| Foreword | 6 |
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| Contents | 8 |
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| Contributors | 10 |
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| Chapter 1: RNAi: A New Paradigm in Cancer Gene Therapy | 16 |
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| 1 Introduction | 17 |
| 2 Clinical Significance of the RNAi Processing Machinery | 18 |
| 3 Clinical Application of RNAi | 19 |
| 4 Off-Target Effects | 23 |
| 5 RNAi Imaging: Biodistribution and Target Modulation | 25 |
| 6 Development of RNAi-Based Gene Therapy: Clinical Trials | 26 |
| 7 Future Development | 27 |
| References | 28 |
| Chapter 2: Gene-Based Therapy for Cancer: Brain Tumors | 31 |
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| 1 Introduction | 31 |
| 2 Replication-Deficient Viral Vectors | 32 |
| 2.1 Ad-p53 | 32 |
| 2.2 HSVtk/GCV Gene Therapy | 34 |
| 3 Oncolytic Viruses | 35 |
| 3.1 Adenovirus | 35 |
| 3.1.1 ONYX-015 | 36 |
| 3.1.2 Delta-24-RGD | 37 |
| 3.2 Herpes Simplex Virus-1 | 38 |
| 3.3 Reovirus | 39 |
| 3.4 Measles Virus | 40 |
| 3.5 Newcastle Disease Virus | 40 |
| 4 Future Perspectives | 41 |
| References | 42 |
| Chapter 3: Gene Therapy of Prostate Cancer | 47 |
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| 1 Introduction | 47 |
| 2 Enzyme/Prodrug Gene Therapy | 48 |
| 2.1 Enzyme/Prodrug Gene Therapy Using Replication-Defective Adenoviruses | 48 |
| 2.2 Enzyme/Prodrug Gene Therapy Using Replication-Competent Adenoviruses | 50 |
| 3 Vaccine-Based Gene Therapy Strategies | 55 |
| 3.1 Poxvirus-Based Vaccines | 55 |
| 3.2 Cell-Based Vaccines | 57 |
| 4 Replication-Competent, Oncolytic Adenoviruses | 58 |
| 5 Summary | 59 |
| References | 60 |
| Chapter 4: siRNA Versus shRNA for Personalized Cancer Therapy: Mechanisms and Applications | 64 |
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| 1 Introduction | 65 |
| 2 Personalized Cancer Therapy | 65 |
| 3 Mechanisms of RNAi | 66 |
| 3.1 siRNA | 66 |
| 3.2 shRNA | 68 |
| 3.2.1 Bifunctional shRNA | 69 |
| 4 SiRNA Versus shRNA | 70 |
| 4.1 Comparative Efficacy | 70 |
| 4.2 Dicer/Drosha Expression in Cancer and RNAi Effector Suitability | 70 |
| 4.3 Off-Target Effects | 71 |
| 4.3.1 Specific Off-Target Effects | 71 |
| 4.3.2 Nonspecific Off-Target Effects | 71 |
| 5 Delivery Strategies for Clinical Translation | 72 |
| 6 Conclusions | 73 |
| References | 73 |
| Chapter 5: Tumor Suppressor Gene Therapy | 76 |
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| 1 Tumor Suppressor Gene Therapy | 77 |
| 2 Gene Replacement by p53 in Laboratory Studies | 78 |
| 3 Clinical Trials of p53 Gene Replacement | 79 |
| 4 Gene Replacement in Combination with DNA Damaging Agents | 81 |
| 5 Clinical Trials of Tumor Suppressor Gene Replacement Combined with Chemotherapy | 82 |
| 6 Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy | 82 |
| 7 Systemic Gene Therapy for Metastases | 84 |
| 8 Summary and Conclusions | 87 |
| References | 88 |
| Chapter 6: Targeted Oncolytic Adenovirus for Human Cancer Therapy: Gene-Based Therapies for Cancer | 92 |
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| 1 Introduction | 92 |
| 2 Telomerase Activity for Transcriptional Cancer Targeting | 94 |
| 3 Telomerase-Specific Oncolytic Adenovirus for Cancer Therapeutics | 94 |
| 3.1 Structure of hTERT Promoter-Driven Oncolytic Adenovirus | 94 |
| 3.2 Preclinical Studies of hTERT Promoter-Driven Oncolytic Adenovirus | 95 |
| 3.3 Immune Activation by hTERT Promoter-Driven Oncolytic Adenovirus | 98 |
| 4 Telomerase-Specific Oncolytic Adenovirus for Cancer Diagnostics | 99 |
| 4.1 hTERT Promoter-Driven GFP-Expressing Oncolytic Adenovirus | 99 |
| 4.2 Ex vivo Imaging of Human Circulating Tumor Cells with GFP Fluorescence | 99 |
| 4.3 In Vivo Imaging of Lymph Node Micrometastasis with GFP Fluorescence | 100 |
| 5 Clinical Application of Telomerase-Specific Oncolytic Adenovirus | 101 |
| 6 Conclusions and Perspectives | 101 |
| References | 103 |
| Chapter 7: Gene Therapy for Malignant Pleural Mesothelioma | 107 |
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| 1 Background | 107 |
| 2 MPM as a Target for Gene Therapy | 108 |
| 3 Preclinical Investigations | 108 |
| 3.1 Induction of Apoptosis | 108 |
| 3.2 Antiangiogenesis | 110 |
| 3.3 Suicide-Gene Therapy | 110 |
| 3.4 Immunogene Therapy | 112 |
| 3.5 Replicating, Tumor-Selective Oncolytic Viral Vectors | 113 |
| 4 Clinical Investigations | 114 |
| 4.1 Suicide Gene Therapy | 114 |
| 4.2 Cytokine Gene Therapy | 116 |
| 5 Summary | 118 |
| References | 119 |
| Chapter 8: Mesenchymal Stem/Stromal Cells as Cellular Vehicles for Tumor Targeting | 124 |
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| 1 Introduction | 124 |
| 1.1 Tumor Cell-Centric View on Tumor Development | 124 |
| 1.2 Stroma is a Common Ground for Numerous Cancers | 125 |
| 1.3 Role of Fibroblasts and Stromal Precursors | 128 |
| 2 Tropism of MSC for Wounds and Tumors | 129 |
| 2.1 But Which Cell in the Stroma to Target | 130 |
| 2.2 Rationale for Targeting Tumors Using Stromal Precusor Cells | 131 |
| 2.3 Migratory Factors | 132 |
| 3 Use of Stem Cells as Cellular Vehicles to Target Tumors | 133 |
| 3.1 MSC as Cell Vehicles for Cancer | 135 |
| 4 Interferons | 136 |
| 5 Interleukins | 137 |
| 6 Conditionally Replication Adenoviral Vectors | 138 |
| 7 Chemokines and Growth Factor Antagonists | 139 |
| 8 Suicide Genes | 139 |
| 9 Tumor Necrosis Factor-Related Apoptosis Inducing Ligand | 140 |
| 10 Alternative Mesenchymal Tissues as Sources for Anticancer Therapies | 140 |
| 11 Conclusions | 141 |
| References | 142 |
| Chapter 9: Retargeting Adenovirus for Cancer Gene Therapy | 151 |
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| 1 Introduction | 151 |
| 2 Adenovirus Life Cycle and Genomic Organization | 152 |
| 3 Strategies for Ad-Based Cancer Gene Therapy | 153 |
| 3.1 Cancer Gene Therapy Vectors | 153 |
| 3.2 Immunotherapy Vectors | 153 |
| 3.3 Virotherapy Vectors | 154 |
| 4 A Need for Retargeted Adenovirus-Based Vectors for Cancer Therapy | 154 |
| 5 Transductional Targeting | 155 |
| 5.1 Adapter-Based Targeting | 155 |
| 5.2 Genetic Modifications | 156 |
| 6 Cellular Control of Ad Vecto
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