Reifenberger / Barciszewski Therapeutic Ribonucleic Acids in Brain Tumors

1. Auflage 2009
ISBN: 978-3-642-00475-9
Verlag: Springer
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 494 Seiten

In the past few years nucleic acids technologies have grown into a powerful analytical and also increasingly therapeutic tool. It has been applied not only to the uncovering of gene functions in many organisms, but also to pathogenetic analysis and recently also for the treatment of human diseases. The book discusses in depth the potential of these innovative methods in the broad field of central nervous system and brain tumours particularly. Whereas there is currently no comprehensive overview on potential and challenges of nucleic acids technologies for basic brain tumours and for the clinical management of patients with brain tumours, this book does explicitly cover the many other aspects of the 'RNA World' (pathogenic and therapeutic potential of microRNAs, aptamer technology, etc.), too. With this significantly broadened scope as compared to currently existing books it appears to be an urgently needed new publication.

Autoren/Hrsg.

Reifenberger, Guido

Barciszewski, Jan

Inhaltsverzeichnis

1;Therapeutic Ribonucleic Acids in Brain Tumors;2
1.1;Preface;5
1.2;Contents;9
1.3;Contributors;11
1.4;Molecular Biology of Malignant Gliomas;17
1.4.1;1 Introduction;18
1.4.2;2 Altered Pathways Involved in Human Gliomas;19
1.4.2.1;2.1 pRb/E2F Axis in Human Gliomas;19
1.4.2.2;2.2 P53/MDM2/p14-ARF;20
1.4.2.3;2.3 PI3K/PTEN/Akt/PKB;25
1.4.2.4;2.4 EGFR;25
1.4.2.5;2.5 PDGF and PDGFR;27
1.4.2.6;2.6 VEGFR;27
1.4.2.7;2.7 K-Ras/Raf/MAPK;27
1.4.3;3 Lessons from Microarray Studies;28
1.4.4;4 Glioma Stem-Like Cells;33
1.4.5;5 Challenges for Therapies;35
1.4.6;References;35
1.5;Molecular Neurooncology and Neoangiogenesis of Malignant Gliomas;39
1.5.1;1 Molecular Pathways in Malignant Gliomas;41
1.5.1.1;1.1 Genetic Pathways of Primary (De Novo) and Secondary Glioblastomas;42
1.5.1.2;1.2 Major Signaling Pathways Regulating Tumor Growth;46
1.5.1.2.1;1.2.1 EGF/EGFR Signaling Pathway;46
1.5.1.2.2;1.2.2 PDGF/PDGFR Signaling Pathway;48
1.5.1.2.3;1.2.3 TGF/TGF-R Signaling Pathway;48
1.5.1.2.4;1.2.4 FGF/FGFR Signaling Pathway;50
1.5.1.2.5;1.2.5 IGF/IGFR Signaling Pathway;50
1.5.1.2.6;1.2.6 Gas6/Axl Signaling Pathway;50
1.5.1.3;1.3 Major Signaling Pathways Regulating Tumor-Angiogenesis;51
1.5.1.3.1;1.3.1 VEGF/VEGFR Signaling Pathway;51
1.5.1.3.2;1.3.2 Angiopoietins;53
1.5.1.3.3;1.3.3 Integrins;53
1.5.1.4;1.4 Major Intracellular Signal Transduction Pathways;54
1.5.1.4.1;1.4.1 Ras Signal Transduction;54
1.5.1.4.2;1.4.2 PI3K/Akt/PTEN/mTOR Signaling Pathway;54
1.5.2;2 Neoangiogenesis in Malignant Gliomas;55
1.5.2.1;2.1 Cellular Mechanisms;56
1.5.2.2;2.2 Molecular Mechanisms;56
1.5.2.3;2.3 Structural Abnormalities of Brain Tumor Blood Vessels and Blood Brain Barrier;58
1.5.2.4;2.4 Tumor Edema in Malignant Gliomas;60
1.5.2.4.1;Attendum;60
1.5.2.4.1.1;Growth Factor Receptors;60
1.5.2.4.1.2;Ras-GDP Pathway;60
1.5.2.4.1.3;PI3K Pathway;61
1.5.3;References;62
1.6;Molecular Therapies for Malignant Gliomas;72
1.6.1;1 Principles of Molecular Targeted Therapies;74
1.6.1.1;1.1 Monoclonal Antibodies;74
1.6.1.2;1.2 Small Molecule Inhibitors;75
1.6.1.3;1.3 Antisense Oligodeoxy-Nucleotides;75
1.6.1.4;1.4 Obstacles to Successful Targeted Therapyof Malignant Gliomas;76
1.6.2;2 Preclinical and Clinical Studies of Molecular Therapies in Malignant Gliomas;77
1.6.2.1;2.1 Targeting Receptor Tyrosine Kinase Signaling Pathways;77
1.6.2.1.1;2.1.1 Targeting the PDGF/PDGFR Signaling Pathway;77
1.6.2.1.2;2.1.2 Targeting the EGF/EGFR Signaling Pathway;83
1.6.2.1.3;2.1.3 Targeting the FGF/FGFR Signaling Pathway;84
1.6.2.1.4;2.1.4 Targeting the IGF/IGFR Signaling Pathway;84
1.6.2.1.5;2.1.5 Targeting Intracellular Signaling Pathways;84
1.6.2.2;2.2 Multitargeting Small Molecule Inhibitors;85
1.6.2.3;2.3 Antiangiogenic Treatment in Malignant Gliomas;88
1.6.2.3.1;2.3.1 Antiangiogenic Treatment Regimes Used in Malignant Gliomas;89
1.6.2.3.2;2.3.2 Effects of Antiangiogenic Treatment on Brain Tumor Edema;90
1.6.2.3.3;2.3.3 Evaluation of Brain Tumor Response to AntiangiogenicTherapy Approaches;90
1.6.2.3.4;2.3.4 Potential CNS Toxicity of Antiangiogenic Agents;92
1.6.2.4;2.4 Targeting TGF-Beta: Antisense Oligodeoxynucleotide Therapy Approaches of Malignant Gliomas;92
1.6.3;3 Conclusions and Future Directions;93
1.6.4;References;94
1.7;Novel Strategies for the Treatment of Brain Cancer;100
1.7.1;1 Introduction;101
1.7.2;2 Current Management of GBM;101
1.7.3;3 Molecular Pathomechanism of GBM as the Basis for Innovative Treatments;101
1.7.3.1;3.1 Signaling Pathways in GBM as Therapeutic Targets;102
1.7.3.2;3.2 Cancer Stem Cells and GBM;102
1.7.4;4 Innovative Strategies for the Treatment of GBM;103
1.7.4.1;4.1 Antiangiogenesis Approaches for Treatment of GBM;103
1.7.4.2;4.2 Innovations in Drug Delivery to GBM;107
1.7.4.2.1;4.2.1 Anticancer Agents with Increased Penetrationof Blood-Brain Tumor Barrier;107
1.7.4.2.2;4.2.2 Local Delivery of Chemotherapeutic Agents into the Tumor;108
1.7.4.2.3;4.2.3 Convection-Enhanced Delivery;109
1.7.4.2.4;4.2.4 Liposomes for Drug Delivery to GBM;109
1.7.4.2.5;4.2.5 Use of Nanoparticles for Drug Delivery to GBM;110
1.7.5;5 Personalized Management of GBM;110
1.7.5.1;5.1 Genetic/Genomic Basis for Personalizing Treatment of GBM;111
1.7.5.2;5.2 Molecular Diagnostics for Personalized Management of GBM;111
1.7.5.2.1;5.2.1 Diffusion MRI as a Biomarker;112
1.7.5.2.2;5.2.2 Combined Neuroimaging and DNA Microarray Analysis;112
1.7.5.2.3;5.2.3 Proteomics of GBM;112
1.7.5.2.4;5.2.4 Epigenetic Biomarkers of GBM;113
1.7.5.2.5;5.2.5 Personalized Chemotherapy of GBM;113
1.7.5.2.6;5.2.6 Molecular Determinants of Response to EGFR Inhibitors;113
1.7.5.2.7;5.2.7 Simulating Chemotherapeutic Schemes for Individualization;114
1.7.5.2.8;5.2.8 Personalized Therapy of GBM Based on Cancer Stem Cells;114
1.7.6;6 Limitations of Current Therapies for GBM;114
1.7.7;7 Future Prospects;115
1.7.8;References;116
1.8;Gene Therapy for Malignant Glioma;118
1.8.1;1 Introduction;119
1.8.2;2 The Transgenes;120
1.8.3;3 The Vectors;121
1.8.3.1;3.1 Viral Vectors;122
1.8.4;4 Oncolytic Vectors for Glioma;125
1.8.4.1;4.1 Enhancement of CRAd's Tropism for Brain Tumor Cells;126
1.8.4.1.1;4.1.1 Redesigning the Adenoviral Capsid to PromoteTransduction in Neoplastic Cells;126
1.8.4.1.2;4.1.2 Transcriptional Targeting of Viral Genes or Transgenes Using Tumor Specific Promoters;128
1.8.4.1.3;4.1.3 Deletion of Viral Genomic Regions that are not Required for Replication in Cancer Cells;129
1.8.5;5 Future Directions: Stem Cells Aid Gene and Oncolytic Therapy Vectors to Reach Distant Tumor Pockets on Infiltrating Gliomas;130
1.8.6;6 Conclusions;131
1.8.7;Acknowledgements;132
1.8.8;References;132
1.9;Immunotherapeutic Approach for Glioma by Alphaviruses as Positive Strand RNA Viruses;140
1.9.1;1 Introduction;141
1.9.2;2 RNA Viruses as Gene Expression Vectors;142
1.9.3;3 The Biology of Alphaviruses;142
1.9.4;4 Heterologous Gene Expression Using Alphavirus Vectors;143
1.9.5;5 Gene Therapy Strategies Using Alphavirus Vectors;144
1.9.5.1;5.1 Immunotherapeutic Approach;145
1.9.5.2;5.2 Replication-Competent Alphaviruses;149
1.9.6;6 Alphavirus Vector Development for Gene Therapy Application;149
1.9.7;7 Conclusions;151
1.9.8;References;152
1.10;Diagnosis of Brain Tumors Through Global Specific DNA Methylation Analysis;156
1.10.1;1 DNA Methylation;157
1.10.2;2 5-Methylcytosine as a Main Epigenetic Marker in DNA;158
1.10.3;3 Oxidative Damage of m5C;159
1.10.4;4 Methods of DNA Methylation Analysis;161
1.10.5;5 Epigenetic Method of 5-Methylcytosine Analysisin DNA from Different Tissues;162
1.10.5.1;5.1 Description of the Method;163
1.10.6;6 Analysis of 5-Methylcytosine in DNA of Patients with Brain Tumors;163
1.10.7;7 Analysis of 5-Methylcytosine in DNA of Patientswith Other Diseases;166
1.10.8;8 Aging;167
1.10.9;9 Conclusions;168
1.10.10;References;168
1.11;Molecular Markers of Gliomas;171
1.11.1;1 Introduction;172
1.11.1.1;1.1 Most Relevant Affected Pathways in Gliomas;173
1.11.2;2 Loss of Heterozygosity on Chromosome 1p and 19q;176
1.11.2.1;2.1 LOH on Chromosome 1p and 19q in ODs;176
1.11.2.2;2.2 LOH on Chromosome 1p and 19q in oligoastrocytomas;177
1.11.2.3;2.3 Partial Deletion on 1p;177
1.11.2.4;2.4 Clinical Relevance of LOH on Chromosome 1p and 19q;178
1.11.2.5;2.5 Genes Targeted by Deletions on 1p and 19q;178
1.11.3;3 LOH on Chromosome 10q and PTEN Mutations;179
1.11.3.1;3.1 LOH on Chromosome 10q and PTEN Mutations in Different Glioma Subtypes;179
1.11.3.2;3.2 Clinical Relevance of LOH on Chromosome 10q and PTEN Mutations;180
1.11.4;4 LOH on Chromosome 17p and P53 Mutations;181
1.11.4.1;4.1 LOH on Chromosome 17p and P53 Mutationsin Different Glioma Subtypes;181
1.11.5;5 EGFR;183
1.11.5.1;5.1 EGFR Amplification/Overexpression;183
1.11.5.2;5.2 Monoclonal Antibodies Against EGFR;183
1.11.6;6 O6-Methylguanine DNA Methyltransferase;185
1.11.6.1;6.1 MGMT Promoter Methylation Status in Different Glioma Subtypes;186
1.11.6.2;Note;187
1.11.7;7 CD133;187
1.11.8;References;187
1.12;Microarray and Proteomic Analysis of Gliomas: Target Strategies;192
1.12.1;1 Introduction;193
1.12.2;2 Background;194
1.12.2.1;2.1 Glioblastoma Multiforme;194
1.12.2.2;2.2 The Five Tools;194
1.12.3;3 Source of GBM Material for Target Identification Using Gene Expression Tools, Genomic Analyses, and Proteomic Analyses;195
1.12.3.1;3.1 Tumor Biopsies;195
1.12.3.2;3.2 Microdissection of GBM Cells;196
1.12.3.3;3.3 In Vitro Cultures of GBM Cells;196
1.12.3.4;3.4 Xenografted GBM Cells as a Source;197
1.12.3.5;3.5 Analysis of Recurrent Tumor Cells That Have BeenTreated with Radiotherapy and/or Temozolamide;198
1.12.4;4 Targets;198
1.12.5;5 Target Validation;200
1.12.6;6 Delivery Systems;202
1.12.6.1;6.1 Administration Validation;202
1.12.6.2;6.2 Adenoviral Vector Delivery System;202
1.12.6.3;6.3 Adeno-Associated Vector Delivery System;203
1.12.6.4;6.4 Poliovirus Vector Delivery System;204
1.12.6.5;6.5 Retroviral Vector Delivery System;204
1.12.6.6;6.6 Artificial Viral Particle Delivery System;204
1.12.6.7;6.7 Lipsomal, PLL or PEI In Vivo Gene Delivery;204
1.12.6.8;6.8 Local Electroporation;205
1.12.6.9;6.9 Direct Oligo-Nucleotide Delivery;205
1.12.7;7 Future Perspectives and Discussion;205
1.12.8;Acknowledgements;206
1.12.9;References;206
1.13;Nanosystems for the Delivery of RNAi;210
1.13.1;1 Introduction;211
1.13.1.1;1.1 Functional Analysis of Tumor-Relevant Genes in Brain Tumors Through Knockdown Approaches;211
1.13.2;2 RNA Interference;212
1.13.2.1;2.1 Discovery and Mechanism;213
1.13.2.1.1;2.1.1 The Initiation Phase: Dicer Mediates Cleavage of Long dsRNA;215
1.13.2.1.2;2.1.2 The Effector Phase: RISC-Mediated Cleavage of mRNA;215
1.13.2.2;2.2 siRNA and shRNA;216
1.13.2.2.1;2.2.1 Vector-Based RNAi;217
1.13.3;3 Delivery Strategies for siRNA and shRNA: General Considerations;217
1.13.3.1;3.1 Carriers for siRNA and shRNA Construct Delivery;218
1.13.3.2;3.2 Delivery Across the Blood-Brain Barrier;219
1.13.4;4 Systems for Local Application of siRNA/shRNA Constructs;220
1.13.5;5 Systemic Application of siRNA/shRNA Constructs;225
1.13.6;6 Outlook;227
1.13.7;References;228
1.14;Interference RNA Intervention in Brain Tumors;234
1.14.1;1 Introduction;235
1.14.2;2 Tenascin-C;237
1.14.3;3 Selected Molecular Targets for Brain Tumor Treatment;244
1.14.4;4 Current Anti-invasion Clinical Trials;249
1.14.5;5 RNA Interference for Tenascin-C Inhibitionin Brain Tumors;251
1.14.6;6 Perspectives;258
1.14.7;References;259
1.15;Blood-Brain Barrier Transport for RNAi;267
1.15.1;1 Introduction;268
1.15.2;2 Trojan Horse Liposome Technology;271
1.15.3;3 Brain Expression of shRNA RNAi Genes Using THL;271
1.15.4;4 In Vivo Silencing of Gene Expression in a Brain Tumor Model and Increased Survival Rate;274
1.15.5;5 In Vivo Delivery of SiRNA with Targeted MAbs and Avidin-Biotin Technology;277
1.15.6;6 Conclusions and Future Directions;280
1.15.7;References;282
1.16;Therapeutic Potential of Small Interfering RNA for Brain Diseases;286
1.16.1;1 RNA Interference;287
1.16.2;2 Spinocerebellar Ataxia and Other Polyglutamine-Associated Ataxias;290
1.16.3;3 Alzheimer's Disease;292
1.16.4;4 Parkinson's Disease;295
1.16.5;5 Amyotrophic Lateral Sclerosis;295
1.16.6;6 Multiple Sclerosis;297
1.16.7;7 Brain Tumors;299
1.16.8;8 Conclusions;302
1.16.9;References;302
1.17;RNA Interference-Based Therapies Against Brain Tumors: Potential Clinical Strategies;307
1.17.1;1 Introduction;308
1.17.1.1;1.1 RNA Interference: The Beginnings;309
1.17.1.2;1.2 The Expanding Family of Small RNAs and Their Widening Role in Cellular Functions;310
1.17.1.3;1.3 MicroRNA: The siRNA of the Genome;311
1.17.2;2 RNAi: The Mechanisms of Interference;312
1.17.2.1;2.1 siRNA and Its Mechanism of Interference;312
1.17.2.2;2.2 miRNA and Its Mechanism of Interference;314
1.17.3;3 The Design of siRNA for Preclinical Evaluation;314
1.17.3.1;3.1 The Evolving Rules for Rational siRNA Design;314
1.17.3.2;3.2 Minimizing Off-Target Effects of siRNA;314
1.17.3.3;3.3 Unintended Interactions Between Designed siRNA and 3 Untranslated Regions of ``Off-Target´´ mRNA;316
1.17.3.4;3.4 Which Strand is Selected as the Guide Strand?;316
1.17.4;4 Experimental Strategies;316
1.17.4.1;4.1 Experimental Strategies with siRNA;316
1.17.4.2;4.2 Experimental Strategies with miRNA;317
1.17.4.3;4.3 miRNA/siRNA Hybrids;318
1.17.4.4;4.4 In Vivo Imaging of RNAi Delivery;318
1.17.5;5 siRNA Targets in Glioma: Preclinical Studies;319
1.17.5.1;5.1 Targeting Glioma Cell-Surface Receptors via RNAi;319
1.17.5.1.1;5.1.1 The EGF Receptor;320
1.17.5.1.2;5.1.2 Formyl Peptide Receptor (FPR);320
1.17.5.1.3;5.1.3 Ephrin Receptor;321
1.17.5.1.4;5.1.4 The Urokinase Plasminogen Activator Receptor (uPAR);321
1.17.5.1.5;5.1.5 CXCR4 Receptor;321
1.17.5.1.6;5.1.6 Other Glioma Cell-Surface Receptors and Glioma Proteins Targeted by siRNA;321
1.17.5.2;5.2 Targeting Glioma Invasion via RNAi;322
1.17.5.3;5.3 Induction of Glioma Apoptosis via RNAi;323
1.17.5.4;5.4 Enhancing Chemo-sensitivity and Radiosensitivity via RNAi;323
1.17.5.5;5.5 Targeting Hypoxia-Induced Glioma Angiogenesis Cascades via RNAi;324
1.17.5.6;5.6 Targeting Glioma Metabolism via RNAi;324
1.17.5.7;5.7 Other Glioma Signaling Pathways Targeted by RNAi;325
1.17.5.8;5.8 siRNA Mediated Modulation of Immuno-Activity Against Glioma;325
1.17.5.9;5.9 Targeting Brain Tumor Stem Cells via RNAi;325
1.17.6;6 MicroRNA Targets in Glioma;326
1.17.7;7 Systemic Delivery of RNAi to Brain Tumors;326
1.17.8;8 RNAi in the Clinic: Current and Future Perspectives;327
1.17.9;9 Conclusions;328
1.17.10;Acknowledgements;328
1.17.11;References;328
1.18;MicroRNA: Biogenesis, Regulation, and Role in Primary Brain Tumors;336
1.18.1;1 Introduction;337
1.18.2;2 Genomic Organization of miRNA Loci;338
1.18.3;3 MiRNA Biogenesis;340
1.18.4;4 MiRNA Effector Mechanisms;341
1.18.5;5 Regulation of miRNA Expression and Function;343
1.18.6;6 MiRNA Detection and Quantification;344
1.18.7;7 In Vitro and In Vivo Modulation of miRNA Levels;348
1.18.8;8 MiRNAs in Cancer;349
1.18.9;9 MiRNA in Brain Tumors;350
1.18.9.1;9.1 Pituitary Adenomas;351
1.18.9.2;9.2 Medulloblastomas;351
1.18.9.3;9.3 Gliomas;355
1.18.10;10 Summary and Perspectives;357
1.18.11;References;357
1.19;Treatment of High-Grade Gliomas in Adults;364
1.19.1;1 Surgical Treatment of Newly Diagnosed Gliomas;365
1.19.2;2 Surgery for Recurrent Disease;367
1.19.3;3 Adjuvant Therapies at Resection;367
1.19.3.1;3.1 Carmustine Wafers;368
1.19.3.2;3.2 Convection-Enhanced Delivery;368
1.19.3.3;3.3 Interstitial Brachytherapy;369
1.19.3.4;3.4 Radioimmunotherapy;369
1.19.4;4 Radiotherapy;370
1.19.4.1;4.1 Adjuvant Radiotherapy;370
1.19.4.2;4.2 Radiosurgery;371
1.19.4.3;4.3 Proton Therapy;372
1.19.4.4;4.4 Radiation Sensitizers;372
1.19.5;5 Chemotherapy for Newly Diagnosed Gliomas;373
1.19.5.1;5.1 Nitrosoureas;373
1.19.5.2;5.2 Temozolomide;373
1.19.5.3;5.3 Pseudoprogression;375
1.19.6;6 Chemotherapy for Recurrent High-Grade Gliomas;375
1.19.6.1;6.1 Bevacizumab;376
1.19.7;7 Anaplastic Oligodendrogliomas and Oligoastrocytomas;376
1.19.7.1;7.1 PCV;377
1.19.7.2;7.2 Temozolomide;378
1.19.8;8 Investigational Therapies;378
1.19.8.1;8.1 Targeted Molecular Therapies;378
1.19.8.2;8.2 Anti-Angiogenic Treatments;381
1.19.8.3;8.3 Other Therapies;382
1.19.9;9 Conclusions and Future Directions;382
1.19.10;Acknowledgement;382
1.19.11;References;383
1.20;Treatment of Malignant Gliomas with Antisense Oligonucleotides;392
1.20.1;1 Introduction;393
1.20.1.1;1.1 Technique and Types of Oligonucleotides;393
1.20.1.2;1.2 Selection of Target Genes for Therapeutic Ablation Using Antisense ODN Strategy;396
1.20.1.3;1.3 Selection of Target Sequences for Therapeutic Ablation by a Antisense Oligonucleotides;397
1.20.2;2 Preclinical Approaches with Antisense ODNS in Gliomas;397
1.20.3;3 Clinical Studies with Antisense ODNs in Human Glioma Patients;399
1.20.3.1;3.1 In Vivo Targeting of Intracellular Signaling Pathways by a PKC-Alpha-Specific S-ODN (Affinitak) in Malignant Gliomas;400
1.20.3.2;3.2 In Vivo Targeting of Extracellular Receptor for IGF-1 in Human Malignant Gliomas;403
1.20.3.3;3.3 In Vivo Targeting of Toll-Like Receptor 9 by CpG-28 S-ODNs in Malignant Gliomas;404
1.20.3.4;3.4 In Vitro and In Vivo Development of TGF-Beta as Target for High-Grade Gliomas;405
1.20.4;4 Conclusion;409
1.20.5;References;410
1.21;Suppression of EGFR Expression by Antisense RNA and RNAi;415
1.21.1;1 Introduction;416
1.21.2;2 Construction of Antisense EGFR RNA and EGFR siRNA Expression Plasmids;417
1.21.3;3 Transfection of Antisense EGFR RNA and EGFR siRNA Expression Plasmids and Detection of EGFR Expression;418
1.21.4;4 Effects of Antisense EGFR RNA and EGFR siRNA on the Viability and Invasive Ability of U251 Cells In Vitro;419
1.21.5;5 Effects of Antisense EGFR RNA and EGFR siRNA on the Glioma Growth In Vivo;421
1.21.6;6 Discussion;424
1.21.7;Acknowledgement;429
1.21.8;References;429
1.22;Brain Tumor Therapy with Antisense Oligonucleotides;433
1.22.1;1 General Aspects;434
1.22.2;2 Targets for Antisense Oligonucleotides in Brain Tumor Therapy;435
1.22.2.1;2.1 Receptor Tyrosine Kinase c-Metc-Met;436
1.22.2.2;2.2 Ras/Raf-KinaseRas/Raf-Kinase;437
1.22.2.3;2.3 Oncogene Bcl-2Bcl-2;437
1.22.2.4;2.4 Insulin-Like Growth Factor Type IInsulin-like growth factor type I;438
1.22.2.5;2.5 Vascular Endothelial Growth FactorVascular Endothelial Growth Factor;439
1.22.2.6;2.6Epidermal growth factor receptor Epidermal Growth Factor Receptor;440
1.22.2.7;2.7 Telomerastelomerase;440
1.22.2.8;2.8 Protein Kinase C AlphaProtein Kinase C alpha;441
1.22.3;3 Antisense in Plasma;442
1.22.4;4 Unspecific, Nonantisense Effectsnon-antisense effects of AON Treatment;443
1.22.5;5 Antisense and BBB;444
1.22.6;6 Administration of Antisense for Brain Tumor Therapy;445
1.22.6.1;6.1 Delivery of AON by Liposomesliposomes;445
1.22.6.2;6.2 AON Attached to Nanoparticlesnanoparticles;446
1.22.6.3;6.3 Direct Administration into the Cerebro-Spinal-Fluid;448
1.22.6.4;6.4 Administration via Convection-Enhanced Deliveryconvection enhanced delivery;449
1.22.6.5;6.5 Antisense as Intranasal Drug;450
1.22.7;7 Antisense Against TGF-beta2;451
1.22.8;8 Antisense for Other Immunological Approachesimmunological approaches;452
1.22.9;9 Conclusion;453
1.22.10;References;453
1.23;Noncoding RNAs in the Development, Function and Pathologies of the Central Nervous System;460
1.23.1;1 Introduction;460
1.23.2;2 Regulatory RNAs;461
1.23.2.1;2.1 NcRNAs in Epigenetic Regulation;463
1.23.2.2;2.2 NcRNAs in the Regulation of Transcription;464
1.23.2.3;2.3 NcRNAs in Posttranscriptional Regulation;465
1.23.3;3 NcRNAs in the Development of Nervous System;466
1.23.4;4 Noncoding RNAs in Diseases Affecting the Nervous System;468
1.23.4.1;4.1 Neurological Diseases;468
1.23.4.2;4.2 Brain Cancer Tumors;470
1.23.5;5 NcRNAs as Therapeutic Targets;472
1.23.6;References;473
1.24;The Non-Coding Oncofetal H19 Gene in Brain Tumors;478
1.24.1;1 H19: An Imprinted Non-coding RNA Gene;480
1.24.2;2 H19 and IGF2 in Developing and Adult Brain;480
1.24.3;3 H19 Tumorigenic Properties are Reactivated During Various Stages of Tumor Development;481
1.24.4;4 H19-IGF2 Locus and Brain Tumors;483
1.24.5;5 Hypoxia and p53 Mutations, Which are Hallmarks of Astrocytomas are Known Determinants of H19 Expression;484
1.24.6;6 H19-DTA/H19-DTA-P4-DTA and H19-siRNAs-Putative Therapeutic Agents Against Brain Tumors;487
1.24.7;References;489
1.25;Index;492