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Effects of Combination Therapy of PDE5 Inhibitor Sildenafil and Multikinase Inhibitors Sorafenib and Sunitinib in NSCLC

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Effects of Combination Therapy of PDE5 Inhibitor Sildenafil and Multikinase Inhibitors Sorafenib and Sunitinib in NSCLC Effects of combination therapy of PDE5 inhibitor sildenafil and multikinase inhibitors sorafenib and sunitinib in NSCLC Inauguraldissertation zur Erlangung des Grades eines Doktors der Medizin des Fachbereiches Medizin der Justus - Liebig - Universität Gießen Vorgelegt von Stefanie Kurian, geb. Pfrogner aus Wetzlar Gießen/Bad Nauheim 2015 Aus dem Zentrum für Innere Medizin Medizinische Klinik IV und V, Hämatologie und Onkologie, Palliativmedizin des Universitätsklinikums Gießen und Marburg, Standort Gießen Leiter: Prof. Dr. Dr. F. Grimminger Gutachter: PD Dr. med. A. G. Banat Gutachter: Prof. Dr. Middendorff Tag der Disputation: 10.09.2015 II Sworn statement “Ich erkläre: Ich habe die vorgelegte Dissertation selbständig, ohne unerlaubte fremde Hilfe und nur mit den Hilfen angefertigt, die ich in der Dissertation angegeben habe. Alle Textstellen, die wörtlich oder sinngemäß aus veröffentlichten oder nicht veröffentlichten Schriften entnommen sind, und alle Angaben, die auf mündlichen Auskünften beruhen, sind als solche kenntlich gemacht. Bei den von mir durchgeführten und in der Dissertation erwähnten Untersuchungen habe ich die Grundsätze guter wissenschaftlicher Praxis, wie sie in der “Satzung der Justus- Liebig-Universität Gießen zur Sicherung guter wissenschaftlicher Praxis” niedergelegt sind, eingehalten.” III Widmung IV Table of contents Sworn statement .............................................................................................................. III Widmung ........................................................................................................................ IV List of Figures .............................................................................................................. VIII List of Tables .................................................................................................................. IX 1 Introduction ............................................................................................................... 1 1.1 Lung cancer ........................................................................................................ 1 1.1.1 Lung cancer pathology ................................................................................ 1 1.1.2 Classification ............................................................................................... 2 1.1.3 Risk factors .................................................................................................. 3 1.2 Therapy ............................................................................................................... 4 1.2.1 Surgery ........................................................................................................ 4 1.2.2 Chemotherapy ............................................................................................. 4 1.2.3 Radiation therapy ........................................................................................ 4 1.2.4 Targeted therapy .......................................................................................... 4 1.3 Growth factors .................................................................................................... 5 1.3.1 Platelet-derived growth factor ..................................................................... 5 1.3.2 Vascular endothelial growth factor ............................................................. 6 1.4 Multikinase inhibitors ......................................................................................... 8 1.4.1 Sunitinib ...................................................................................................... 8 1.4.2 Sorafenib ..................................................................................................... 9 1.5 Phosphodiesterases ........................................................................................... 10 1.5.1 Cyclic nucleotide signalling ...................................................................... 10 1.5.2 Phosphodiesterase family .......................................................................... 11 1.5.3 Inhibitors ................................................................................................... 13 1.5.4 Phosphodiesterase 5 and the specific inhibitor sildenafil .......................... 14 2 Aims of the study .................................................................................................... 16 V 3 Material ................................................................................................................... 17 3.1 Cell culture ....................................................................................................... 17 3.2 Immunohistochemistry ..................................................................................... 17 3.3 Reagents ............................................................................................................ 18 3.4 Antibodies ......................................................................................................... 19 3.4.1 Immunohistochemistry .............................................................................. 19 3.5 Primer ............................................................................................................... 20 3.6 Equipment Table ............................................................................................... 21 4 Methods ................................................................................................................... 22 4.1 Animals ............................................................................................................. 22 4.1.1 Anaesthesia for subcutaneous infiltration ................................................. 22 4.1.2 Tumor growth in nude mice ...................................................................... 22 4.1.3 Treatment groups ....................................................................................... 22 4.2 Cell culture ....................................................................................................... 23 4.3 RNA isolation ................................................................................................... 23 4.4 cDNA synthesis ................................................................................................ 24 4.5 Quantitative real time polymerase chain reaction ............................................ 24 4.6 Immunohistochemistry ..................................................................................... 25 4.6.1 Staining methods ....................................................................................... 25 4.7 Quantification ................................................................................................... 27 4.8 Statistics ............................................................................................................ 28 5 Results ..................................................................................................................... 29 5.1 Profiling of receptor expression........................................................................ 29 5.2 Tumor growth ................................................................................................... 31 5.3 Tyrosine kinase receptor expression ................................................................. 33 6 Discussion ............................................................................................................... 38 VI 6.1 Expression profile of tyrosine kinase receptor in tumor, monocytes, macrophages, lymphocytes and fibroblasts ................................................................. 38 6.2 In vivo effects of the PDE5 inhibitor sildenafil together with multikinase inhibitor sunitinib or sorafenib in the adenocarcinoma mouse model ........................ 40 6.3 Analysis of morphology, angiogenesis and proliferation in tumor tissue ........ 42 6.4 Analysis of the role of angiogenesis in tumor tissue growth ............................ 43 7 Summary ................................................................................................................. 44 8 Zusammenfassung ................................................................................................... 46 9 Literature ................................................................................................................. 48 10 Abbreviations .......................................................................................................... 53 11 Acknowledgements ................................................................................................. 55 12 Curriculum vitae ...................................................................................................... 56 VII List of Figures Figure 1: Cyclic nucleotide phosphodiesterase signalling. ............................................. 11 Figure 2: Quantification by Leica Qwin, Example picture ............................................. 27 Figure 3: Dualstanding Analyse, Screenshot example .................................................... 28 Figure 4: mRNA expression of tyrosine kinase receptors ............................................... 30 Figure 5: Subcutaneous tumor size over the course of time............................................ 31 Figure 6: HE (1) and trichrome (2) stainings of original scanned slides of A549 tumor tissue ....................................................................................................................
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