Molecularly targeted imaging and radionuclide therapy of non-thyroidal tumors following viral and non-viral sodium iodide symporter (NIS) gene delivery [Elektronische Ressource] / Kathrin Klutz. Betreuer: Ernst Wagner

Kathrin Klutz

Sujets

• Gesundheit

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2010
• Nombre de lectures: 19
• Langue: Deutsch
• Poids de l'ouvrage: 7 Mo

Extrait

Dissertation
zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie der
Ludwig-Maximilians-Universität München




Molecularly targeted imaging and radionuclide therapy
of non-thyroidal tumors following viral and non-viral
sodium iodide symporter (NIS) gene delivery


vorgelegt von
Kathrin Klutz
aus Aalen
2010

Erklärung
Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29.
Januar 1998 von Frau Professor Dr. C. Spitzweg betreut und von Herrn Professor Dr. E.
Wagner vor der Fakultät für Chemie und Pharmazie vertreten.

Ehrenwörtliche Versicherung
Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.

München, am …………………..


……..…………………..
(Unterschrift des Autors)







Dissertation eingereicht am 07.09.2010
1. Gutachter: Prof. Dr. Ernst Wagner
2. Gutachterin: Prof. Dr. Christine Spitzweg
Mündliche Prüfung am 28.10.2010

Table of Contents

Table of Contents
1. Introduction ..................................................................................................................1
The sodium iodide symporter (NIS)...................................................................................1
The sodium iodide symporter and its role as therapy gene ............................................1
Iodide organification and alternative radionuclides .......................................................3
The sodium iodide symporter and its role as reporter gene............................................4
Cancer Gene Therapy.........................................................................................................5
Viral vector systems .......................................................................................................6
Non-viral vector systems................................................................................................7
Aims of the thesis .............................................................................................................10
131 1882. Chapter 1 Comparison study of I and Re therapy in liver cancer after
tumor-specific in vivo sodium iodide symporter (NIS) gene transfer....................11
Abstract ............................................................................................................................12
Introduction ......................................................................................................................13
Materials and Methods .....................................................................................................15
Results ..............................................................................................................................20
Discussion ........................................................................................................................28
Acknowledgments ............................................................................................................33
Author Disclosure Statement............................................................................................33
3. Chapter 2 Targeted radioiodine therapy of neuroblastoma tumors following
systemic non-viral delivery of the sodium iodide symporter (NIS) gene...............34
Statement of Translational Relevance..............................................................................35
Abstract ............................................................................................................................36
Introduction ......................................................................................................................37
Materials and Methods .....................................................................................................40
Results ..............................................................................................................................44
Discussion ........................................................................................................................52
Acknowledgments ............................................................................................................57
4. Chapter 3 Image-guided tumor-selective radioiodine therapy of liver cancer
following systemic non-viral delivery of the sodium iodide symporter gene ........58
Abstract ............................................................................................................................59
Introduction ......................................................................................................................60
Materials and Methods .....................................................................................................63
Table of Contents

Results ..............................................................................................................................67
Discussion ........................................................................................................................76
Acknowledgments ............................................................................................................80
5. Chapter 4 Epidermal growth factor receptor-targeted radioiodine therapy of
hepatocellular cancer following systemic non-viral delivery of the sodium iodide
symporter gene ...........................................................................................................81
Statement of Translational Relevance..............................................................................82
Abstract ............................................................................................................................83
Introduction ......................................................................................................................84
Materials and Methods .....................................................................................................87
Results ..............................................................................................................................92
Discussion ......................................................................................................................101
Acknowledgments ..........................................................................................................107
6. Summary ...................................................................................................................108
7. Publications...............................................................................................................110
Original papers ...............................................................................................................110
Manuscripts in preparation.............................................................................................110
Poster presentations........................................................................................................111
Oral presentations...........................................................................................................112
Award .............................................................................................................................113
8. References .................................................................................................................114
9. Acknowledgments.....................................................................................................123
10. Curriculum Vitae .....................................................................................................125
Introduction

1. Introduction
The sodium iodide symporter (NIS)
The sodium iodide symporter and its role as therapy gene
The sodium iodide symporter (NIS) represents an intrinsic plasma membrane glycoprotein
Human Sodium Iodide Symporterwith 13 transmembrane domains localized at the 497485
Extracellular 139
225 7 111 51 3baslolateral membrane of thyroid follicular cells that
11 79 86 217 241 417157 163 308 340 411 468 522
mediates the active transport of iodide in the thyroid
I II III IV V VI VII VIII IX X XI XII XIII
37 54 191 260 286 368 388 444 550gland (Fig. 1). Cloning and molecular characterization 111 136 182 438
6 12
2 4 10Intracellular 8
1 - Sequence Numbers 643 14of the NIS gene (Spitzweg and Morris, 2002b) allowed
I - Transmembrane Domains
1 - ExM Domains
- N-linked glycosylation sites
investigation of its expression and regulation in
Fig. 1: Schematic illustration of the
sodium iodide symporter (NIS). thyroidal and nonthyroidal tissues (Spitzweg et al.,
With permission reproduced from
Spitzweg et al., 2001c.
1998; Spitzweg et al., 1999b; Spitzweg et al., 2000a;
Spitzweg et al., 2001b; Spitzweg and Morris, 2002b; Unterholzner et al., 2006; Willhauck
et al., 2008c), its pathophysiological role in benign and malignant thyroid disease as well its
potential role in diagnosis and therapy of cancer outside the thyroid gland (Spitzweg et al.,
1999a; Spitzweg et al., 2000a; Spitzweg and Morris, 2002b).
+ +NIS-mediated iodide transport is inhibited by the Na /K -ATPase inhibitor