| 51. |
- Proszenyák, Agnes, et al.
(författare)
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Synthesis, antimicrobial and antineoplastic activities for agelasine and agelasimine analogs with a beta-cyclocitral derived substituent.
- 2007
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Ingår i: Archiv der Pharmazie. - : Wiley. - 0365-6233 .- 1521-4184. ; 340:12, s. 625-634
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Tidskriftsartikel (refereegranskat)abstract
- Agelasines and agelasimines are antimicrobial and cytotoxic purine derivatives isolated from marine sponges (Agelas sp.). We have synthesized structurally simplified analogs of these natural products starting from beta-cyclocitral. The novel compounds were found to be strong inhibitors of a wide variety of pathogenic microorganisms (incl. Mycobacterium tuberculosis) as well as cancer cell lines. The biological activities were generally in the same range as those previously found for the structurally more complex agelasines and agelasimines isolated in small amounts from natural sources. We also report for the first time that agelasine and agelasimine analogs inhibit growth of protozoa (Acanthamoeba castellanii and Acanthamoeba polyphaga). Acanthamoeba keratitis is an increasingly common and severe corneal infection, closely associated with contact lens wear.
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| 52. |
- Quartino, Angelica, et al.
(författare)
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Modeling of in vitro drug activity and prediction of clinical outcome in acute myeloid leukemia
- 2007
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 47:8, s. 1014-1021
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Tidskriftsartikel (refereegranskat)abstract
- The objectives of this study were to develop a population pharmacodynamic model describing the in vitro drug sensitivity of tumor cells and to relate in vitro parameters to clinical outcome. Cell samples from 179 patients with acute myelocytic leukemia were exposed to cytosine arabinoside and daunorubicin, and cytotoxicity was analyzed using the fluorometric microculture cytotoxicity assay. A sigmoid E(max)-model for daunorubicin and an E(max)-model for cytosine arabinoside described the data. The model predicted drug potency (EC(50)) adequately from 1 concentration measurement. A logistic regression on individual in vitro parameters of 46 patients treated with the daunorubicin plus cytosine arabinoside regimen showed that the probability of complete response was significantly (P < .05) related to the product of the E(max)/EC(50) ratio of the two drugs. The findings demonstrate the value of population pharmacodynamic modeling of in vitro drug sensitivity data and a significant relationship between the in vitro parameters and clinical outcome.
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| 53. |
- Rickardson, Linda, et al.
(författare)
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Image-based screening for the identification of novel proteasome inhibitors
- 2007
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 12:2, s. 203-210
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Tidskriftsartikel (refereegranskat)abstract
- The proteasome is a new, interesting target in cancer drug therapy, and the proteasome inhibitor bortezomib has shown an effect in myeloma patients. It is of interest to efficiently discover and evaluate new proteasome inhibitors. The authors describe the development of an image-based screening assay for the identification of compounds with proteasome-inhibiting activity. The stably transfected human embryo kidney cell line HEK 293 ZsGreen Proteasome Sensor Cell Line expressing the ZsProSensor-1 fusion protein was used for screening and evaluation of proteasome inhibitors. Inhibition of the proteasome leads to accumulation of the green fluorescent protein ZsGreen, which is measured in the ArrayScan® High Content Screening system, in which cell morphology is studied simultaneously. When screening the LOPAC1280 substance library, several compounds with effect on the proteasome were found; among the hits were disulfiram and ammonium pyrrolidinedithiocarbamate (PDTC). Cytotoxic analysis of disulfiram and PDTC showed that the compounds induced cytotoxicity in the myeloma cell line RPMI 8226. The average Z' value for the assay was 0.66. The results indicate that the assay rapidly identifies new proteasome- inhibiting substances, and it will be further used as a tool for image-based screening of other chemically diverse compound libraries.
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| 54. |
- Rickardson, Linda, 1980-
(författare)
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New Methods to Screen for Cancer Drugs and to Evaluate their Mechanism of Action
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a common disease and due to problems with resistance against cancer drugs and the limited benefit from chemotherapy in many diagnoses, there is a need to develop new cancer drugs. In this thesis new methods to screen for cancer drugs and to evaluate their mechanism of action are discussed. In Paper I, it was found that by studying the gene expression of a cell line panel and combining the data with sensitivity data of a number of cytotoxic drugs, it was possible to cluster compounds according to mechanism of action as well as identifying genes associated with chemosensitivity. In Paper II, studies of compounds with selective activity in drug-resistant cell lines revealed the glucocorticoids as a group of interesting compounds. The glucocorticoid receptor was overexpressed in 8226/Dox40 and the difference in sensitivity was abolished when the cells were treated with a glucocorticoid receptor antagonist. In Paper III, an image-based screening method for new proteasome inhibitors was successfully developed and the compounds disulfiram, PDTC and NSC 95397 were identified as inhibitors of the proteasome. In Paper IV, disulfiram and PDTC were shown to induce cytotoxic activity, to inhibit the activation of the transcription factor NFkappaB and to inhibit the degradation of proteins normally degraded by the proteasome. In Paper V, NSC 95397 was shown to be cytotoxic to all cells in the resistance-based cell line panel as well as to patient samples from a variety of cancer diagnoses. Connectivity Map was successfully used as a tool to propose a new mechanism of action of NSC 95397. The gene expression induced by NSC 95397-treatment was similar to that induced by several proteasome inhibitors not present in the Connectivity Map.
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| 55. |
- Rickardson, Linda, et al.
(författare)
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Screening of an annotated compound library for drug activity in a resistant myeloma cell line
- 2006
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 58:6, s. 749-758
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Resistance to anticancer drugs is a major problem in chemotherapy. In order to identify drugs with selective cytotoxic activity in drug-resistant cancer cells, the annotated compound library LOPAC(1280), containing compounds from 56 pharmacological classes, was screened in the myeloma cell line RPMI 8226 and its doxorubicin-resistant subline 8226/Dox40. Methods: Cell survival was measured by the Fluorometric Microculture Cytotoxicity Assay. Results: Selective cytotoxic activity in 8226/Dox40 was obtained for 33 compounds, with the most pronounced difference observed for the glucocorticoids. A microarray analysis of the cells showed a difference in mRNA-expression for the glucocorticoid receptor suggesting potential mechanisms for the difference in glucocorticoid sensitivity. In the presence of the glucocorticoid-receptor antagonist RU486, the sensitivity to the glucocorticoids was reduced and a similar effect level in RPMI 8226 and 8226/Dox40 was achieved. Conclusion: In conclusion, screening of mechanistically annotated compounds on drug-resistant cancer cells can identify compounds with selective activity and provide a basis for the development of novel treatments of drug-resistant malignancies.
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| 56. |
- Rosén, Josefin, 1978-, et al.
(författare)
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ChemGPS-NP mapping of chemical compounds for prediction of anticancer mode of action
- 2009
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Ingår i: QSAR & combinatorial science (Print). - : Wiley. - 1611-020X .- 1611-0218. ; 28:4, s. 436-446
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Tidskriftsartikel (refereegranskat)abstract
- A combined graph describing the growth inhibition values from a number of human cancer cell lines represents an activity profile for a compound. The fact that compounds with similar activity profiles often show similar mode of action (MOA) has frequently been used in prediction of MOA. Obtaining the profiles is demanding with respect to both time and resources. Therefore, as a work and time efficient alternative, we explore the central premise of medicinal chemistry that structurally similar molecules often have similar biological activity. In this study we investigate correlations between chemical structure and MOA, and subsequently use this as a complementing basis for prediction. The correlations between MOA and activity profile on one hand and between MOA and chemical structure on the other were analyzed for anticancer agents, classified with regard to MOA, using principal component analysis (PCA), chemographic mapping with ChemGPS-NP, and orthogonal partial least squares discriminant analysis (OPLS-DA). The compounds clustered according to MOA both based on chemical structures and activity profiles. The subsequent validation with external test sets showed that initial PCA scores prediction or chemographic mapping followed by OPLS-DA could be used for prediction of MOA as well as identification of novel MOAs in a highly accurate way. An efficient and straight forward procedure for prediction of MOA of anticancer agents is suggested. With today’s resistance problems in cancer therapy, there is a need for new anticancer agents and mechanisms. We believe that the fast initial virtual guidance this procedure implies, especially the novel step using ChemGPS-NP, could be of general use in early stages of cancer research.
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| 57. |
- Sanchez, Javier, et al.
(författare)
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Surface-adsorbed fibrinogen and fibrin may activate the contact activation system
- 2008
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 122:2, s. 257-263
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: This study was designed to investigate whether fibrinogen, soluble desAA-fibrin, and insoluble desAABB-fibrin are able to induce clotting by triggering the plasma contact activation system when adsorbed to polystyrene. MATERIALS AND METHODS: The above-mentioned substances were individually prepared on polystyrene meshwork squares, and then exposed to a purified FXII solution or non-calcium containing plasma (citrated and dialyzed normal pooled plasma) in polystyrene cuvettes coated with surface-immobilized heparin, to completely block contact activation and the coagulation mechanism that might be induced by the cuvette surfaces. Sodium glass beads were used as the reference material. RESULTS: On exposure to purified FXII solution and plasma, all the tested materials adsorbed and activated FXII to varying degrees. This activation led to the formation of FXIa in the exposed plasma, with the highest activation occurring upon exposure to glass, desAA-fibrin and desAABB-fibrin and the lowest upon exposure to fibrinogen-adsorbed or unmodified polystyrene meshwork squares. Following recalcification, in cuvettes with surface-immobilized heparin, a spectrophotometric assay showed that the surface-exposed plasma aliquots clotted within 5 min after contact with glass, within 10 to 15 min after contact with the two forms of fibrin, and somewhat longer after contact with adsorbed fibrinogen. The longest lag phase, close to 20 min, occurred in plasma exposed to unmodified polystyrene meshwork. Whole blood deposited in surface heparinized cuvettes directly from the cubital vein did not clot during the observation time (2 h). CONCLUSIONS: These results indicate that domains induced by conformational changes in adsorbed fibrinogen and fibrin are capable of activating adsorbed proenzymes and that various forms of fibrin are considerably stronger activators of the contact activation system than are adsorbed fibrinogen or a polystyrene meshwork. The delayed coagulation in plasma exposed to the unmodified polystyrene meshwork can be explained by a two-step process: first, adsorption of fibrinogen, and second, activation of FXII. Under our experimental conditions, the adsorption and activation of FXII on fibrinogen and fibrin seems to be an important mechanism for triggering coagulation.
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| 58. |
- Thorslund, Sara, et al.
(författare)
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A PDMS-based disposable microfluidic sensor for CD4+ lymphotic counting
- 2008
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Ingår i: Biomedical microdevices (Print). - : Springer Science and Business Media LLC. - 1387-2176 .- 1572-8781. ; 10:6, s. 851-857
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Tidskriftsartikel (refereegranskat)abstract
- A refined sensor for CD4+ lymphocyte count was developed and evaluated by comparison to flow cytometry. The micropillar structured sensor surface was cast in PDMS polymer and surface modified to gain biocompatibility and CD4-cell capturing properties. The sensor works by pure capillary action and sample filling and rinsing is performed without external equipment. Whole blood samples showed acceptable agreement (79%) with flow cytometry, however when diluting the blood in PBS buffer we discovered that a larger number of cells were drawn into the sensor microchannel compared to the initial sample, explained by enhanced shear-induced cell migration. Using plasma or PBS with glycerol or albumin additives as diluting media greatly influenced this cell behavior, showing the importance of controlling the dilution media when working with devices based on capillary filling. The sensors need to be further tested with blood samples with lower CD4-counts (<500 cells/μl), which are clinically relevant.
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| 59. |
- Thorslund, Sara, et al.
(författare)
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Bioactivated PDMS microchannel evaluated as sensor for human CD4+ cells : The concept of a point-of-care method for HIV monitoring
- 2007
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Ingår i: Sensors and actuators. B, Chemical. - : Elsevier BV. - 0925-4005 .- 1873-3077. ; 123:2, s. 847-855
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Tidskriftsartikel (refereegranskat)abstract
- Up to today, the number of CD4(+) lymphocytes remains the most important biological marker to determine the clinical stage of an HIV-infection. Analysis by flow cytometry, the standard method used today, is unsuitable in many developing countries, because of high costs involved and practical inconveniences. We here present the concept of an inexpensive PDMS-based point-of-care device for CD4(-)count. A simple fluorescence microscope for stained leucocytes counting is the only detection equipment needed. The biosensor surface consists of an initial heparin-based coating that adds hydrophilicity and thromboresistance to the PDMS material. The specific capturing chemistry is based on an avidin/biotin-antibody surface architecture. Pure capillary forces draw whole blood, as well as rinsing buffer, into the biosensor channel, minimizing the need of external equipment. Detection of the captured cells was performed by fluorescence imaging of HOECHST (stains cell nuclei) and CD3-FITC signals. It was shown that the non-specific adsorption of CD4(-) leucocytes was minimal to none. and the detection could therefore be done by only counting the easy identifiable HOECHST+ cells. Characterization of the biosensor coating process was additionally performed with the quartz crystal microbalance-dissipation technique.
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| 60. |
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