Дисертації з теми "Kinase inhibitor treatments"
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Losson, Hélène. "Combinaisons de nouveaux inhibiteurs de désacétylase d’histones 6 avec des inhibiteurs de tyrosine kinase pour le traitement de la leucémie myéloïde chronique." Thesis, Université de Lorraine, 2020. http://www.theses.fr/2020LORR0003.
Повний текст джерелаBreakpoint cluster region-Abelson (BCR-ABL)+ chronic myeloid leukemia (CML) patients receive tyrosine kinase inhibitors (TKIs) such as imatinib as the first-line treatment; however, some patients develop resistances and severe adverse effects. Combination treatments, especially with histone deacetylase (HDAC)6 inhibitors (HDAC6i), appear as an attractive option to prevent TKI resistances considering the capacity of HDAC6i to downregulate BCR-ABL. Moreover, HDAC6 is implicated in protein degradation pathways, so that its inhibition combined with that of the proteasome could sensitize cells to TKIs. Thus, we hypothesized that HDAC6i combined to TKIs could be effective for CML treatment. In the first part, we compared the anti-CML effects of a HDAC6i identified in our laboratory, compound 7b, to the reference HDAC6i tubacin, in combination with imatinib. Results showed that the imatinib-7b combination generated stronger anti- CML effects than imatinib-tubacin. Especially, the imatinib-7b combination elicited a potent synergistic caspase- dependent apoptotic cell death and drastically reduced the proportion of cancer stem cells in K562 CML cells, whereas it only moderately impacted various healthy cell models. Ultimately, the imatinib-7b combination decreased more potently the colony forming capacities and tumor mass formation of CML cells in a semisolid methylcellulose medium and in xenografted zebrafishes, respectively, compared to each compound alone. Mechanistically, the combination induced BCR-ABL ubiquitination and downregulation leading to a dysregulation of multiple key proteins of its downstream pathways involved in CML proliferation and survival. Results tend to demonstrate that 7b could target the second site. In the second part, we initiated a study of a novel hydroxamate-based HDAC6i, MAKV-15, and preliminary results demonstrated it triggered BCR-ABL downregulation. Accordingly, in pre-treatment with bortezomib it sensitizes CML cells to imatinib leading to enhanced caspase-dependent apoptotic death in imatinib-sensitive and imatinib-resistant CML cells. Considering that HDAC6 is reported to possess two functional catalytic sites, we finally attempted to determine which catalytic site is targeted by these HDAC6i. Taken together, our results suggest that HDAC6i potentiate the effect of imatinib and could overcome TKI resistance in CML cells and therefore such combination may represent a promising therapeutic approach for CML patients
Shor, Audrey Cathryn. "Src kinase inhibitors for the treatment of sarcomas : cellular and molecular mechanisms of action." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001906.
Повний текст джерелаZhang, Wen. "Identification of novel pyruvate dehydrogenase kinase 1 (PDK1) inhibitors for anticancer therapeutics." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3953604.
Повний текст джерелаAlsfouk, Aisha. "Synthesis and biological evaluation of selective inhibitory kappa B kinase-alpha (IKKa) inhibitors for the treatment of prostate and pancreatic cancer." Thesis, University of Strathclyde, 2018. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=29272.
Повний текст джерелаD'Cunha, Ronilda Raymond. "Treatment strategies to reverse efflux transporter-mediated resistance to Tyrosine kinase inhibitors." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6563.
Повний текст джерелаPadi, Sathish K. R., Libia A. Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H. Song, Jon C. Aster, Xue-Zhong Yu, Shikhar Mehrotra, and Andrew S. Kraft. "Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset." IMPACT JOURNALS LLC, 2017. http://hdl.handle.net/10150/624055.
Повний текст джерелаMcIntyre, Neil A. "Synthesis of ring-constrained thiazolylpyrimidines : inhibitors of cyclin-dependent kinases." Thesis, University of St Andrews, 2006. http://hdl.handle.net/10023/353.
Повний текст джерелаHaaning, Kelsey L. "Deletion of the phosphoinositide-3-kinase RhoGAP domain to assess inhibition of Staphylococcus aureus infection." Virtual Press, 2008. http://liblink.bsu.edu/uhtbin/catkey/1398713.
Повний текст джерелаDepartment of Biology
Deininger, Michael Werner Nikolaus. "STI571, a novel tyrosine kinase inhibitor : pre-clinical evaluation and application to identify downstream targets of BCR-ABL." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325912.
Повний текст джерелаTrousil, Sebastian. "Choline kinase inhibition as a treatment strategy of cancers with deregulated lipid metabolism." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/25146.
Повний текст джерелаAshcroft, Jonathan William. "Assessment of the potential of a narrow spectrum kinase inhibitor in the treatment of influenza infection." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/44083.
Повний текст джерелаStillman, Anthony D. "Targeting Sphingosine Kinase 2 as a Treatment for Cholangiocarcinoma." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/6067.
Повний текст джерелаTawati, Salha M. "Design, synthesis and biological evaluation of sphingosine kinase inhibitors for the treatment of prostate cancer." Thesis, University of Strathclyde, 2018. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=30298.
Повний текст джерелаChakraborty, Kanishka, John B. Bossaer, R. Patel, and K. Krishnan. "Successful Treatment of Nilotinib-Induced Pleural Effusion with Prednisone." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etsu-works/2318.
Повний текст джерелаNakano, Kenji. "Risk factors of pneumothorax in advanced and/or metastatic soft tissue sarcoma patients during pazopanib treatment: a single-institute analysis." Kyoto University, 2018. http://hdl.handle.net/2433/232072.
Повний текст джерелаMazanetz, Michael Philip. "Approaches towards the design and synthesis of selective kinase inhibitors for the treatment of neurodegenerative diseases." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508226.
Повний текст джерелаSykora, Vladimir. "Computational approaches in the development of cyclin-dependent kinase 2 inhibitors for the treatment of cancer." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506664.
Повний текст джерелаFarina, Anne Kata. "Regulation of cadherin-11 by GSK3 inhibition and TGFbeta1 treatment in cancer cells." Connect to Electronic Thesis (CONTENTdm), 2008. http://worldcat.org/oclc/457179663/viewonline.
Повний текст джерелаSchneider, Melanie. "Integrative chemoinformatics to guide drug design : application to re-design a clinical protein kinase inhibitor." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT057.
Повний текст джерелаDespite years of intensive research and development, cancer remains one of the leading causes of death worldwide. Chemotherapy is the most commonly used treatment for cancer, as surgery and radiation therapy are often not effective in treating cancer at every location where it spreads. However,drug resistance of cancer cells to chemotherapeutic agents and/or reduction in effectiveness of a drug is the leading cause of failure of chemotherapy. Drugs are developed to bind efficiently to a given therapeutic target, called the primary target. Unfortunately, drug treatments can suffer from bindingto a secondary target that perturbs drug activity and/or impacts its metabolism. The main aim of the PhD project was to develop an integrative chemoinformatics approach to optimize drug design by studying not only the primary target but also putative secondary effects at the atomic level in order to compute more accurate binding modes and to derive better affinity estimates.The presented drug design project aims for an improved inhibitor of the serine/threonine kinase mutant BRAFV600E with simultaneous loss of binding to the secondary target PXR. Focus is on the study of both, protein kinase BRAF and nuclear receptor PXR, which is involved in regulation of xenobiotic metabolism. A machine learning tool is first developed on the well studied nuclear receptor ERα due to large amounts of experimental data, and subsequently similarly generated for BRAFV600E. Despite its recognized importance in drug metabolism, we are still lacking sufficient structural information and affinity measurements to develop machine learning models for PXR. So, an alternative approach that relies on molecular dynamics combined with the Molecular Mechanics Poisson-Boltzmann Surface Area method is employed in order to obtain a precise estimation of ligand affinities. Finally, diverse computational tools are applied to design new derivatives of the initial drug, which is too rapidly metabolized in many patients resulting in resistance and cancer relapse. The properties of the new compounds prevent activation of metabolizing enzymes that are degrading the original drug. This is expected to provide a new drug-candidate with much better pharmacokintics properties and enhanced efficacy.This thesis comprises a complete drug design pipeline and presents an integrated strategy that includes modeling, in silico design and synthesis, virtual screening, affinity predictions, in vitro tests and X-ray crystallography. The main focus is on the computational part that comprises complementary approaches from the drug’s and from the proteins’ point of view
Choi, Ho-ying, and 蔡可盈. "Review of clinical benefits and cost effectiveness of epidermal growthfactor receptor-tyrosine kinase inhibitor (EGFR-TKI) as first linetreatment for patients with advanced non-small cell lung cancer(NSCLC)." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46935320.
Повний текст джерелаLilly, Scott Matthew. "Protein Kinase A Alterations Following Chronic Flurazepam Treatment: Implications for Inhibitory and Excitatory Synaptic Plasticity in Rat Hippocampal CA1." Connect to full-text via OhioLINK ETD Center, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1145293063.
Повний текст джерела"In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Elizabeth I. Tietz. Includes abstract. Document formatted into pages: iv, 234 p. Title from title page of PDF document. Bibliography: pages 86-95,126-135,167-174,190-232.
Yacoub, Jeanine. "Synthesis of Agents for the Treatment and Analysis of Tropical Diseases." Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/6441.
Повний текст джерелаCarpenter, Kent James. "Inhibition of PIM and AXL Kinases As Potential Treatments for a Variety of Hematological Malignancies and Solid Tumors." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/3842.
Повний текст джерелаJohnson, Neil. "Investigation into the therapeutic potential of novel cyclin dependent kinase (CDK) inhibitors in the treatment of antiestrogen sensitive and resistant breast cancer." Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427304.
Повний текст джерелаMohedas, Agustin Humberto. "Development of BMP type I receptor kinase inhibitors for the treatment of fibrodysplasia ossificans progressiva and the study of the BMP signaling pathway." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90173.
Повний текст джерела164
Page 130 blank. Cataloged from PDF version of thesis.
Includes bibliographical references (pages 121-129).
The BMP signaling pathway is essential for embryonic development and the maintenance of tissue homeostasis. Dysregulated BMP signaling, both loss and gain-of-function, has been demonstrated in the pathogenesis of diseases including cancer, atherosclerosis, anemia and particularly hereditary disorders such as pulmonary arterial hypertension, hereditary hemorrhagic telangiectasia, and fibrodysplasia ossificans progressiva (FOP). FOP is a rare and disabling condition caused by a highly recurrent mutation in the ACVR1 gene encoding the BMP type I receptor activin-like kinase 2 (ALK2), characterized by the progressive heterotopic ossification (HO) of skeletal muscle and connective tissue leading to widespread joint immobilization, with significant morbidity and premature mortality. There are currently no effective treatments for FOP. The goal of this thesis is to develop and characterize highly selective BMP type I receptor inhibitors targeting ALK2 for the treatment of FOP. Despite the high degree of structural homology between all the BMP and TGF-[beta] type I receptors, I hypothesized that potent and selective inhibitors targeting a single BMP type I receptor, ALK2, could be developed based on a previously identified pyrazolo[1,5-a]pyrimidine core scaffold. I screened a library of pyrazolo[1,5-a]pyrimidine derivatives in a high throughout sensitive radiometric assay of BMP and TGF-[beta] type I receptor kinase activities. I identified a derivative with a unique chemical moiety (5-quinoline) that demonstrated high selectivity for ALK2, but with lower potency than the parent molecule. We synthesized a new 5-quinoline derivative with increased potency and selectivity for ALK2 over the other BMP type I receptors and greatly improved selectivity against the TGF--[beta] type I receptors. I used this highly selective compound to examine ALK2-mediated BMP signaling in vitro and demonstrated in vivo efficacy in two mouse models of HO. In a complementary approach, we generated a library of novel BMP type I receptor inhibitors based on the 2-aminopyridine core scaffold. I developed a structure activity relationship to determine the key structural elements responsible for potency and selectivity. We identified a several novel derivative compounds with improved potency and selectivity for ALK2 over the parent. We successfully used this set of derivatives to address a specific question in FOP biology, of whether ATP-competitive kinase inhibitors exert differential activity against wild-type or diverse FOP-causing ALK2 mutants. Finally, in our SAR of pyrazolopyrimidine compounds, we identified a highly potent inhibitor of both BMP and TGF-[beta] type I receptor activity. I characterized the ability of this compound to inhibit ligand-induced BMP and TGF-[beta] signaling in a variety of cell culture models, as well as inhibit the activity of individual type I receptors. We then used this compound to examine the contribution of individual BMP and TGF-[beta] receptors to signal transduction. We used the broad activity of this inhibitor to limit signaling of all endogenous BMP and TGF-[beta] type I receptors in cells, while reconstituting the activity of specific type I receptors using engineered, inhibitor-resistant mutant receptor kinases which we developed by modifying gatekeeper residues critical for interactions with inhibitor. These mutant receptor kinases demonstrated preserved basal and ligand-mediated signaling functions which were unaffected by inhibitor. These results demonstrate proof-of-principle of a system for examining the function of individual receptors of this pathway in isolation. The work presented in this thesis advances the development of novel BMP type I receptor kinase inhibitors of high selectivity and potency which could serve as important tools for the study of BMP signaling and as therapies for diseases of excessive BMP signaling such as FOP. Development of highly potent and selective inhibitors of ALK2 offers the hope of rational disease modifying therapy for the treatment of FOP.
by Agustin Humberto Mohedas.
Ph. D.
Tohme, Rita. "DIRECT PP2A ACTIVATION FOR THE TREATMENT OF KRAS- AND EGFR-DRIVEN LUNG ADENOCARCINOMA." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1526073628472942.
Повний текст джерелаGhelli, Luserna di Rorà Andrea <1987>. "The Inhibition of Chk1/Chk2 and Wee-1 Kinases as a Promising Therapy for the Treatment of Adult Acute Lymphoblastic Leukemia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7529/.
Повний текст джерелаXiao, Zhiguang [Verfasser], Bernhard [Akademischer Betreuer] Küster, and Axel [Akademischer Betreuer] Ullrich. "Combinatorial treatment of lung cancer monolayer cells and their spheroids with tyrosine kinase inhibitors and Salinomycin / Zhiguang Xiao. Gutachter: Bernhard Küster ; Axel Ullrich. Betreuer: Bernhard Küster." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1069127760/34.
Повний текст джерелаHähnel, Tom, Christoph Baldow, Joëlle Guilhot, François Guilhot, Susanne Saussele, Satu Mustjoki, Stefanie Jilg, et al. "Model-based inference and classification of immunological control mechanisms from TKI cessation and dose reduction in CML patients." American Association for Cancer Research (AACR), 2020. https://tud.qucosa.de/id/qucosa%3A74320.
Повний текст джерелаHorn, Matthias. "Optimierung der Therapie von chronischer myeloischer Leukämie mit Hilfe eines dynamischen Modells normaler und leukämischer Stammzellorganisation." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-154574.
Повний текст джерелаFrémond, Marie-Louise. "Clinical and molecular characterisation of the type I interferonopathies and approaches to therapy Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in three children Blockade of TANK-binding kinase 1/IKKε mutant stimulator of interferon genes (STING)-mediated inflammatory responses in human peripheral blood mononuclear cells". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB098.
Повний текст джерелаThe term 'type I interferonopathies', first coined in 2011, refers to a set of Mendelian disorders associated with constitutive up-regulation of type I interferon (IFN) signalling. All of the genes associated with Aicardi-Goutières syndrome (AGS), the first Mendelian type I interferonopathy described, have been implicated in either the processing or sensing of nucleic acids. Beyond AGS, the other mutated proteins associated with type I interferonopathies have a direct, indirect, or currently undefined action on nucleic acid signalling. Type I IFNs drive the expression of IFN-stimulated genes (ISGs) through the engagement of a common receptor and the subsequent activation of Janus kinase 1 (JAK1) and tyrosine kinase 2, and phosphorylation of STAT1 and STAT2. Our team has developed diagnostic tools to identify type I interferonopathies, comprising a so-called IFN signature, involving the assessment of mRNA expression of 6 ISGs and, more recently, a high sensitivity assay of IFN alpha protein using single molecule array technology. Monogenic mutations so far recognised as type I interferonopathies are associated with a wide spectrum of phenotype. The hallmark of these diseases is their significant morbidity and mortality, associated with an apparent absence of response to conventional immunosuppressive therapies. Activating mutations in TMEM173, encoding stimulator of IFN genes (STING), cause a severe inflammatory condition referred to as STING-associated vasculopathy with onset in infancy (SAVI), characterised by skin vasculopathy and interstitial lung disease leading to end-stage respiratory failure. The endoplasmic reticulum (ER) protein STING is a central component of DNA sensing that induces type I IFNs through phosphorylation of IRF3. An international cohort of 20 STING patients is reported in this thesis, emphasising the clinical heterogeneity of this condition. We also investigated the link between heterozygous mutations in COPA and type I IFN signalling. COPA encodes the alpha subunit of the 7 member coatomer complex I, involved in retrograde transport from the golgi to the ER. Heterozygous mutations in COPA cause a phenotype showing some overlap with SAVI, and are associated with increased ER stress and priming of a Th17 response. However, the precise pathophysiology of this disease is so far undefined. We have studied a group of 8 patients illustrating the phenotypic variability of this emerging disease. We observed commonalities in the lung pathology in COPA and SAVI, as well as an IFN signature, raised levels of IFN alpha in the serum and phosphorylation of STAT1 in patient T cells. In a cellular model, phosphorylation of IRF3 and increased ISG expression were observed in cells co-transfected with wild type STING and mutant COPA plasmids, suggesting that mutations in COPA lead to constitutive activation of type IFN signalling through STING. We reported, for the first time, the successful use of a JAK1 inhibitor, ruxolitinib, in the context of SAVI. We observed a marked clinical effect, which was mirrored by the results of in vitro and ex vivo experiments. Because of the severity of SAVI, we also aimed to evaluate alternative therapeutic approaches to block type I IFN signalling and showed that IKK inhibition efficiently abrogated in vitro constitutive activation of type I IFN production and signalling in cells from STING patients. Considering the promising results of JAK1 blockade in SAVI, we then trialled ruxolitinib in other monogenic type I interferonopathies (TREX1, COPA) and in a child with severe dermatomyositis, a disease where type I IFN has been suggested to play a key pathogenic role
Van, Sebille Ysabella. "Characterisation and Treatment of Pan-Human Epidermal Receptor Tyrosine Kinase Inhibitor-Induced Gastrointestinal Toxicity." Thesis, 2017. http://hdl.handle.net/2440/122124.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2017
Yen, Nai-Jung, and 顏乃容. "Polo-like kinase 1 modulated by HDAC inhibitors treatment in gastric cancer cells." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/36137596198636985692.
Повний текст джерела國立陽明大學
醫學生物技術暨檢驗學系暨研究所
96
Histone deacetylase inhibitors (HDIs), Sodium butyrate (NaB) and Tritrostatin A (TSA), are promising chemotherapeutic candidates. Although they could block proliferation of cancer cells and induce their apoptosis, it is known that some HDIs treatment also brings about unwanted cytotoxicity. Therefore, it is our interests to find a kinase target could have combinatory effect for HDI treatment. Only limited numbers of studies have examined the HDI modulated kinases, which were aberrantly expressed in cancer cells resulting in increasing cell survival, progression and malignancies. We used a restriction analysis of gene expression (RAGE) screening tool which had previously established and could generate comprehensive kinase profiles by using degenerate PCR primers targeting the conserved kinase motifs. Based on the PTK profiling results of this technique, we further found that both TSA and NaB treatments in NUGC cells generated surprisingly similar modulation effect on protein kinase expression. According to subsequent real-time PCR validated results, we demonstrated several kinases were up regulated in TSA or NaB treated NUGC cells, like Fyn, Tnk1, PdgfrB, and a few kinases down regulated such as ErbB2 and Plk1. Based on the validation results and additional evidence, we selected Plk1 (polo-like kinase 1) for further studies. Plk1 is a serine/threonine kinase that functions in cell cycle regulation and spindle assembly during mitosis. It is found to be over-expressed in many human cancer types and has become a new target for cancer therapeutics. However, little is known about Plk1 regulation by HDI treatment. From our observation on HDI modulation of Plk1 expression, it is possible that Plk1 could play critical roles in HDI modulated cancer cell apoptosis. We further analyzed the combinatory effects of the Plk1 inhibitor and HDI to enhance gastric cancer cell death by reducing HDI dosage and toxicity with the addition of Plk1 inhibitor. We demonstrated that Plk1 seems to be important in HDI mediated cell death and could have important applications in enhancing the clinical treatment strategy of TSA in human cancers. The use of RAGE kinase expression profiling method is beneficial in discovering important oncogenic kinases in cancer malignant progression. With the discovery of noval kinase gene targets, new chemotherapeutic strategies could be formulated by taking advantages of many new kinase inhibitors developed.
Yeung, David Tak On. "Prognostic markers associated with tyrosine kinase inhibitor treatment response and maintenance of treatment free remission in chronic myeloid leukaemia." Thesis, 2016. http://hdl.handle.net/2440/119800.
Повний текст джерелаThesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Medicine, 2016.
"Src kinase inhibitors for the treatment of sarcomas: Cellular and molecular mechanisms of action." UNIVERSITY OF SOUTH FLORIDA, 2007. http://pqdtopen.proquest.com/#viewpdf?dispub=3260112.
Повний текст джерелаTsai, Yu-Chieh, and 蔡育傑. "Utilizing New-Generation EGFR Tyrosine Kinase Inhibitor as Radiosensitizer in the Treatment of Urinary Bladder Cancer." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/01747075121732497583.
Повний текст джерела國立臺灣大學
臨床醫學研究所
103
Bladder cancer is the ninth most common cancer in the world and in Taiwanese male population. For many patients with localized muscle-invasive bladder cancer, radical cystectomy is not a feasible treatment, and considerable interest was focused on the optimal use of radiotherapy in ”bladder preservation” protocol. However, the long-term survival of patients receiving radiation-based therapy in muscle invasive bladder cancer is about 10% inferior to patients receiving standard radical cystectomy. Traditionally chemotherapeutic agents are used as radiosensitizer but they have many well-known toxicities. Therefore, there is a strong need to find agents enhancing the radiation effect in urinary bladder cancer treatment while not increasing the toxicities. A reasonable way to enhance the outcome of radiotherapy is by concomitantly using agents that inhibit radiation-activated signaling pathways. Epidermal growth factor receptor (EGFR) is the most important target. Cetuximab, an anti-EGFR antibody, has shown clinical benefit in head and neck cancer when combined with radiotherapy. In bladder cancer, gefitinib, an EGFR tyrosine kinase inhibitor (TKI), has moderate in vitro and marginal in vivo radiosensitizing activities. Therefore the topic deserves further investigation. In pilot study, I tested the radiosensitizing activities of erlotinib (EGFR inhibitor), trastuzumab (HER2 inhibitor) and lapatinib (EGFR/HER2 inhibitor) in bladder cancer cells. None of them showed good potential. Instead, afatinib, a new-generation EGFR inhibitor with activity against both EGFR and HER2, is more promising. In murine bladder cancer model, I demonstrated for the first time the in vitro and in vivo radiosensitizing activity of afatinib, an EGFR/HER2 dual inhibitor. The animal study was performed in immunocompetent mice and mimic human physiologic status. Afatinib likely mediates its effect on bladder cancer cells by suppressing radiation-activated EGFR and HER2 signals and thereby causing enhanced DNA damage and cell apoptosis. Based on the findings I hypothesized that in bladder cancer cells, the concomitant inhibition of EGFR and HER2 tyrosine kinase activity by afatinib has greater radiosensitizing activity than the inhibition of EGFR tyrosine kinase activity alone by erlotinib To confirm the hypothesis, in human bladder cancer model the radiosensitizing effects of different generations of clinically useful EGFR TKIs were compared for the first time. I showed the inadequacy of EGFR inhibition alone and the advantage of concomitant blockade of radiation-activated EGFR and HER2 signaling to inhibit the in vitro and in vivo growth of bladder cancer cells. The radiosensitizing effect of an EGFR inhibitor was much higher in HER2 knocked-down than wild-type cells, therefore HER2 may play a synergistic role with EGFR in determining radiosensitivity. I also showed evidence to support that receptor heterodimerization plays an important role in the radiosensitizing effect of afatinib. In Prospect I mentioned how to continue current project and apply the data to clinical use. I hope that the results of this study can help to meet the need of enhancing the radiation effect in urinary bladder cancer treatment while not increasing the toxicities.
Bansal, Ruchi. "An inhibitor of the mitotic kinase, MPS1, is selective towards pancreatic cancer cells." Thesis, 2014. http://hdl.handle.net/1805/6184.
Повний текст джерелаThe abysmal five year pancreatic cancer survival rate of less than 6% highlights the need for new treatments for this deadly malignancy. Cytotoxic drugs normally target rapidly dividing cancer cells but unfortunately often target stem cells resulting in toxicity. This warrants the development of compounds that selectively target tumor cells. An inhibitor of the mitotic kinase, MPS1, which has been shown to be more selective towards cancer cells than non-tumorigenic cells, shows promise but its effects on stem cells has not been investigated. MPS1 is an essential component of the Spindle Assembly Checkpoint and is proposed to be up-regulated in cancer cells to maintain chromosomal segregation errors within survivable limits. Inhibition of MPS1 kinase causes cancer cell death accompanied by massive aneuploidy. Our studies demonstrate that human adipose stem cells (ASCs) and can tolerate higher levels of a small molecule MPS1 inhibitor than pancreatic cancer cells. In contrast to PANC-1 cancer cells, ASCs and telomerase-immortalized pancreatic ductal epithelial cells did not exhibit elevated chromosome mis-segregation after treatment with the MPS1 inhibitor for 72hrs. In contrast, PANC-1 pancreatic cancer cells exhibited a large increase in chromosomal mis-segregation under similar conditions. Furthermore, growth of ASCs was minimally affected post treatment whereas PANC-1 cells were severely growth impaired suggesting a favorable therapeutic index. Our studies, demonstrate that MPS1 inhibition is selective towards pancreatic cancer cells and that stem cells are less affected in vitro. These data suggest MPS1 inhibition should be further investigated as a new treatment approach in pancreatic cancer.
Yang, I.-Chi, and 楊毅奇. "Study on the Potential Usage of Phosphatidylinositol 3-kinase/ Akt Pathway Inhibitor for the Treatment of Oral Cancer." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/79517331164098657092.
Повний текст джерела國立臺灣大學
口腔生物科學研究所
92
Oral cancer is the fourth leading cause of cancer-related deaths in male population in Taiwan. Despite recent advances in radiotherapy and chemotherapy, the survival of patients with oral cancer has not improved significantly. Continued investigation of new chemotherapeutic agents is thus needed. Recent studies have shown that feeding rotenone inhibited carcinogen-induced mouse oral carcinogenesis. However, the mechanisms by which it inhibits oral carcinogenesis are not well understood. We examined the effects of rotenone on proliferation, cell cycle and apoptosis of oral cancer cell lines SAS using MTT assay, flow cytometry analysis, TUNEL assay, DNA fragmentation assay and Western blotting of cleaved PARP. Rotenone significantly inhibited the proliferation of SAS oral cancer cell lines in a dose-dependent manner with a 50% inhibition concentration (IC50) of rotenone about 2.35 �嵱. However, the IC50 of normal oral mucosa fibroblasts (OMF) was 44.55�嵱. It was almost 22 times higher than the IC50 of SAS. DNA flow cytometric analysis showed that rotenone treatment induced a G2/M arrest. Rotenone treatment also caused significant apoptosis of SAS cells as evidenced by Hoechst 33258 staining, TUNEL labeling, DNA fragmentation and cleavage of PARP. These results indicate that the inhibitory effects of rotenone on oral carcinogenesis may be related to the G2/M phase arrest and induction of apoptosis. Furthermore, nuclear p53 protein and its downstream targets, p21CIP1/WAF1 and Bax, could be induced in SAS (p53-wild type) cells after treatment with rotenone. Rotenone could induce the activation of caspase 8 and caspase 9 in SAS cells, which was different from the previous studies found in other cell types.
Ross, David Morrall. "Minimal residual disease in chronic myeloid leukaemia after imatinib treatment." 2010. http://hdl.handle.net/2440/60064.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010
Ross, David Morrall. "Minimal residual disease in chronic myeloid leukaemia after imatinib treatment." Thesis, 2010. http://hdl.handle.net/2440/60064.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010
Tang, En-kuei, and 湯恩魁. "Usefulness of delE746-A750 and L858R Mutation-Specific Antibodies of EGFR for Predicting Treatment Outcome of Tyrosine Kinase Inhibitors." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/95277095378599958170.
Повний текст джерела國立中山大學
生物科學系研究所
100
Efficacy of tyrosine kinase inhibitor (TKI) therapy depends on epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). There has been an increasing interest in studying mutation-specific rabbit monoclonal antibodies of delE746-A750 mutation in exon 19 and L858R point mutation in exon 21 for detecting EGFR mutants. These two mutations account for approximately 90% of all EGFR mutations. We evaluated the two mutation-specific monoclonal antibodies for the detection of EGFR mutations by immunohistochemistry (IHC) and the relationship with treatment outcome and survival. Twenty-five patients (58.1%) harbored EGFR mutations. These mutations include delE746-A750 mutation for seven patients, L858R point mutation for in eighteen patients. IHC showed, for the delE746-A750 and L858R mutations, sensitivity (57.1% and 66.7%), specificity (97.3% and 100%), positive predictive value (80.0% and 100%), and negative predictive value (94.7% and 80.6%). Analysis for progression-free survival was not correlated to IHC staining, but the overall survival was correlated to IHC staining. These mutation-specific antibodies for delE746-A750 and L858R mutations have high positive predictive value and specificity for predefined EGFR mutations and may be suitable for screening for these predefined mutations. However, negative IHC results required further mutation analyses before excluding EGFR TKI therapy.
"New Approaches For The Treatment Of Erectile Dysfunction In Conditions Of Low Nitric Oxide Formation Or Bioavailability: Investigation Of Rho-kinase Inhibitors And Soluble Guanylate Cyclase-targeted Therapies." Tulane University, 2014.
Знайти повний текст джерелаacase@tulane.edu
Wen-ChangTzeng and 曾文璋. "Identification of metastasis related phosphotyrosine proteins in response to tyrosine kinase inhibitor treatment in human lung cancer cells using label-free quantitative analysis." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/53742724473299540703.
Повний текст джерелаChen-FangWei and 魏辰芳. "Evidence Based Research on Tyrosine Kinase Inhibitors Use for Non-Small Cell Lung Cancer Treatment: Reimbursement Policy Assessment and Comparative Effectiveness Analysis." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/35396671925915139644.
Повний текст джерела山村, 和生, and Kazuo Yamamura. "Combination Treatment of Human Pancreatic Cancer Xenograft Models with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib and Oncolytic Herpes Simplex Virus HF10." Thesis, 2014. http://hdl.handle.net/2237/20368.
Повний текст джерела"Toward an Improved Chronic Myelogenous Leukemia Treatment: Blocking the Stem Cell Factor–Mediated Innate Resistance With Anti–c-Kit Synthetic-Antibody Inhibitors." Thesis, 2015. http://hdl.handle.net/10388/ETD-2015-03-1990.
Повний текст джерелаTonsing-Carter, Eva Y. "Modulation of the Mdm2 signaling axis sensitizes triple-negative breast cancer cells to carboplatin." Thesis, 2014. http://hdl.handle.net/1805/6306.
Повний текст джерелаChen, Yi-Wen, and 陳依玟. "Ⅰ. Proteomics study of oxidative stress, Src kinase inhibition and quercetin in H9C2 cardiomyocytes: a cell model of heart ischemia reperfusion injury and treatment Ⅱ. The application of proteomics for disease biomarker discovery and mechanism study." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/81922667673395367359.
Повний текст джерела國立清華大學
生物資訊與結構生物研究所
103
PART І. Proteomics study of oxidative stress, Src kinase inhibition (PP1) and Quercetin in H9C2 cardiomyocytes: a cell model of heart ischemia reperfusion injury and treatment. Oxidative stress production of myocardial ischemia/reperfusion injury leads to protein phosphorylation in regulating gene expression, metabolism, cell adhesion and survival. In this thesis, we used hydrogen peroxide treatment of H9C2 rat cardiomyocytes as a model of oxidative stress in heart ischemia reperfusion injury. A proteomics approach using anti-phosphotyrosine affinity purification and LC-MS/MS was then used to identify the stress-induced protein phosphorylation. We showed that oxidative stress induces a robust tyrosine phosphorylation of multiple proteins in this cell type. Most of identified tyrosine phosphorylated proteins were relative to cell-cell junctions, the actin cytoskeleton and cell adhesion. This suggested that oxidative stress may have a profound effect on intercellular connections and the cytoskeleton to affect cell adhesion, morphology and survival. After stress-induced phosphotyrosine proteins were analyzed by STRING, Src kinase was shown to be a major upstream regulator of these events. Furthermore, immunofluorescence studies, fluorescent activated cell sorting and cell-based assays were used to demonstrate H2O2-induced modifications of cell adhesion structures and cytoskeleton, de-adhesion and apoptosis, which were reversed by treatment with the Src kinase inhibitor PP1 or quercetin. Moreover, quercetin likely blocked the H2O2-induced inflammatory response through STAT3 modulation, which also contributed in preventing ischemia/reperfusion injury in cardiomyocytes. These findings provide the critical role of Src kinase in oxidative stress-induced phosphorylation and cell damage in cardiomyocytes and suggested that targeting Src kinase or quercetin may be an effective strategy for preventing ischemia reperfusion injury in the heart. PART П. The application of Proteomics for disease biomarker discovery Cancer and diabetic are high incidence and mortality in worldwide; however, early detection, surgical resection and postoperative therapy can lead to survival improvement for cancer or diabetes. In recent study, body fluids of patient were used to screen markers, such as plasma, urine and cerebrospinal fluid. Here, plasma of critical limb ischemia (CLI), type 1 diabetic (T1DM), transition carcinoma cancer and uterine leiomyoma were collected and analyzed by 2D-DIGE and MALDI-TOF. Then, particular protein markers were found in specific diseases, such as dual adapter for phosphotyrosine and 3-phosphotyrosine and 3-phosphoinositide (DAPP1) in CLI, hemopexin in T1DM, selenocysteine-specific elongation factor in TCC and vitamin D-binding protein in uterine leiomyoma. Nevertheless, most identified plasma proteins are related to inflammatory responses and blood coagulation. Therefore, a cell-based platform was established to screen protein markers relating to gemcitabine (GEM)-induced drug resistance pancreatic cells and tumorigenic breast cells. In GEM-induced drug resistant pancreatic cells, ribonucleoside-diphosphate reductase large subunit significantly overexpressed and tumor suppressor protein p53 may interplay with GEM-induced pancreatic cell resistance. In addition, in breast cancer cells, the level of calcium-binding mitochondrial carrier protein SCaMC-1 in tumorigenetic breast cancer cells or breast cancer patients’ plasma was higher than that of normal cell or health donors’ plasma. These data demonstrate that plasma proteomics provides a lot of common proteins between various diseases, but a cell based strategy provides a good platform for specific protein markers discovery in particular disease and afterwards these protein markers are potential for disease screening.