted by fibers that contained 20% 6AN. These results show that 6AN release from aligned, electrospun fibers can decrease astrocyte activity while still directing axonal outgrowth.

  14. 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. PMID:26919657

  15. Targeting tumor glycolysis by a mitotropic agent.

    Science.gov (United States)

    Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-01

    Metabolic reprogramming is one of the hallmarks of cancer. Altered metabolism in cancer cells is exemplified by enhanced glucose utilization, a biochemical signature that is clinically exploited for cancer diagnosis using positron-emission tomography and computed tomography imaging. Accordingly, disrupting the glucose metabolism of cancer cells has been contemplated as a potential therapeutic strategy against cancer. Experimental evidences indicate that targeting glucose metabolism by inhibition of glycolysis or oxidative phosphorylation promotes anticancer effects. Yet, successful clinical translation of antimetabolites or energy blockers to treat cancer remains a challenge, primarily due to lack of efficacy and/or systemic toxicity. Recently, using nanotechnology, Marrache and Dhar have documented the feasibility of delivering a glycolytic inhibitor through triphenylphosphonium (TPP), a mitotropic agent that selectively targets mitochondria based on membrane potential. Furthermore, by utilizing gold nanoparticles the investigators also demonstrated the potential for simultaneous induction of photothermal therapy, thus facilitating an additional line of attack on cancer cells. The report establishes that specific inhibition of tumor glycolysis is achievable through TPP-dependent selective targeting of cancer cells. This nanotechnological approach involving TPP-guided selective delivery of an antiglycolytic agent complemented with photothermal therapy provides a new window of opportunity for effective and specific targeting of tumor glycolysis. PMID:26420565

  16. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma.

    Science.gov (United States)

    Cloughesy, Timothy F; Landolfi, Joseph; Hogan, Daniel J; Bloomfield, Stephen; Carter, Bob; Chen, Clark C; Elder, J Bradley; Kalkanis, Steven N; Kesari, Santosh; Lai, Albert; Lee, Ian Y; Liau, Linda M; Mikkelsen, Tom; Nghiemphu, Phioanh Leia; Piccioni, David; Walbert, Tobias; Chu, Alice; Das, Asha; Diago, Oscar R; Gammon, Dawn; Gruber, Harry E; Hanna, Michelle; Jolly, Douglas J; Kasahara, Noriyuki; McCarthy, David; Mitchell, Leah; Ostertag, Derek; Robbins, Joan M; Rodriguez-Aguirre, Maria; Vogelbaum, Michael A

    2016-06-01

    Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165). PMID:27252174

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

    Directory of Open Access Journals (Sweden)

    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.

  18. 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

  19. An update on liver transplantation: A critical review.

    Science.gov (United States)

    Neuberger, James

    2016-01-01

    Liver transplantation, although now a routine procedure, with defined indications and usually excellent outcomes, still has challenges. Donor shortage remains a key issue. Transplanted organs are not free of risk and may transmit cancer, infection, metabolic or autoimmune disease. Approaches to the donor shortage include use of organs from donors after circulatory death, from living donors and from those previously infected with Hepatitis B and C and even HIV for selected recipients. Normothermic regional and/or machine perfusion, whether static or pulsatile, normo- or hypothermic, are being explored and will be likely to have a major place in improving donation rates and outcomes. The main indications for liver replacement are alcoholic liver disease, HCV, non-alcoholic liver disease and liver cancer. Recent studies have shown that selected patients with severe alcoholic hepatitis may also benefit from liver transplant. The advent of new and highly effective treatments for HCV, whether given before or after transplant will have a major impact on outcomes. The role of transplantation for those with liver cell cancer continues to evolve as other interventions become more effective. Immunosuppression is usually required life-long and adherence remains a challenge, especially in adolescents. Immunosuppression with calcineurin inhibitors (primarily tacrolimus), antimetabolites (azathioprine or mycophenolate) and corticosteroids remains standard. Outcomes after transplantation are good but not normal in quality or quantity. Premature death may be due to increased risk of cardiovascular disease, de novo cancer, recurrent disease or late technical problems. PMID:26350881

  20. 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.

  1. Vitamin D in combination cancer treatment

    Science.gov (United States)

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

    2010-01-01

    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. PMID:20842231

  2. L-Canavanine potentiates the cytotoxicity of doxorubicin and cisplatin in arginine deprived human cancer cells

    Science.gov (United States)

    Wink, Michael

    2016-01-01

    The non-protein amino acid L-canavanine (L-CAV), an antimetabolite of L-arginine (L-ARG), can alter the 3D conformation of proteins when incorporated into a protein instead of L-ARG. L-CAV inhibits the proliferation of some tumour cells. The deprivation of L-ARG in the culture medium enhances the response of cells to L-CAV. This study aimed to investigate the interaction of L-CAV in combination with the chemotherapeutic drugs, doxorubicin (DOX) or cisplatin (CIS), in cancer cells, especially in the absence of L-ARG. A combination method based on the median-effect principle and mass-action law was used. The following cancer cells were employed: HeLa and Caco-2 cells, overexpressing argininosuccinate synthase (ASS), pancreatic cells (MIA PaCa-2 and BxPC-3) and hepatocellular carcinoma cells (Hep G2 and SK-HEP-1), with down-regulated ASS. When constant and non-constant ratios of L-CAV were combined with DOX and CIS, a synergistic potentiation of cytotoxicity was recorded. Cells expressing high levels of ASS were more sensitive to the treatment as compared to the cells with reduced ASS levels. Overall, this study may provide a new approach to targeting some cancer cells with L-CAV in combination with DNA-targeting drugs such as DOX and CIS, especially those cells which overexpress ASS, such as human cervical and colorectal carcinoma cells. PMID:26839743

  3. Promising biological therapies for ulcerative colitis: A review of the literature

    Institute of Scientific and Technical Information of China (English)

    Hirotada; Akiho; Azusa; Yokoyama; Shuichi; Abe; Yuichi; Nakazono; Masatoshi; Murakami; Yoshihiro; Otsuka; Kyoko; Fukawa; Mitsuru; Esaki; Yusuke; Niina; Haruei; Ogino

    2015-01-01

    Ulcerative colitis(UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants(including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor(TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab(anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab(another anti-TNF-α agent), tofacitinib(a Janus kinase inhibitor), and vedolizumab and etrolizumab(integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC.

  4. Multidrug resistance associated proteins in multidrug resistance

    Institute of Scientific and Technical Information of China (English)

    Kamlesh Sodani; Atish Patel; Rishil J. Kathawala; Zhe-Sheng Chen

    2012-01-01

    Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters.These ABC transporters together form the largest branch of proteins within the human body.The MRP family comprises of 13 members,of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell.They are mainly lipophilic anionic transporters and are reported to transport free or conjugates of glutathione (GSH),glucuronate,or sulphate.In addition,MRP1 to MRP3 can transport neutral organic drugs in free form in the presence of free GSH.Collectively,MRPs can transport drugs that differ structurally and mechanistically,including natural anticancer drugs,nucleoside analogs,antimetabolites,and tyrosine kinase inhibitors.Many of these MRPs transport physiologically important anions such as leukotriene C4,bilirubin glucuronide,and cyclic nucleotides.This review focuses mainly on the physiological functions,cellular resistance characteristics,and probable in vivo role of MRP1 to MRP9.

  5. 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.

  6. Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats

    Directory of Open Access Journals (Sweden)

    Tristan J. King

    2015-08-01

    Full Text Available Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc of MTX (0.75 mg/kg. MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001, increased osteoclast density on the trabecular bone surface (p < 0.05, and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001. Genistein supplementation preserved body weight gain (p < 0.05 and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001. However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.

  7. Administration of Three Natural Products as Protective Agents Against The Genotoxic And Cytotoxic Effect of Methotrexate in Mice (Mus Musculus.

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    Zowail, M.E.M.; Awwad, M.H.; Khater, E.H. and Nafie, Ebtesam. H.O

    2013-01-01

    Full Text Available Background: Methotrexate is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases.Material and methods: 210 healthy adult male Swiss albino mice (Mus musculus, were allotted among three groups. The animal were given daily (0.065mg/ml of methotrexate intraperitonealy followed by injection of Omega-3 plus at dose (8.58 mg/20g mice, Apple at dose (1.43 mg/20 g mice and Psyllium at dose (18.2mg /20 g mice for five days. Results: Various Structural and numerical chromosomal aberrations in bone marrow cells; mitotic activity and sperm head abnormality were recorded, quantitated, and statistically analyzed. Also DNA extraction and apoptosis detection in liver was done. The intensity of apoptotic bands located at 200 b p; 400b p ; 600 b p;800 b p and intact DNA measured by software Gel Pro program as maximum optical density values. Conclusion:, Methotrexate had adverse effect on chromosomal and sperm head structure, also it induce apoptosis, necrosis and decrease total DNA in mice liver.Omega-3 plus, Apple, and Psyllium attenuate the methotrexate-related toxic effects

  8. Radioiodination and biological evaluation of Cladribine as potential agent for tumor imaging and therapy

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    Bayoumi, Noha Anwer; Amin, Abeer M.; El-Kolaly, Mohamed T. [Egyptian Atomic Energy Authority, Cairo (Egypt). Hot Lab Center; Ismail, Nasser S.M.; Abouzid, Khaled A.M. [Ain-Shams Univ., Cairo (Egypt). Pharmaceutical Chemistry Dept.

    2015-07-01

    Cladribine, a purine analogue antimetabolite, was radioiodinated with {sup 125}I via direct electrophilic substitution reaction. The maximum radiochemical yield (92.5 ± 0.8%) was obtained when the reaction was done at ambient temperature for 30 min using 100 μg of Cladribine and 10 μg N-chlorosuccinamide (NCS) in 150 μL of 0.2 M phosphate buffer, pH 7. In vitro stability studies of HPLC purified {sup 125}I-Cladribine sample dissolved in 0.5 ml of 0.2 M phosphate buffer pH 7 at ambient temperature showed that {sup 125}I-Cladribine is stable up to 12 h post labeling. Biodistribution results revealed excretion of {sup 125}I-Cladribine mainly by kidneys. The uptake of {sup 125}I-Cladribine in the induced Ehrlich Ascites Carcinoma was 2.8 ± 0.4%ID/g at 1 h post injection with maximum tumor/muscle ratio of 5.5. The good uptake of {sup 125}I-Cladribine confirms the molecular docking studies results which indicate that iodinated Cladribine binds with polymerase enzyme with a good-CDOCKER energy. As a result, radioiodinated Cladribine may be used as a valuable agent for tumor diagnosis and therapy.

  9. Late-Onset Glaucoma-Filtrating Bleb Leak in a Penetrating Keratoplasty Patient: A Case Report

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    Zuleyha Yalniz-Akkaya

    2012-01-01

    Full Text Available Introduction. Late-onset bleb leaks occur more frequently after the use of adjunctive antimetabolites and require surgical management to seal and preserve filtrating bleb. Case Presentation. A 48-year-old female presented with decreased visual acuity for five days in her left eye. She had a left penetrating keratoplasty one year earlier and two trabeculectomies 7 years earlier. Visual acuity was hand motions, intraocular pressure was 3 mmHg, corneal graft was clear, mature cataract was present, and axial length was 30.48 mm. The conjunctiva covering the superotemporal sclerotomy was avascular, flat, and partially lost. After heavily painting the bleb with a fluorescein, late-onset point leak was revealed. Overlying conjunctiva was excised. The atrophic, irregular, and partially absent scleral flap was covered by a processed human pericardium graft and conjunctival advancement. Postoperatively, intraocular pressure stabilized around 16 mmHg. After four months, phacoemulsification and intraocular lens implantation were performed. Visual acuity did not exceed 0.1 (in decimal notation due to degenerative myopia-related macular atrophy. Corneal graft remained clear at her 6-month followup period. Conclusion. Surgical bleb revision using a pericardium graft and conjunctival advancement seems to be an effective method for treating late bleb leaks. However, careful follow-up is required for detecting recurrent leaks and elevated intraocular pressure.

  10. The Epigenetic Drug 5-Azacytidine Interferes with Cholesterol and Lipid Metabolism*

    Science.gov (United States)

    Poirier, Steve; Samami, Samaneh; Mamarbachi, Maya; Demers, Annie; Chang, Ta Yuan; Vance, Dennis E.; Hatch, Grant M.; Mayer, Gaétan

    2014-01-01

    DNA methylation and histone acetylation inhibitors are widely used to study the role of epigenetic marks in the regulation of gene expression. In addition, several of these molecules are being tested in clinical trials or already in use in the clinic. Antimetabolites, such as the DNA-hypomethylating agent 5-azacytidine (5-AzaC), have been shown to lower malignant progression to acute myeloid leukemia and to prolong survival in patients with myelodysplastic syndromes. Here we examined the effects of DNA methylation inhibitors on the expression of lipid biosynthetic and uptake genes. Our data demonstrate that, independently of DNA methylation, 5-AzaC selectively and very potently reduces expression of key genes involved in cholesterol and lipid metabolism (e.g. PCSK9, HMGCR, and FASN) in all tested cell lines and in vivo in mouse liver. Treatment with 5-AzaC disturbed subcellular cholesterol homeostasis, thereby impeding activation of sterol regulatory element-binding proteins (key regulators of lipid metabolism). Through inhibition of UMP synthase, 5-AzaC also strongly induced expression of 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) and promoted triacylglycerol synthesis and cytosolic lipid droplet formation. Remarkably, complete reversal was obtained by the co-addition of either UMP or cytidine. Therefore, this study provides the first evidence that inhibition of the de novo pyrimidine synthesis by 5-AzaC disturbs cholesterol and lipid homeostasis, probably through the glycerolipid biosynthesis pathway, which may contribute mechanistically to its beneficial cytostatic properties. PMID:24855646

  11. The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism.

    Science.gov (United States)

    Poirier, Steve; Samami, Samaneh; Mamarbachi, Maya; Demers, Annie; Chang, Ta Yuan; Vance, Dennis E; Hatch, Grant M; Mayer, Gaétan

    2014-07-01

    DNA methylation and histone acetylation inhibitors are widely used to study the role of epigenetic marks in the regulation of gene expression. In addition, several of these molecules are being tested in clinical trials or already in use in the clinic. Antimetabolites, such as the DNA-hypomethylating agent 5-azacytidine (5-AzaC), have been shown to lower malignant progression to acute myeloid leukemia and to prolong survival in patients with myelodysplastic syndromes. Here we examined the effects of DNA methylation inhibitors on the expression of lipid biosynthetic and uptake genes. Our data demonstrate that, independently of DNA methylation, 5-AzaC selectively and very potently reduces expression of key genes involved in cholesterol and lipid metabolism (e.g. PCSK9, HMGCR, and FASN) in all tested cell lines and in vivo in mouse liver. Treatment with 5-AzaC disturbed subcellular cholesterol homeostasis, thereby impeding activation of sterol regulatory element-binding proteins (key regulators of lipid metabolism). Through inhibition of UMP synthase, 5-AzaC also strongly induced expression of 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) and promoted triacylglycerol synthesis and cytosolic lipid droplet formation. Remarkably, complete reversal was obtained by the co-addition of either UMP or cytidine. Therefore, this study provides the first evidence that inhibition of the de novo pyrimidine synthesis by 5-AzaC disturbs cholesterol and lipid homeostasis, probably through the glycerolipid biosynthesis pathway, which may contribute mechanistically to its beneficial cytostatic properties. PMID:24855646

  12. Pharmacogenetics of thiopurines. Can posology be guided by laboratory data?

    International Nuclear Information System (INIS)

    Background. The purpose of this study was to investigate the relationships between the presence of mutations in the TPMT gene, the consequent reduced enzymatic activity, and the clinical toxicity of the treatment with thiopurine antimetabolite drugs. Materials and methods. The study was performed on 44 patients with inflammatory bowel disease treated with AZA. DNA was extracted from blood samples collected from each patient, and genotyping was performed using specific polymerase chain reaction assays in order to detect the three more frequent mutations of the gene. Enzymatic activity was measured on red blood cell lysates by HPLC. Results. Among the subjects, 4 (9.0%) were heterozygous for mutations in the TPMT gene; no subject was homozygous for mutations in the TPMT gene. A complete concordance between TPMT mutated genotype and reduced enzymatic activity could be determined. The incidence of toxicity in the subjects with a mutated genotype was not different from that observed in the patients with a normal TPMT gene. Conclusion. Genotyping methods provide a simple and reliable DNA-based strategy to identify TPMT homozygotes that should avoid thiopurines administration. However, it seems that the most common, less dangerous forms of thiopurine toxicity could be caused by factors different from TPMT gene mutations examined. (author)

  13. Gemcitabine-Induced Pulmonary Toxicity During Adjuvant Therapy in a Patient with Pancreatic Cancer

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    Walid Shaib

    2008-11-01

    Full Text Available Context Gemcitabine is a pyrimidine antimetabolite with activity in a number of cancers. Gemcitabine is the accepted standard for the adjuvant and metastatic treatment of pancreatic cancer, however, it also has indications in breast, ovarian, and non-small cell lung cancers. The most common side effect is myelosuppression. Dyspnea is reported in 23% and bronchospasm occurs in less than 2% of subjects. Acute respiratory distress syndrome is rare with single agent use or in combination. Case report A 68-year-old man being treated for stage IIA pancreatic cancer after pancreaticoduodenectomy developed hypoxemic respiratory distress after the second dose of gemcitabine 1,000 mg/m2. The radiographic findings on computed tomography scans evolved from ground glass opacities to findings suggestive of cryptogenic organizing pneumonia over the course of two weeks. He was treated with antibiotics, steroids, nebulizers and oxygen. A follow-up computed tomography scan of chest four weeks after presentation showed complete resolution of pneumonitis. Conclusions We report the first case of gemcitabine-induced pneumonitis encountered during the adjuvant treatment of pancreatic cancer. Physicians seeing such patients should be aware of this rare but real pulmonary toxicity. A delay in diagnosis and treatment can lead to potentially fatal outcomes.

  14. 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.

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    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.

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

    International Nuclear Information System (INIS)

    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 AUC0-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

  16. In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells

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    Wouters An

    2010-08-01

    Full Text Available Abstract Background Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA and gemcitabine (2',2'-difluorodeoxycytidine, dFdC with irradiation (RT seems promising. This in vitro study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules. Methods The cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC and CAL-27 (SCCHN cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24 h MTA combined with 1 h or 24 h dFdC were analysed. Results Including a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect. Conclusions Results from our in vitro model suggest that the sequence 24 h MTA → 1 h dFdC → RT is the most rational design and would, after confirmation in an in vivo setting, possibly provide the greatest benefit in the clinic.

  17. 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.

  18. Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective.

    Science.gov (United States)

    Ciccolini, Joseph; Serdjebi, Cindy; Peters, Godefridus J; Giovannetti, Elisa

    2016-07-01

    Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral conversion into active triphosphorylated nucleotides interfering with DNA synthesis and targeting ribonucleotide reductase. Gemcitabine is a mainstay for treating pancreatic and lung cancers, alone or in combination with several cytotoxic drugs (nab-paclitaxel, cisplatin and oxaliplatin), and is an option in a variety of other solid or hematological cancers. Several determinants of response have been identified with gemcitabine, i.e., membrane transporters, activating and inactivating enzymes at the tumor level, or Hedgehog signaling pathway. More recent studies have investigated how germinal genetic polymorphisms affecting cytidine deaminase, the enzyme responsible for the liver disposition of gemcitabine, could act as well as a marker for clinical outcome (i.e., toxicity, efficacy) at the bedside. Besides, constant efforts have been made to develop alternative chemical derivatives or encapsulated forms of gemcitabine, as an attempt to improve its metabolism and pharmacokinetics profile. Overall, gemcitabine is a drug paradigmatic for constant searches of the scientific community to improve its administration through the development of personalized medicine in oncology. PMID:27007129

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

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    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.

  20. Amniotic Membrane Transplantation for Exuberant Bleb Following Filtration Surgery

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    Lan-Hsin Chuang

    2006-08-01

    Full Text Available The use of antimetabolites in filtration surgery, cystic, large, leaking blebs often lead tocomplications. We report a case of glaucoma that received amniotic membrane transplantationfor repairing the exuberant bleb. This female patient had a history of several eye surgeries,including a scleral buckle and cyclocryotherapy for one eye and the other received filteringsurgery. The latter had been revised once with autologous conjunctival advancementafter an episode of bleb leakage. The large bleb, overlaying the cornea 3 mm from the limbus,had caused corneal erosion beneath the bleb and the patient suffered burning sensations.Further conjunctival advancement of the exuberant bleb is difficult to achive, because it hadbeen revised once with this treatment. Amniotic membrane was used for further reconstructionafter the excision of the pre-existing bleb. A normal intraocular pressure was regained.The symptom of burning sensations subsequently subsided. A ten-month follow-up was conducted.Amniotic membrane transplantation is a feasible option for exuberant or late onsetbleb leakage, to prevent further destruction of ocular surface tissue and to maintain theintraocular pressure.

  1. Immunosuppressive therapy in non-infections uveitis and retinovasculitis

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    E. A. Drozdova

    2014-07-01

    Full Text Available Purpose: to evaluate the efficacy and safety of the immunosuppressive therapy for severe forms of non-infections uveitis and retinovasculitis.Methods: 107 patients (62 males and 45 females aged 9 to 54 years who received low dose methotrexate — 7.5-20 mg once a week (n=79 cyclosporine A 3.5-5.0 mg/kg/d (n=21 with prednisone or other antimetabolites and local corticosteroid therapy for severe forms of inflammatory eye diseases.Results: the efficacy of methotrexate as monotherapy was 51.8% of patients with chronic uveitis. Control of acute inflammation was achived in 71.1% patients, who received methotrexate in combination with prednisolone. Cyclosporine A was more effective in controlling inflammatory of the eye: remission of uveitis was achived in 85.7% in combination with glucocorticoids. No significant side effects have been noted.Conclusion: Methotrexate and cyclosporine A with low dose of prednisolone are well tolerated immunosuppressive agents andrather effective in the treatment of non-infectious uveitis and retinovasculitis that fails to respond to conventional steroid treatment.

  2. A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development.

    Science.gov (United States)

    Enrique Salcedo-Sora, J; Mc Auley, Mark T

    2016-03-23

    The metabolic biochemistry of folate biosynthesis and utilisation has evolved into a complex network of reactions. Although this complexity represents challenges to the field of folate research it has also provided a renewed source for antimetabolite targets. A range of improved folate chemotherapy continues to be developed and applied particularly to cancer and chronic inflammatory diseases. However, new or better antifolates against infectious diseases remain much more elusive. In this paper we describe the assembly of a generic deterministic mathematical model of microbial folate metabolism. Our aim is to explore how a mathematical model could be used to explore the dynamics of this inherently complex set of biochemical reactions. Using the model it was found that: (1) a particular small set of folate intermediates are overrepresented, (2) inhibitory profiles can be quantified by the level of key folate products, (3) using the model to scan for the most effective combinatorial inhibitions of folate enzymes we identified specific targets which could complement current antifolates, and (4) the model substantiates the case for a substrate cycle in the folinic acid biosynthesis reaction. Our model is coded in the systems biology markup language and has been deposited in the BioModels Database (MODEL1511020000), this makes it accessible to the community as a whole. PMID:26794619

  3. Metabolic engineering and classic selection of the yeast Candida famata (Candida flareri) for construction of strains with enhanced riboflavin production.

    Science.gov (United States)

    Dmytruk, Kostyantyn V; Yatsyshyn, Valentyna Y; Sybirna, Natalia O; Fedorovych, Daria V; Sibirny, Andriy A

    2011-01-01

    Currently, the mutant of the flavinogenic yeast Candida famata dep8 isolated by classic mutagenesis and selection is used for industrial riboflavin production. Here we report on construction of a riboflavin overproducing strain of C. famata using a combination of random mutagenesis based on the selection of mutants resistant to different antimetabolites as well as rational approaches of metabolic engineering. The conventional mutagenesis involved consecutive selection for resistance to riboflavin structural analog 7-methyl-8-trifluoromethyl-10-(1'-d-ribityl)isoalloxazine), 8-azaguanine, 6-azauracil, 2-diazo-5-oxo-L-norleucine and guanosine as well as screening for yellow colonies at high pH. The metabolic engineering approaches involved introduction of additional copies of transcription factor SEF1 and IMH3 (coding for IMP dehydrogenase) orthologs from Debaryomyces hansenii, and the homologous genes RIB1 and RIB7, encoding GTP cyclohydrolase II and riboflavin synthetase, the first and the last enzymes of riboflavin biosynthesis pathway, respectively. Overexpression of the aforementioned genes in riboflavin overproducer AF-4 obtained by classical selection resulted in a 4.1-fold increase in riboflavin production in shake-flask experiments. D. hansenii IMH3 and modified ARO4 genes conferring resistance to mycophenolic acid and fluorophenylalanine, respectively, were successfully used as new dominant selection markers for C. famata. PMID:21040798

  4. [Overproduction of riboflavin in mutants of Pichia guilliermondii yeasts resistant to 7-methyl-8-trifluoromethyl-10-(1'-D-ribityl)isoalloxazine].

    Science.gov (United States)

    Shavlovskiĭ, G M; Sibirnyĭ, A A; Ksheminskaia, G P; Pinchuk, G E

    1980-01-01

    Mutants resistant to 7-methyl-8-trifluoromethyl-10-(1'-D-ribityl)isoalloxazine were selected from the yeast Pichia guilliermondii, strain MS14-A10, possessing a multiple sensitivity to antibiotics and antimetabolites. A lot of such mutants displayed an elevated flavinogenic activity. The investigation of the properties of three mutants with the highest flavinogenic activity, viz. RZ4, RZ7 and RZ11, has shown that their capability for riboflavin overproduction does not stem from disordered regulation of the de novo purine biosynthesis, from the damaged transport of iron ions into the cell, or from changes in the allosteric properties of GTP cyclohydrolase. A twofold increase in the specific activities of GTP cyclohydrolase and riboflavin synthase was observed in the two mutants, RZ4 and RZ11. These data suggest that the mechanism for repression of the synthesis of flavinogenic enzymes, in which iron ions are involved, is impaired in these mutants. The reason for riboflavin overproduction in the mutant RZ7 remains obscure. PMID:7442566

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

    Science.gov (United States)

    Razeghinejad, Mohammad Reza; Masoumpour, Masoumeh; Eghbal, Mohammad Hossein; Myers, Jonathan S; Moster, Marlene R

    2016-09-01

    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. PMID:27582594

  6. 5-FU-induced cardiac toxicity - an underestimated problem in radiooncology?

    International Nuclear Information System (INIS)

    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

  7. Radioactive Iodo-azathioprine as a possible model for cancer imaging and therapy

    International Nuclear Information System (INIS)

    Azathioprine (Aza) is antimetabolite drug, could be labeled with the auger emitters iodine-125. Aza could be used an ideal vehicle to deliver radioactive decay energy to DNA of tumor cells causing DNA double strand break, thus stop DNA synthesis. In this study, the process of labeling was done via direct labeling technique using chloramine-T as an oxidizing agent and heating to 75 degree C, for 30 minutes at ph using 0.5 M phosphate buffer. The radiochemical purity of the labeled compound, at the above conditions, was determined using electrophoresis technique and was above 90%. About 2.5x106 of enrich ascites carcinoma (EAC) was injected intraperitoneally(i.p) to produce ascites and intramuscularly (i.m) in the right thigh to produce solid tumor in female mice. Biodistribution studies were carried out by injecting solution of 125I-aza in normal and tumor bearing mice. The uptake in ascites was over 40 % of the injected dose at 12 h post injection and above 20 % in solid tumor . These data revealed localization of the tracer in the tumor tissues with high percentage sufficient to give radiotherapeutic effect as well as promising tool for diagnosis.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-01-21

    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.

  9. Radioiodination and biological evaluation of Cladribine as potential agent for tumor imaging and therapy

    International Nuclear Information System (INIS)

    Cladribine, a purine analogue antimetabolite, was radioiodinated with 125I via direct electrophilic substitution reaction. The maximum radiochemical yield (92.5 ± 0.8%) was obtained when the reaction was done at ambient temperature for 30 min using 100 μg of Cladribine and 10 μg N-chlorosuccinamide (NCS) in 150 μL of 0.2 M phosphate buffer, pH 7. In vitro stability studies of HPLC purified 125I-Cladribine sample dissolved in 0.5 ml of 0.2 M phosphate buffer pH 7 at ambient temperature showed that 125I-Cladribine is stable up to 12 h post labeling. Biodistribution results revealed excretion of 125I-Cladribine mainly by kidneys. The uptake of 125I-Cladribine in the induced Ehrlich Ascites Carcinoma was 2.8 ± 0.4%ID/g at 1 h post injection with maximum tumor/muscle ratio of 5.5. The good uptake of 125I-Cladribine confirms the molecular docking studies results which indicate that iodinated Cladribine binds with polymerase enzyme with a good-CDOCKER energy. As a result, radioiodinated Cladribine may be used as a valuable agent for tumor diagnosis and therapy.

  10. In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells

    International Nuclear Information System (INIS)

    Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This in vitro study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules. The cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC) and CAL-27 (SCCHN) cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24 h MTA combined with 1 h or 24 h dFdC were analysed. Including a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect. Results from our in vitro model suggest that the sequence 24 h MTA → 1 h dFdC → RT is the most rational design and would, after confirmation in an in vivo setting, possibly provide the greatest benefit in the clinic

  11. Post-transplantation diabetes mellitus

    Directory of Open Access Journals (Sweden)

    N Zbiti

    2012-01-01

    Full Text Available To determine the prevalence of post-kidney transplantation diabetes (PTDM and to assess its risk factors, we retrospectively studied 92 non-diabetic kidney transplant patients. The immunosuppressive drugs used to prevent rejection included prednisone, a calcineurin inhibitor (cyclosporine or tacrolimus and an antimetabolite (azathioprine or mycofenolate mofetil. Diabetes was defined according to the WHO criteria and the American Diabetes Association. The mean age of our patients was 35.8 ± 10.5 years, and there was a clear male predominance (56 men and 36 women. The graft was from living related donor in 71/92 (76% patients. The prevalence of dia-betes in post-kidney transplant was 15.2%. The factors increasing the occurrence of PTDM included advanced age, high doses of steroids and cyclosporine. Management of PTDM included diet modification, oral anti-diabetic and insulin. We conclude that the prevalence of PTDM is significant in our transplant population and risk factors for its development are multiple and require aggressive multifaceted management.

  12. 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. PMID:26975374

  13. Antifolates targeting purine synthesis allow entry of tumor cells into S phase regardless of p53 function.

    Science.gov (United States)

    Bronder, Julie L; Moran, Richard G

    2002-09-15

    The class of folate antimetabolites typified by (6R)-dideazatetrahydrofolate (lometrexol, DDATHF) are specific inhibitors of de novo purine synthesis because of potent inhibition of glycinamide ribonucleotide formyltransferase (GART) but do not induce detectable levels of DNA strand breaks. As such, they are a test case of the concept that ribonucleotide depletion can be sensed by p53, resulting in a G(1) cell cycle block. The GART inhibitors have been proposed previously to be cytotoxic in tumor cells lacking p53 function but only cytostatic in p53 wild-type tumor cells. We have investigated this concept. Cell cycle progression into and through S phase was slowed by DDATHF, but both p53 +/+ and -/- human colon carcinoma cells entered and completed one S phase in the presence of drug. This inability of p53 to initiate a G(1) arrest after DDATHF treatment was mirrored by an independence of the cytotoxicity of DDATHF on p53 function. We conclude that carcinoma cells are killed equally well by DDATHF and related compounds whether or not the p53 pathway is intact and that the utility of GART inhibitors would not be limited to p53-negative tumors. PMID:12234990

  14. Three biotechnical processes using Ashbya gossypii, Candida famata, or Bacillus subtilis compete with chemical riboflavin production.

    Science.gov (United States)

    Stahmann, K P; Revuelta, J L; Seulberger, H

    2000-05-01

    Chemical riboflavin production, successfully used for decades, is in the course of being replaced by microbial processes. These promise to save half the costs, reduce waste and energy requirements, and use renewable resources like sugar or plant oil. Three microorganisms are currently in use for industrial riboflavin production. The hemiascomycetes Ashbya gossypii, a filamentous fungus, and Candida famata, a yeast, are naturally occurring overproducers of this vitamin. To obtain riboflavin production with the gram-positive bacterium Bacillus subtilis requires at least the deregulation of purine synthesis and a mutation in a flavokinase/FAD-synthetase. It is common to all three organisms that riboflavin production is recognizable by the yellow color of the colonies. This is an important tool for the screening of improved mutants. Antimetabolites like itaconate, which inhibits the isocitrate lyase in A. gossypii, tubercidin, which inhibits purine biosynthesis in C. famata, or roseoflavin, a structural analog of riboflavin used for B. subtilis, have been applied successfully for mutant selections. The production of riboflavin by the two fungi seems to be limited by precursor supply, as was concluded from feeding and gene-overexpression experiments. Although flux studies in B. subtilis revealed an increase both in maintenance metabolism and in the oxidative part of the pentose phosphate pathway, the major limitation there seems to be the riboflavin pathway. Multiple copies of the rib genes and promoter replacements are necessary to achieve competitive productivity. PMID:10855708

  15. Isolation of an oxalate-resistant Ashbya gossypii strain and its improved riboflavin production.

    Science.gov (United States)

    Sugimoto, Takashi; Morimoto, Aki; Nariyama, Masashi; Kato, Tatsuya; Park, Enoch Y

    2010-01-01

    An oxalate-resistant strain of Ashbya gossypii was naturally isolated from spores grown on an oxalate-containing medium, and its medium was optimized to improve riboflavin production. Riboflavin production by the resistant strain was three-fold higher than that by the wild-type organism when grown in flask cultures. Medium optimization increased the riboflavin production by the resistant strain to 5 g l(-1), which was five-fold higher than that obtained by the wild-type strain. The productivity was reproduced in a 3-l bioreactor. During the early growth phase, the specific activity of isocitrate lyase in the oxalate-resistant strain was slightly higher than that in the wild-type strain. Proteomic analysis of the oxalate-resistant strain revealed that the expression of aldose reductase and cobalamin-independent methionine synthase decreased significantly. This is the first report that describes the natural isolation of a riboflavin producer using an antimetabolite-containing medium to enhance the riboflavin production level. This method should also be useful for improving the productivity of other bioproducts since it does not require any mutations or genetic modifications of the microorganism. PMID:19826846

  16. 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.

  17. Immunosuppressive treatment for kidney transplantation.

    Science.gov (United States)

    Zivčić-Ćosić, S; Trobonjača, Z; Rački, S

    2011-01-01

    Immunosuppressive treatment minimizes unwanted immune reactivity, but it also leads to complications such as metabolic disorders, cardiovascular diseases and malignant tumours. In this paper we summarise the recent developments in action mechanisms of available immunosuppressive drugs and their usage for renal transplantation. These drugs act at various levels of lymphocytic activation and proliferation, and they may have additive or synergic effects when combined. In the majority of patients, the immunosuppressive protocol includes a calcineurin inhibitor (tacrolimus or cyclosporin), an antimetabolite (mycophenolate mofetil or mycophenolic acid) and a corticosteroid. Most patients also receive induction with monoclonal or polyclonal antilymphocytic antibodies. These immunosuppressive drugs allow a one-year survival of renal allografts in over 90% of cases and an incidence of acute rejection episodes below 15%. In most cases, acute cell-mediated rejection can be reversed with pulse doses of methylprednisolone; less often antilymphocytic antibodies must be applied. Acute humoral rejection can be suppressed with high doses of intravenous immunoglobulines or low doses of cytomegalovirus hyperimmune globuline, in combination with plasmapheresis, to obtain a satisfactory reduction of anti-donor antibodies. This treatment also allows renal transplantation for sensitised recipients, or transplantation against a positive cross match or AB0 incompatibility. Less often, immunoadsorption, alemtuzumab, rituximab or splenectomy are applied. New immunosuppressive drugs and protocols are currently under investigation. Immunosuppressive agents and methods targeting the induction of immune tolerance to the donor organ are especially promising. PMID:22286615

  18. Advanced glaucoma: Management pearls

    Directory of Open Access Journals (Sweden)

    Girum W Gessesse

    2013-01-01

    Full Text Available A significant proportion of glaucoma patients present late, particularly in the developing world, and unfortunately, in an advanced stage of the disease. They are at imminent danger of losing remaining vision, and may also be afflicted with various socioeconomic and health challenges. The encounter with such a patient is typically characterized by anxiety/fear and sometimes hopelessness from the patient′s perspective. The physician may also feel that they are in a difficult position managing the patient′s disease. When dealing with such cases, we suggest a holistic, individualized approach taking into account the ′biopsychosociospiritual′ (BPSS profile of each patient. The BPSS model takes into account relevant ocular as well as systemic biology (factors such as the mechanism of glaucoma, level of intraocular pressure [IOP], rate of progression, life expectancy, general health, psychological considerations (e.g., fear, depression, socio-economic factors and spiritual/cultural values and beliefs before being able to decide with the patient and their care partner(s what treatment goals should be and how they can best be approached. Treatment for advanced glaucoma can be highly effective, and patients and their care partners should be informed that aggressive IOP lowering to the low teens or even single digits offers the best chance of protecting remaining vision. This can be achieved safely and effectively in most cases with trabeculectomy (including an antimetabolite, and in some cases with medical and/or laser therapy. Vision rehabilitation and psychosocial support should also be considered in order to optimize remaining vision, replace fear with hope as appropriate, and thus improve the overall quality of life.

  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. PMID:24585629

  20. Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations

    Directory of Open Access Journals (Sweden)

    Tourkova Irina L

    2009-07-01

    Full Text Available Abstract The dose-delivery schedule of conventional chemotherapy, which determines its efficacy and toxicity, is based on the maximum tolerated dose. This strategy has lead to cure and disease control in a significant number of patients but is associated with significant short-term and long-term toxicity. Recent data demonstrate that moderately low-dose chemotherapy may be efficiently combined with immunotherapy, particularly with dendritic cell (DC vaccines, to improve the overall therapeutic efficacy. However, the direct effects of low and ultra-low concentrations on DCs are still unknown. Here we characterized the effects of low noncytotoxic concentrations of different classes of chemotherapeutic agents on human DCs in vitro. DCs treated with antimicrotubule agents vincristine, vinblastine, and paclitaxel or with antimetabolites 5-aza-2-deoxycytidine and methotrexate, showed increased expression of CD83 and CD40 molecules. Expression of CD80 on DCs was also stimulated by vinblastine, paclitaxel, azacytidine, methotrexate, and mitomycin C used in low nontoxic concentrations. Furthermore, 5-aza-2-deoxycytidine, methotrexate, and mitomycin C increased the ability of human DCs to stimulate proliferation of allogeneic T lymphocytes. Thus, our data demonstrate for the first time that in low noncytotoxic concentrations chemotherapeutic agents do not induce apoptosis of DCs, but directly enhance DC maturation and function. This suggests that modulation of human DCs by noncytotoxic concentrations of antineoplastic drugs, i.e. chemomodulation, might represent a novel approach for up-regulation of functional activity of resident DCs in the tumor microenvironment or improving the efficacy of DCs prepared ex vivo for subsequent vaccinations.

  1. 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

  2. Medication treatment of pediatric noninfectious uveitis%儿童非感染性葡萄膜炎的药物治疗

    Institute of Scientific and Technical Information of China (English)

    王敏; 张美芬

    2015-01-01

    儿童葡萄膜炎占所有葡萄膜炎的5%~10%,多数起病隐匿、病程迁延,常合并多种眼部并发症.儿童葡萄膜炎多为非感染性,其中绝大多数为特发性,最常见的全身病因为幼年特发性关节炎.儿童葡萄膜炎治疗棘手,常用药物为糖皮质激素、抗代谢药、T细胞抑制剂.近年来生物制剂的使用为儿童非感染性葡萄膜炎的治疗提供了新方法.玻璃体腔植入糖皮质激素缓释装置可长时间控制眼内炎症,但在儿童中使用的安全性及有效性仍待进一步研究.%Pediatric uveitis is accounting for 5%~ 10% of all the uveitis.Most individuals have an insidious onset and persistent duration,ocular complications are common.Most pediatric uveitis are noninfectious and idiopathic,the most common etiologic diagnosis is juvenile idiopathic arthritis.Treatment of pediatric uveitis is tough,the mainstays of therapy include corticosteroids,antimetabolites,and T-cell inhibitors.In the last decade,biologic agents provide us new methods for treating pediatric uveitis.Intravitreal corticosteroid delivery devices have enhanced our ability to provide longer-lasting local disease control,but there are very limited data showing the efficacy and safety in children.

  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. 2-Deoxyglucose as an adjuvant in improving radiotherapy of malignant gliomas

    International Nuclear Information System (INIS)

    Experimental studies in model systems (tumor cell lines, organ cultures and tumor bearing mice) have shown that the glucose anti-metabolite, 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, can selectively enhance radiation damage in cancer cells, by inhibiting energy dependent DNA and cellular repair processes. Phase I/II clinical trials demonstrated that the 2-DG administration (200 mg/kg b.wt, orally) 30 minutes before hypofractionated radiotherapy (RT) was well tolerated by glioma patients. Present studies were undertaken to evaluate the tolerance and toxicity of the combined treatment (2-DG + RT) with increasing doses of 2-DG in GBM patients. Seven weekly fractions (5 Gy/fraction) of 60 Co gamma-rays were delivered to tumor (pre-surgical CT evaluation) plus 3 cm margin. 2-DG (200-300 mg/kg body wt.) was administered orally 30 min. before irradiation, after overnight fasting. Treatment was well tolerated up to a 2-DG dose of 250 mg/kg b.wt. with transient symptoms similar to hypoglycemia, which were self-limiting due to the increase in the levels of blood glucose. At 300 mg/kg body wt. 2 patients out of 6 felt very restless and discontinued the treatment after 2 fractions, however, life threatening changes in vital parameters were not observed in these patients. MRI studies did not reveal any significant damage to the normal brain in 6 patients (out of 10), who were alive with improved quality of life between 12 and 41 months after the diagnosis. Multi-center phase II studies to evaluate the feasibility, safety and efficacy of combining 2-DG with radiotherapy/radiosurgery in GBM patients are currently ongoing

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

    Directory of Open Access Journals (Sweden)

    Arrebola Eva

    2012-01-01

    Full Text Available Abstract 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.

  6. 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)

    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

  7. Cytosine Deaminase/5-Fluorocytosine Exposure Induces Bystander and Radiosensitization Effects in Hypoxic Glioblastoma Cells in vitro

    International Nuclear Information System (INIS)

    Purpose: Treatment of glioblastoma (GBM) is limited by therapeutic ratio; therefore, successful therapy must be specifically cytotoxic to cancer cells. Hypoxic cells are ubiquitous in GBM, and resistant to radiation and chemotherapy, and, thus, are logical targets for gene therapy. In this study, we investigated whether cytosine deaminase (CD)/5-fluorocytosine (5-FC) enzyme/prodrug treatment induced a bystander effect (BE) and/or radiosensitization in hypoxic GBM cells. Methods and Materials: We stably transfected cells with a gene construct consisting of the SV40 minimal promoter, nine copies of a hypoxia-responsive element, and the yeast CD gene. During hypoxia, a hypoxia-responsive element regulates expression of the CD gene and facilitates the conversion of 5-FC to 5-fluorouracil, a highly toxic antimetabolite. We used colony-forming efficiency (CFE) and immunofluorescence assays to assess for BE in co-cultures of CD-expressing clone cells and parent, pNeo- or green fluorescent protein-stably transfected GBM cells. We also investigated the radiosensitivity of CD clone cells treated with 5-FC under hypoxic conditions, and we used flow cytometry to investigate treatment-induced cell cycle changes. Results: Both a large BE and radiosensitization occurred in GBM cells under hypoxic conditions. The magnitude of the BE depended on the number of transfected cells producing CD, the functionality of the CD, the administered concentration of 5-FC, and the sensitivity of cell type to 5-fluorouracil. Conclusion: Hypoxia-inducible CD/5-FC therapy in combination with radiation therapy shows both a pronounced BE and a radiosensitizing effect under hypoxic conditions

  8. Use of the radiometric method at creation cell test-systems for pre-screening of anticancer preparations

    International Nuclear Information System (INIS)

    Full text: Development of cancer chemotherapy is tightly bound with investigation of biological activity of different compounds on in vitro test systems. Our research has been directed on definition of sensitivity of the cell line KML removed by us from passed of mice melanoma B-16. We had been investigated action of 18 clinical antineoplastic preparations of different classes: alkylating - sarcolysinum, thiophosphamide, dopan, fhthordopan; antimetabolites - cytararibinum, methotrexatum, 6-mercaptopurinum, 5-fhthorouracilum, fhthorafur; antineoplastic antibiotics- adriamycinum, neomycinum, rubomycinum, bruneomycinum, carminomycinum, olivomycinum; plant substances - vinblastinum, colchaminum (component of ointment which used at treatment of skin cancer) and other - carboplatin. Cytotoxic effect of preparations estimated two methods - radiometric on inclusion of 3H - timidine in cells and spectrophotometric by definition of total amount nucleic acids and protein. For this purpose KML cells passed in quantity of 120 thousand in 3 ml of nutrient medium RPMI 1640, 10 % calf embryo serum in bottles and after 24 hours entered substances in dozes from 0,01 up to 100 μg/ml. Contact of substances to cells was 24 hours, then 10 μ Ci 3H - timidine was injected on bottles at 1 hour. Cells transferred on GFC-filters, washed from not connected label. Filters transferred in scintillation liquid and a level of a radio-activity determined on β-counter. All tested clinical preparations appeared active within the criteria of activity, thus the radiometric method was more sensitive, than spectrophotometric. Thus, testing results of model have shown that stable cell line KML was sensitive to action of 18 clinical preparations with various mechanisms of action by different estimations of damaging action. This model can be used for biological activity of new potential cancerolytics pre-screening. This work was supported by the Center of Science and Technology of the Republic of

  9. Melatonin overcomes resistance to clofarabine in two leukemic cell lines by increased expression of deoxycytidine kinase.

    Science.gov (United States)

    Yamanishi, Miho; Narazaki, Hidehiko; Asano, Takeshi

    2015-03-01

    Drug resistance remains a serious problem in leukemia therapy. Among newly developed nucleoside antimetabolites, clofarabine has broad cytotoxic activity showing therapeutic promise and is currently approved for relapsed acute lymphoblastic leukemia. To investigate the mechanisms responsible for clofarabine resistance, we established two clofarabine-resistant lymphoblastic leukemia cell lines from parental lines. To elucidate the mechanisms against clofarabine resistance in two newly established clofarabine-resistant cell lines, we measured the expression of export pumps multidrug resistance protein 1, multidrug resistance-associated protein 1, and ATP-binding cassette subfamily G member 2. There were no differences in the expression between clofarabine-sensitive and -resistant cell lines. Next, we determined expression of deoxycytidine kinase (dCK), which phosphorylates clofarabine to exert cytotoxicity, in clofarabine-sensitive and -resistant cells. Clofarabine-resistant cells showed significantly decreased expression of dCK RNA when compared with sensitive cells. To elucidate the mechanisms of decreased dCK expression in clofarabine-resistant cells, we analyzed the methylation status of CpG islands of the dCK promoter and found no differences in methylation status between clofarabine-sensitive and -resistant cells. Next, we measured the acetylation status of histone and found that total histone acetylation, and histone H3 and H4 acetylation on chromatin immunoprecipitation assay were significantly decreased in resistant cells. Melatonin is an indolamine that functions in the regulation of chronobiological rhythms to exert cytotoxic effects. We examined the effects of melatonin in clofarabine-resistant cells and found that melatonin treatment led to significantly increased cytotoxicity with clofarabine in resistant cells via increased acetylation. Melatonin may be a useful candidate for overcoming clofarabine resistance in two newly established clofarabine

  10. Current management of gout in patients unresponsive or allergic to allopurinol.

    Science.gov (United States)

    Bardin, Thomas

    2004-11-01

    The manifestations of gout can be abolished permanently by lifelong urate-lowering therapy maintaining serum urate levels under 360 mmol/l, as this ensures dissolution of pathogenic crystals of monosodium urate monohydrate. Benzbromarone has been withdrawn from the market, leaving allopurinol as the only urate-lowering drug readily available in France. Allopurinol may induce unacceptable side effects, and in patients with dose-limiting renal failure it may not be sufficiently effective. Because allopurinol can induce serious side effects when given concomitantly with purine antimetabolites, it is contraindicated in organ transplant recipients. In patients who cannot tolerate allopurinol, dietary treatment, discontinuation of diuretic agents, and use of losartan or fenofibrate to treat concomitant hypertension or dyslipidemia, respectively, may ensure adequate control of serum urate levels. Desensitization to allopurinol can be attempted in patients with mild cutaneous hypersensitivity reactions but is difficult to perform and rarely used. Uricosuric agents may be helpful in patients with normal or diminished urate excretion. Probenecid is available in France from hospital pharmacies, and benzbromarone can be prescribed via a time-limited authorization procedure. Rasburicase, an Aspergillus urate oxidase produced by genetic engineering, is indicated to prevent acute hyperuricemia induced by chemotherapy for hematological malignancies. Factors that limit the use of rasburicase include the absence of a marketing authorization, the need for parenteral administration, and the absence of validated treatment schedules. Patients with renal failure precluding the use of effective allopurinol dosages are good candidates for benzbromarone therapy. Organ transplant recipients can be given benzbromarone, within the current restrictions to its use; alternatively, mycophenolate mofetil can be substituted for calcineurin inhibitors, which elevate serum urate levels, or for

  11. Correlation between osteoporosis and skin thickness on CT scan

    International Nuclear Information System (INIS)

    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

  12. A new paradigm for pattern recognition of drugs.

    Science.gov (United States)

    Potemkin, Vladimir A; Grishina, Maria A

    2008-01-01

    A new paradigm is suggested for pattern recognition of drugs. The approach is based on the combined application of the 4D/3D quantitative structure-activity relationship (QSAR) algorithms BiS and ConGO. The first algorithm, BiS/MC (multiconformational), is used for the search for the conformers interacting with a receptor. The second algorithm, ConGO, has been suggested for the detailed study of the selected conformers' electron density and for the search for the electron structure fragments that determine the pharmacophore and antipharmacophore parts of the compounds. In this work we suggest using a new AlteQ method for the evaluation of the molecular electron density. AlteQ describes the experimental electron density (determined by low-temperature highly accurate X-ray analysis) much better than a number of quantum approaches. Herein this is shown using a comparison of the computed electron density with the results of highly accurate X-ray analysis. In the present study the desirability function is used for the first time for the analysis of the effects of the electron structure in the process of pattern recognition of active and inactive compounds. The suggested method for pattern recognition has been used for the investigation of various sets of compounds such as DNA-antimetabolites, fXa inhibitors, 5-HT(1A), and alpha(1)-AR receptors inhibitors. The pharmacophore and antipharmacophore fragments have been found in the electron structures of the compounds. It has been shown that the pattern recognition cross-validation quality for the datasets is unity. PMID:18357415

  13. Gallium-67 distribution and whole body retention in methotrexate treated rats

    International Nuclear Information System (INIS)

    Gallium-67 citrate is a radiopharmaceutical which localizes in tumors, abscesses, and inflammmatory lesions. Gallium-67 is used to stage Hodgkin's disease and to follow the course of various neoplastic diseases in patients being treated with chemotherapeutic agents. It is believed that the iron-binding protein transferrin is required for the transport of gallium-67 to the site of localization. Methotrexate is an antimetabolite type cancer chemotherapeutic agent that is hepatotoxic. Since transferrin is synthesized primarily in the liver and treatment with methotrexate may be hepatotoxic, an alteration in the distribution and whole body retention of gallium-67 may occur from chronic treatment with methotrexate. The purpose of this investigation was to examine the biodistribution and whole body retention of gallium-67 in rats which had been treated for up to three weeks with methotrexate. Methotrexate was administered intraperitoneally at a dose of 250 μg/kg per day for five days each week. The influence of methotrexate on the unbound iron-binding capacity and the total iron-binding capacity of transferrin and serum iron was examined, also. Small decreases in gallium-67 levels were observed in blood, spleen, and muscle of drug treated animals in relation to normal saline controls. Although small in magnitude, gallium-67 whole body elimination was more rapid in drug treated animals than controls after two or three weeks of methotrexate treatment. The study showed no effect of methotrexate treatment on the unbound iron-binding capacity or total iron-binding capacity of transferrin or serum iron. The results of the investigation infer that alterations in the biodistribution and retention of gallium-67 from methotrexate treatment may not be of clinical significance

  14. AHPG: 9-[(1-amino-3-hydroxy-2-propoxy)methyl]guanine. Synthesis, biological evaluation, and biochemical mechanism of action in the L1210 cell system

    International Nuclear Information System (INIS)

    This thesis involved the synthesis, biological evaluation, and determination of the mechanism of cytotoxicity of 9-[(1-amino-3-hydroxy-2-propoxy)methyl]guanine, AHPG. This acyclic nucleoside was synthesized by a novel route and purified by state-of-the-art chromatography. The antimetabolite was screened for cytotoxic activity and was found to be most effective against L1210 cells among those systems tested. Initial biochemical studies in this system indicated that AHPG significantly decreased the incorporation of amino acids into L1210 acid-insoluble material without altering the incorporation of precursor molecules into DNA or RNA. Electrophoretic analysis of the nuclear and cytoplasmic proteins formed in the presence of drug indicated that this effect was a generalized phenomenon. Additionally, AHPG was found not to alter amino acid transport into L1210 cells. Since AHPG is a modified precursor of DNA and RNA, it was essential to evaluate the influence of this agent on these macromolecules. DNA and RNA were isolated from L1210 cells which had been treated with radiolabeled AHPG (tritium in the guanine base). HPLC analysis indicated that native AHPG was not present in the nucleic acids and phosphorylated AHPG was not found in cytosolic fractions. Since all the data suggested that the primary effect of AHPG might be directed at the level of translation, ribosomes and polysomes were isolated in the presence and absence of drug. After sixty minutes of exposure to AHPG there was a significant decrease in the levels of these complexes, suggesting that AHPG invokes its initial cytotoxic action directly at the level of protein synthesis. In summary, AHPG produces toxicity in L1210 cells by altering protein metabolism

  15. The role of osteocyte apoptosis in cancer chemotherapy-induced bone loss.

    Science.gov (United States)

    Shandala, Tetyana; Shen Ng, Yeap; Hopwood, Blair; Yip, Yuen-Ching; Foster, Bruce K; Xian, Cory J

    2012-07-01

    Intensive cancer chemotherapy leads to significant bone loss, the underlying mechanism of which remains unclear. The objective of this study was to elucidate mechanisms for effect of the commonly used anti-metabolite methotrexate (MTX) on osteocytes and on general bone homeostasis. The current study in juvenile rats showed that MTX chemotherapy caused a 4.3-fold increase in the number of apoptotic osteocytes in tibial metaphysis, which was accompanied by a 1.8-fold increase in the number of tartrate-resistant acid phosphatase-positive bone resorbing osteoclasts, and a 35% loss of trabecular bone. This was associated with an increase in transcription of the osteoclastogenic cytokines IL-6 (10-fold) and IL-11 (2-fold). Moreover, the metaphyseal bone of MTX-treated animals exhibited a 37.6% increase in the total number of osteocytes, along with 4.9-fold higher expression of the DMP-1 transcript. In cultured osteocyte-like MLO-Y4 cells, MTX treatment significantly increased caspase-3-mediated apoptosis, which was accompanied by the formation of plasma membrane-born apoptotic bodies and an increase in IL-6 (24-fold) and IL-11 (29-fold) mRNA expression. Conditioned media derived from MTX-treated MLO-Y4 cells was twice as strong as untreated media in its capacity to induce osteoclast formation in primary bone marrow osteoclast precursors. Thus, our in vivo and in vitro data suggested that MTX-induced apoptosis of osteocytes caused higher recruitment of DMP-1 positive osteocytes and increased osteoclast formation, which could contribute towards the loss of bone homeostasis in vivo. PMID:21938727

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

    Directory of Open Access Journals (Sweden)

    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

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

    International Nuclear Information System (INIS)

    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 35S and 15N 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.)

  18. The progress of MTX in acute lymphoblastic leukemia%MTX治疗急性淋巴细胞白血病的研究进展

    Institute of Scientific and Technical Information of China (English)

    张培; 沈佐君

    2012-01-01

      Methotrexate(MTX), a kind of anti-folate and antimetabolite medicine, is one of the commonly used chemotherapy drugs to treat malignant tumor which has a strong immunosuppressive effect. It is selective for acute lymphoid leukemia cells to prevent the proliferation of immunoblastic and inhibit the humoral and cellular immune responses. Tumor cells are prone to resistance and transfer recurrence after the acute lymphoid leukemia patients accept MTX treatment. This paper mainly reviewed the relationship between the mechanism, the dose, the timing selection, the level of DNA methylation and EGFR gene with the transfer and invasion on MTX treatment in acute lymphoid leukemia.%  MTX为抗叶酸类抗代谢药,是临床上治疗各种恶性肿瘤常用化疗药物之一,有很强的免疫抑制作用。它选择性作用于急性淋巴细胞白血病细胞阻止免疫母细胞分裂增殖,同时对体液免疫和细胞免疫均有抑制作用。急性淋巴细胞白血病患者接受MTX治疗后肿瘤细胞易产生耐药与转移复发。本文就MTX治疗急性淋巴细胞白血病作用机制、剂量和作用时间选择、DNA甲基化水平变化、EGFR基因和侵袭转移的关系进行综述。

  19. Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction.

    Science.gov (United States)

    Shibata, Takashi; Ebata, Tomoki; Fujita, Ken-ichi; Shimokata, Tomoya; Maeda, Osamu; Mitsuma, Ayako; Sasaki, Yasutsuna; Nagino, Masato; Ando, Yuichi

    2016-02-01

    A clear consensus does not exist about whether the initial dose of gemcitabine, an essential anticancer antimetabolite, should be reduced in patients with liver dysfunction. Adult patients with biliary tract or pancreatic cancer were divided into three groups according to whether they had mild, moderate, or severe liver dysfunction, evaluated on the basis of serum bilirubin and liver transaminase levels at baseline. As anticancer treatment, gemcitabine at a dose of 800 or 1000 mg/m(2) was given as an i.v. infusion once weekly for 3 weeks of a 4-week cycle. The patients were prospectively evaluated for adverse events during the first cycle, and the pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied to determine the optimal initial dose of gemcitabine as monotherapy according to the severity of liver dysfunction. A total of 15 patients were studied. Liver dysfunction was mild in one patient, moderate in six, and severe in eight. All 15 patients had been undergoing biliary drainage for obstructive jaundice when they received gemcitabine. Grade 3 cholangitis developed in one patient with moderate liver dysfunction who received gemcitabine at the dose level of 1000 mg/m(2). No other patients had severe treatment-related adverse events resulting in the omission or discontinuation of gemcitabine treatment. The plasma concentrations of gemcitabine and difluorodeoxyuridine were similar among the groups. An initial dose reduction of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancers is not necessary for patients with hyperbilirubinemia, provided that obstructive jaundice is well managed. (Clinical trial registration no. UMIN000005363.) PMID:26595259

  20. Active-site-directed reductive alkylation of xanthine oxidase by imidazo[4,5-g]quinazoline-4,9-diones functionalized with a leaving group.

    Science.gov (United States)

    Lee, C H; Skibo, E B

    1987-11-17

    A new class of purine antimetabolites, directed toward xanthine oxidase, was designed by employing some of the features found in the bioreductive alkylator mitomycin C. The design involved functionalizing the purine-like imidazo[4,5-g]quinazoline ring system as a quinone (4,9-dione) bearing a 2 alpha leaving group. Due to the presence of the electron-deficient quinone ring, the leaving group cannot participate in alkylation reactions. Reduction to the hydroquinone (4,9-dihydroxy) derivative, however, permits elimination of the leaving group to afford an alkylating quinone methide. In spite of the electronic differences, both quinone and hydroquinone derivatives of the imidazo[4,5-g]quinazoline system are able to enter the purine-utilizing active site of the enzyme. Thus, the hypoxanthine-like quinone derivative [2-(bromomethyl)-3-methylimidazo[4,5-g]quinazoline-4,8, 9(3H, 7H)-trione] and its hydroquinone derivative can act as reducing substrates for the enzyme, resulting in conversion to the xanthane-like 6-oxo derivatives. Hydrolysis studies described herein indicate that the hypoxanthine-like hydroquinone derivative eliminates HBr to afford an extended quinone methide species. The observed alkylation of the enzyme by this derivative may thus pertain to quinone methide generation and nucleophile trapping during enzymatic oxidation at the 6-position. Enzymatic studies indicate that the hypoxanthine-like quinone is an oxidizing suicide substrate for the enzyme. Thus, the reduced enzyme transfers electrons to this quinone, and the resulting hydroquinone inactivates the enzyme. As with mitomycin C, reduction and quinone methide formation are necessary for alkylation by the title quinone. This system is therefore an example of a purine active-site-directed reductive alkylator.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3427077

  1. Pharmacogenetics in breast cancer: steps toward personalized medicine in breast cancer management

    Directory of Open Access Journals (Sweden)

    Sarah Rofaiel

    2010-09-01

    Full Text Available Sarah Rofaiel1, Esther N Muo1, Shaker A Mousa1,21The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA; 2King Saud University, Riyadh, Saudi ArabiaAbstract: There is wide individual variability in the pharmacokinetics, pharmacodynamics, and tolerance to anticancer drugs within the same ethnic group and even greater variability among different ethnicities. Pharmacogenomics (PG has the potential to provide personalized therapy based on individual genetic variability in an effort to maximize efficacy and reduce adverse effects. The benefits of PG include improved therapeutic index, improved dose regimen, and selection of optimal types of drug for an individual or set of individuals. Advanced or metastatic breast cancer is typically treated with single or multiple combinations of chemotherapy regimens including anthracyclines, taxanes, antimetabolites, alkylating agents, platinum drugs, vinca alkaloids, and others. In this review, the PG of breast cancer therapeutics, including tamoxifen, which is the most widely used therapeutic for the treatment of hormone-dependent breast cancer, is reviewed. The pharmacological activity of tamoxifen depends on its conversion by cytochrome P450 2D6 (CYP2D6 to its abundant active metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the coadministration of other drugs that inhibit CYP2D6 function, produce little endoxifen and hence derive limited therapeutic benefit from tamoxifen; the same can be said about the different classes of therapeutics in breast cancer. PG studies of breast cancer therapeutics should provide patients with breast cancer with optimal and personalized therapy.Keywords: pharmacogenomics, genetic, pharmacokinetic, pharmacodynamic, personalized medicine, pharmacotherapy, anticancer drugs, efficacy, safety

  2. The balance of estrogen metabolites in breast cancer and the ways of its correction

    Directory of Open Access Journals (Sweden)

    L. A. Ashrafyan

    2015-09-01

    of metabolic disturbances with antimetabolites is one of the important, pathogenetically sound areas in the prevention of BC. 

  3. Therapeutic potential of 5-[125I]iodo-2'-deoxyuridine and methotrexate in the treatment of advanced neoplastic meningitis

    International Nuclear Information System (INIS)

    Methotrexate (MTX) is used clinically to treat neoplastic meningitis. This antimetabolite also enhances the in-vitro and in-vivo tumor cell uptake of the thymidine analog 5-[125I]iodo-2'-deoxyuridine (125IUdR). We had previously demonstrated that the sequential administration of these two agents (MTX-125IUdR) in rats bearing early (3-day-old) intrathecal (i.t.) TE671 human rhabdomyosarcoma tumors significantly augmented the therapeutic efficacy of the Auger-electron-emitting radiopharmaceutical. We now have compared the effectiveness of MTX and 125IUdR administered sequentially in rats bearing advanced (10-day-old) i.t. TE671 tumors. Nude rats were injected i.t. with TE671 cells. Ten days later, the animals were injected i.t. with (i) saline daily (12 x), (ii) 31 μg MTX every other day (6 x), (iii) 0.2 mCi 125IUdR (1/10 th the maximum tolerated dose [MTD]) every other day (6 x), and (iv) 31 μg MTX (6 x) and 0.2 mCi 125IUdR (6 x) on alternating days. Probability of the onset of paralysis was determined as a function of time. The findings were compared with previous results obtained from 3-day-old treated tumors. The data show that (i) the injection of MTX leads to a modest increase in the onset of paralysis (MMTX = 26 d versus Msaline = 22 d), (ii) the administration of 125IUdR is more effective (M*IUdR= 35 d), (iii) the sequential administration of MTX-125IUdR increases the therapeutic efficacy of 125IUdR (M MTX*IUdR= 43 d), and (iv) while the successive injection of MTX-125IUdR in these advanced tumors is therapeutically efficacious, the treatment is substantially less effective than when used for early tumors. We conclude that the i.t. injection of MTX-125IUdR at 1/10 th the MTD is therapeutically efficacious in the therapy of advanced intrathecal tumors. Furthermore, the effectiveness of the MTX-125IUdR therapeutic regimen is principally due to 125IUdR

  4. Pilot study investigating the prognostic significance of thymidine phosphorylase expression in patients with metastatic breast cancer: a single institution retrospective analysis

    Directory of Open Access Journals (Sweden)

    Tedeschi AL

    2015-04-01

    Full Text Available Anna Lisa Tedeschi,1 Zohreh Eslami,2 Evgenia Garoufalis,1 Ramy R Saleh,3 Atilla Omeroglu,2 Gulbeyaz Altinel,2 Maria Ait-Tihyaty,4 Bertrand Jean-Claude,4 Catalin Mihalcioiu1 1Division of Medical Oncology, Department of Medicine, McGill University Health Center, Royal Victoria Hospital, 2Department of Pathology, 3Department of Medicine, McGill University, 4Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center, Royal Victoria Hospital, Montreal, QC, Canada Background: The thymidine phosphorylase (TP enzyme is expressed in higher levels in cancer tissue when compared with normal tissue. It is involved in the intratumoral activation of widely prescribed pyrimidine-derived antimetabolites such as 5'-deoxy-5-fluorouridine and capecitabine (Xeloda®. The purpose of this study was to determine the clinical correlation between TP expression in tumor tissue and the clinical outcome of capecitabine-based therapy in patients with locally advanced (stage III or metastatic breast cancer (stage IV.Methods: The following variables were analyzed as potential determinants of benefit from a capecitabine-based therapy: TP expression, estrogen receptor (ER and progesterone receptor (PR status, human epidermal growth factor receptor-2 status, and Ki67 status. This was accomplished by immunohistochemical analysis of paraffin-embedded cancer tissues from 18 patients with breast cancer treated with at least one cycle of capecitabine. Clinical outcome was measured as time to progression.Results: TP staining intensities in both the invasive and in situ components in patients with lobular and ductal carcinomas were reported. Higher levels of TP in the invasive component were expressed in ER-negative tumors when compared with ER-positive tumors (P<0.05. The ER-positive group expressing lower levels of TP had a median time to progression of 13 months compared with the ER-negative group expressing higher levels of TP which had a median time

  5. Causes of uveitis in children without juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Engelhard SB

    2015-06-01

    Full Text Available Stephanie B Engelhard, Asima Bajwa, Ashvini K ReddyDepartment of Ophthalmology, University of Virginia, Charlottesville, VA, USABackground: The purpose of this study was to report the demographics, disease characteristics, treatments, and visual outcomes of pediatric uveitis patients without juvenile idiopathic arthritis managed in a tertiary medical center.Methods: A retrospective, observational study was performed in pediatric uveitis patients without juvenile idiopathic arthritis and aged 0–18 years, who were seen at the University of Virginia from 1984 to 2014.Results: Thirty-nine pediatric uveitis patients (57 eyes were identified. The patient population was 51.28% female, 51.28% Caucasian, and 33.33% African American. The mean age at diagnosis was 11.9 years. The mean duration of follow-up was 3.11 years. The mean number of visits to the clinic was 10.41. Of 57 eyes, 31 (54.39% had anterior uveitis, 12 (21.05% had intermediate uveitis, nine (15.79% had posterior uveitis, and five (8.77% had panuveitis. The leading diagnoses were traumatic uveitis (25.64%, undifferentiated anterior uveitis (17.95%, undifferentiated intermediate uveitis (15.38%, HLA-B27-associated anterior uveitis (7.69%, and herpetic anterior uveitis (7.69%. Systemic associations included sarcoidosis, ulcerative colitis, and psoriatic arthritis (n=3. The most common treatment modalities included local steroids (66.67%, systemic steroids (23.08%, and antimetabolites (20.51%. Ocular hypertension was found in five (12.82% patients. Ocular surgery was performed in six (15.38% patients. Mean best-corrected visual acuity (BCVA at baseline across all anatomical locations was 0.458 logMAR, and was 0.411 logMAR at final follow-up. Mean BCVA improved during follow-up in all but the anterior uveitis group. The mean baseline intraocular pressure was 14.27 mmHg, and was 14.22 mmHg at final follow-up.Conclusion: Uveitis in childhood is a vision-threatening group of inflammatory

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

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    Cuezva José M

    2011-02-01

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

  7. Degradation of 5-FU by means of advanced (photo)oxidation processes: UV/H2O2, UV/Fe2+/H2O2 and UV/TiO2 — Comparison of transformation products, ready biodegradability and toxicity

    International Nuclear Information System (INIS)

    The present study investigates the degradation of the antimetabolite 5-fluorouracil (5-FU) by three different advanced photo oxidation processes: UV/H2O2, UV/Fe2+/H2O2 and UV/TiO2. Prescreening experiments varying the H2O2 and TiO2 concentrations were performed in order to set the best catalyst concentrations in the UV/H2O2 and UV/TiO2 experiments, whereas the UV/Fe2+/H2O2 process was optimized varying the pH, Fe2+ and H2O2 concentrations by means of the Box–Behnken design (BBD). 5-FU was quickly removed in all the irradiation experiments. The UV/Fe2+/H2O2 and UV/TiO2 processes achieved the highest degree of mineralization, whereas the lowest one resulted from the UV/H2O2 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/H2O2 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 achieved in all the treatments. • None of the processes were able to fully mineralize 5-FU. • Six transformation products (TPs) were identified during

  8. The role of taxanes in the treatment of breast cancer.

    Science.gov (United States)

    Capri, G; Tarenzi, E; Fulfaro, F; Gianni, L

    1996-02-01

    The taxanes paclitaxel and docetaxel are undergoing extensive evaluation in women with breast cancer in the United States and in Europe. Their dose-limiting toxicity is neutropenia. Paclitaxel also causes peripheral neuropathy, while docetaxel can cause unpredictable and severe skin toxicity, as well as edema and effusions due to a capillary leak syndrome. Due to threshold pharmacodynamics and nonlinear pharmacokinetics, tolerability of paclitaxel is schedule dependent. Single-agent paclitaxel was very active in multiple phase II trials in patients with different numbers and types of prior chemotherapy and disease extent (20% to 60% complete plus partial responses). Effective doses ranged from 135 to 250 mg/m2. Activity was observed with all infusion schedules (1, 3, and 24 hours) and in women with anthracycline-resistant tumors (25% to 38%). The use of a 96-hour infusion schedule was very active in anthracycline-refractory patients (48%) and in women who failed short infusion taxanes. The drug is undergoing extensive evaluation in combination with doxorubicin, cyclophosphamide, cisplatin, and antimetabolites. Very promising efficacy was observed for paclitaxel by 3-hour infusion plus bolus doxorubicin (approximately 40% complete responses and 50% partial responses). The combination also caused a high incidence of clinically reversible congestive heart failure(14% to 18%). Docetaxel also has very good efficacy in breast cancer, with approximately 70% major responses in untreated patients and more than 50% in anthracycline-resistant tumors. There is no evidence that efficacy and tolerability are schedule dependent as is the case for paclitaxel. At recommended doses (100 or 75 mg/m2 by 1-hour infusion every 3 weeks), docetaxel causes a fluid retention syndrome that may affect quality of life. Its common onset after multiple cycles may limit the use of docetaxel for palliation in metastatic breast cancer. These results clearly indicate that the taxanes will become a

  9. 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)

    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

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

    Directory of Open Access Journals (Sweden)

    Salim S

    2012-06-01

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

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

    International Nuclear Information System (INIS)

    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 F16-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)

  12. Early changes in [{sup 18}F]FLT uptake after chemotherapy: an experimental study

    Energy Technology Data Exchange (ETDEWEB)

    Dittmann, Helmut; Dohmen, Bernhard Matthias; Bartusek, Gabi; Pritzkow, Maren; Bares, Roland [Department of Nuclear Medicine, Eberhard-Karls-University, Roentgenweg 13, 72076 Tuebingen (Germany); Kehlbach, Rainer [Department of Diagnostic Radiology, Eberhard-Karls-University, Tuebingen (Germany); Sarbia, Mario [Institute of Pathology, Heinrich-Heine-University, Duesseldorf (Germany)

    2002-11-01

    This study evaluated the use of 3'-deoxy-3'-[{sup 18}F]fluorothymidine ([{sup 18}F]FLT) for monitoring of the early effects of anticancer chemotherapy on tumour cell proliferation. Cells derived from human oesophageal squamous cell carcinoma (OSC-1) were grown for 2 days and incubated with cisplatin (CDDP), 5-fluorouracil (5-FU), methotrexate (MTX) or gemcitabine (GEM) for 4 h. Cultures were incubated with drug doses (CDDP: 0.67, 6.7, 67 {mu}M; 5-FU 15.4, 154, 1,540 {mu}M; MTX: 4.4, 44, 440 {mu}M; GEM: 0.0067, 0.067, 0.67 {mu}M) corresponding to approximately 10%-95% proliferation inhibition (MTX: 10%-75%). Treatment was stopped and cells were allowed to recover for 4, 24 or 72 h. [{sup 18}F]FLT was added for 10-180 min. Control cultures were incubated with [{sup 18}F]fluorodeoxyglucose (FDG). Cell counts, viability, clonogenic activity and cell cycle distribution estimated by flow cytometry were used to evaluate the cytotoxic effects of chemotherapy. Strikingly, FLT uptake per 10{sup 5} viable cells was increased seven- to tenfold 24 h after treatment with 5-FU or MTX irrespective of dose. Thus, total FLT uptake per tissue culture exceeded that of controls despite a considerable decrease in overall cell counts due to cytostasis up to 72 h after treatment. 5-FU-treated cells showed accumulation in early S phase (overall S phase: 88% vs 42%). GEM treatment resulted in a more moderate increase in total FLT accumulation, to a maximum of fivefold at the dose close to the IC{sub 50}. In contrast, FLT accumulation was significantly reduced at cytostatic concentrations of CDDP and was still decreasing in a dose-related manner at 72 h despite considerable S phase arrest. With 5-FU or CDDP, the uptake of FDG did not differ significantly from control values 24 h after treatment. These findings demonstrate that tumour cell uptake of FLT - in contrast to that of FDG - reveals specific changes depending on the cytostatic drug used for treatment. The antimetabolites 5

  13. Efficacy, safety, and lack of interactions with the use of raltegravir in HIV-infected patients undergoing antineoplastic chemotherapy

    Directory of Open Access Journals (Sweden)

    Sara Bañón

    2014-11-01

    Full Text Available Introduction: Concomitant use of combination antiretroviral regimen (cART and cancer chemotherapy is difficult due to complex interactions and increased toxicity. Raltegravir could be an adequate option through its favourable drug-drug interaction profile. Methods: Prospective longitudinal study of HIV patients with cancer, AIDS related or not, undergoing chemotherapy. Patients without resistance or previous failure were switched or initiated raltegravir plus two nucleoside analogues. Plasma trough levels of raltegravir were measured. Results: Overall, 28 patients receiving a raltegravir-based regimen (4 naive with tenofovir-emtricitabine (18 cases or abacavir-lamivudine (10 cases were included. Mean age was 46.2 years (IQR, 39–52.7, and 79% were male. Median time of HIV was 201.7 months, CD4+ nadir was 268 cells/mm3, and 75% had previous AIDS. At the diagnosis of neoplasia, 17 were on protease inhibitors and 4 with efavirenz. Ten patients had a non-HIV-related cancer (three breast, two pancreatic, one Ewing sarcoma, one myeloblastic leukemia, one melanoma, one parotid adenocarcinoma, one lung, and 18 had an HIV-related cancer (nine non-Hodgkin lymphoma, seven Hodgkin disease, two anal. Overall, 43% of patients received more than one line of chemotherapy, including antimetabolites in 12 patients (5-FU, capecitabine, methotrexate, gemcitabine, alkylating agents in 12 cases (ciclophosphamide, iphosphamide, vinca alkaloids in 20 patients (vincristine, vinblastine, vindesine, antitumor antibiotics in 16 cases (adriamycin, cisplatin o carboplatin in six and monoclonal antibodies in six patients (rituximab, trastuzumab, cetuximab. Six patients modified the doses of antineoplastic agents due to toxicity (four neutropenia, not related to raltegravir. During a median follow up of 12.7 patients-year in concomitant therapy, there was only 1 case of virological failure and no patient discontinued raltegravir. Plasma concentrations of raltegravir in eight

  14. 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)

    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/G2 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

  15. Radiosynthesis, in vitro cellular uptake and in vivo biodistribution of 3'-O-(3-benzenesulfonylfuroxan-4-yl)-5-[{sup 125}I]iodo-2'-deoxyuridine, a nucleoside-based nitric oxide donor

    Energy Technology Data Exchange (ETDEWEB)

    Moharram, Sameh [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8 (Canada); Zhou, Aihua [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8 (Canada); Kumar, Piyush [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8 (Canada); Knaus, Edward E. [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8 (Canada); Wiebe, Leonard I. [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8 (Canada)]. E-mail: leonard.wiebe@ualberta.ca

    2005-08-01

    Introduction: 3'-O-(3-Benzenesulfonylfuroxan-4-yl)-5-iodo-2'-deoxyuridine (1) is a cytotoxic nitric oxide (NO) donor-nucleoside dual action prodrug designed to exploit both NO and an antimetabolite nucleoside for cancer therapy. Methods: 1 was radiolabeled by radioiodide exchange and purified by HPLC in 16% overall radiochemical yield. The specific activity of [{sup 125}I]1 was 31.8 {mu}Ci/{mu}g (680 MBq/{mu}M). Protein binding, deiodination, cellular uptake and incorporation of 1 into cellular nucleic acids were measured by standard methods, and its in vivo biodistribution was determined in Balb/c mice bearing implanted EMT-6 tumors following intravenous injection. Results: [{sup 125}I]1 degraded rapidly during the in vitro tests, thus impeding unequivocal assessment but indicating that it was only weakly protein bound and that it was resistant to deiodination under test conditions. Uptake of [{sup 125}I]1 by murine tumor cells (KBALB and KBALB-STK) in vitro was low ({approx}17 fmol/{mu}g protein over 2 h) with only {approx}0.3% (0.04-0.06 fmol/{mu}g protein) of total uptake present in the DNA fraction. In the murine tumor model, liver, kidney, intestine and tumor showed the greatest uptake, with liver, intestine and blood all containing >5 injected dose per gram of tissue (%ID/g) during the 15-min to 2-h postinjection period. Maximum tissue/blood level ratios were 3.6 (2 h) for tumor and 6.4 (24 h) for liver. Low uptake in thyroid and stomach was indicative of minimal in vivo deiodination. Conclusions: [{sup 125}I]1 undergoes only minimal deoiodination under both in vitro and in vivo conditions. Under conditions of the in vitro NO release assay, 1 reacts to produce a single, major, unstable adduct that decomposes upon workup. Protein binding of [{sup 125}I]1 could not be assessed because of similar chemical reaction with albumin. Incorporation of radioactivity into the cellular nucleic acid fraction was low, and in vivo distribution of [{sup 125}I]1 was

  16. 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

  17. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development.

    Science.gov (United States)

    Zhou, Shu-Feng; Wang, Lin-Lin; Di, Yuan Ming; Xue, Charlie Changli; Duan, Wei; Li, Chun Guang; Li, Yong

    2008-01-01

    Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are

  18. Generalized Pyoderma Gangrenosum Associated with Ulcerative Colitis: Successful Treatment with Infliximab and Azathioprine.

    Science.gov (United States)

    Chatzinasiou, Foteini; Polymeros, Dimitrios; Panagiotou, Maro; Theodoropoulos, Konstadinos; Rigopoulos, Dimitrios

    2016-04-01

    management of special situations in patients with ulcerative colitis, systemic corticosteroids are recommended (9). Treatment with corticosteroids (e.g. prednisolone 1-2 mg per kg/day or pulse therapy with 1 g of methylprednisolone) aims to prevent progression and rapidly stop inflammation (6). Additional mesalamine and corticosteroids may be effective in patients with bowel disease (10). In recent years, tumor necrosis alpha (TNF-α) inhibitors, such as infliximab and adalimumab, were reported to be effective for PG associated with IBD. These drugs block the biological activity of TNF-α, which effects regulatory T cells, restoring their capacity to inhibit cytokine production. The TNF-α inhibitors thus suppress the inflammatory processes that is involved in the pathogenesis of PG (11). Infliximab, a chimeric monoclonal antibody, is given by infusion at weeks 0, 2, and 6 and then every 8 weeks, usually at a dosage of 5 mg/kg. UC of patients with frequent disease relapse or those that are resistant or dependent on corticosteroids is often treated with purine antimetabolites, such as azathioprine (AZA) (10). AZA, a purine antimetabolite (2.5 mg per kg/day) is administered for its steroid-sparing effects. The response occurs after 2 to 4 weeks (6, 10). Infliximab can be combined with AZA. Patients with UC treated with infliximab plus AZA were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy (10,12). PMID:27149138

  19. 三七总甙对增生性瘢痕的作用★%Notoginseng glycosides effects on hyperplastic scar

    Institute of Scientific and Technical Information of China (English)

    刘凯; 潘亮亮; 李婷; 刘树发

    2013-01-01

      背景:增生性瘢痕的传统治疗手段如手术切除、类固醇激素、抗代谢药、免疫抑制剂和放射疗法等,均易复发或有严重的不良作用而限制了其临床应用。近年来应用活血化瘀类中药提取成分治疗增生性瘢痕取得了较为理想的进展,而且不良反应小。目的:通过组织染色及相关基因检测的方法,观察三七总甙对兔耳增生性瘢痕的作用以及对转化生长因子β1 mRNA表达的影响。方法:创建兔耳增生性瘢痕模型,约术后4周,按随机数字表法将24只大耳白兔分为3组,三七总甙组、曲安奈德组及空白对照组每组8只。以曲安奈德为阳性对照,分组分次瘢痕基底局部给药,用药5次后取瘢痕组织,以苦味酸酸性复红染色法、苏木精-伊红染色法对胶原纤维、成纤维细胞进行观察,应用反转录PCR方法检测细胞内转化生长因子β1基因的表达情况。结果与结论:苏木精-伊红染色结果示三七总甙组兔耳瘢痕中成纤维细胞数量低于空白对照组,与曲安奈德组无明显差异。苦味酸酸性复红染色结果示三七总甙组兔耳瘢痕中胶原纤维较空白对照组排列整齐,与曲安奈德组无明显差异。基因检测结果显示三七总甙组、曲安奈德组转化生长因子β1 mRNA的表达显著低于空白对照组(P <0.05)。提示三七总甙及曲安奈德均能通过抑制转化生长因子β1 mRNA的表达,降低转化生长因子β1在瘢痕组织中的含量,从而抑制成纤维细胞的过度增殖及以胶原为主的细胞外基质过度沉积,进而降低胶原纤维合成,来达到有效抑制瘢痕组织过度增生的目的。%  BACKGROUND: Traditional treatments for hypertrophic scars, such as surgical resection, steroid hormones, antimetabolite, immunosuppressants and radiotherapy, are prone to resulting in relapse or serious adverse effects that limit their clinical

  20. Genetical Studies On Haploid Production In Some Ornamental Plants

    International Nuclear Information System (INIS)

    , (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) .

  1. Flavor vs Energy Sensing in Brain Reward Circuits

    Directory of Open Access Journals (Sweden)

    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