Lu Pharmaceutical Perspectives of Cancer Therapeutics

1. Auflage 2009
ISBN: 978-1-4419-0131-6
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 694 Seiten

covers a wide variety of therapeutic approaches including gene therapy, immunological therapy; cancer vaccines; strategy for solid tumors as well as for hematological cancers; methods to suppress tumor angiogenesis and metastasis; development and utilization of relevant animal models; introduction of new concepts such as cancer stem cells and new technologies, such as DNA and tissue microarrays; and RNA interference. In addition, clinical application, the development of DNA diagnosis biomarkers and cancer prevention, as well as the utilization of imaging in cancer therapy are also discussed. The use of synthetic carriers, such as lipids, polymers, and peptides for delivery and targeting of small molecules, proteins, and nucleic acids to cancer cells in vivo are discussed. also includes cancer therapy modality in surgery, chemotherapy, and radiotherapy, as well as in combination or multi-modality, giving our book a more focused view of cancer therapy.

Autoren/Hrsg.

Lu, Yi

Inhaltsverzeichnis

1;Preface;6
2;About the Editors;8
3;Contents;9
4;Contributors;11
5;Tumor Microvasculature and Microenvironment: Therapeutic Targets for Inhibition of Tumor Angiogenesis and Metastasis;15
5.1;1 Introduction;15
5.2;2 Tumor Microvasculature and Microenvironment;15
5.2.1;2.1 Tumor Microvasculature;15
5.2.2;2.2 Tumor Microenvironment;16
5.3;3 Angiogenesis;18
5.3.1;3.1 Physiological Angiogenesis;18
5.3.2;3.2 Pathological Angiogenesis;18
5.3.3;3.3 Angiogenic Switch;19
5.4;4 Therapeutic Approaches for Inhibition of Tumor Angiogenesis;21
5.4.1;4.1 From the Emerging Concept that Tumor Growth Is Angiogenesis-Dependent to Clinical Trials;21
5.4.2;4.2 Category of Angiogenesis Inhibitors;22
5.4.2.1;4.2.1 Direct Angiogenesis Inhibitors;22
5.4.2.2;4.2.2 Indirect Angiogenesis Inhibitors;22
5.4.2.3;4.2.3 Endogenous Angiogenesis Inhibitors;23
5.4.2.4;4.2.4 Angiogenesis Inhibitors That Block the Signaling Transduction Pathway;23
5.4.2.5;4.2.5 Angiogenesis Inhibitors That Prevent ECM Breakdown;24
5.4.2.6;4.2.6 Miscellaneous Angiogenesis Inhibitors;24
5.4.3;4.3 Anti-angiogenic Therapy and Pharmaceutic Targets;24
5.4.3.1;4.3.1 VEGF as a Therapeutic Target;24
5.4.3.2;4.3.2 bFGF as a Therapeutic Target;26
5.4.3.3;4.3.3 HIF-1 as a Therapeutic Target;26
5.4.3.4;4.3.4 Other Targets for Angiogenesis Inhibition;28
5.4.4;4.4 Gene Therapy and Other Biological Therapeutic Approaches for Anti-angiogenesis;28
5.4.4.1;4.4.1 Gene Therapy Using Angiostatin;28
5.4.4.2;4.4.2 Gene Therapy Target VEGF;29
5.4.4.2.1;p16 Inhibits VEGF-Mediated Angiogenesis In Vitro;29
5.4.4.2.2;p16 InhibitsVEGF-Mediated Angiogenesis In Vivo;31
5.4.4.3;4.4.3 Other Targets and Protein Replacement Therapy for Anti-angiogenesis;33
5.5;5 Tumor Progression, Metastasis, and Their Therapeutic Targets;34
5.5.1;5.1 Angiogenesis as the Prerequisite for Tumor Progression and Metastasis;34
5.5.2;5.2 Therapeutic Targets for Tumor Vasculature;35
5.5.3;5.3 Therapeutic Target for Tumor Microenvironment - Stroma;37
5.5.4;5.4 Therapeutic Target for Hypoxia and HIF-1;38
5.5.5;5.5 Therapeutic Target for Cancer Stem Cells;39
5.6;6 Challenges and Future Prospects;40
5.6.1;6.1 Unsolved Problems;40
5.6.1.1;6.1.1 Resistance to Anti-angiogenesis Therapy;40
5.6.1.2;6.1.2 Toxicity Associated with Anti-angiogenic Drugs;41
5.6.1.3;6.1.3 Lack of Appropriate Animal Models;41
5.6.2;6.2 Future Directions;42
5.6.2.1;6.2.1 Establishment of Reliable Biomarkers;43
5.6.2.2;6.2.2 Target Stroma and Cancer Stem Cells;43
5.6.2.3;6.2.3 Combination Therapy;43
5.6.2.4;6.2.4 Novel Therapies;44
5.6.2.4.1;Anti-neovascular Therapy;44
5.6.2.4.2;Targeting Key Transduction Pathway Kinase;44
5.6.2.4.3;Cancer ‘‘Normalization’’;44
5.6.2.4.4;Discovery of New Drugs by Chemical Genomics;45
5.7;References;45
6;Anticancer Drug Development;62
6.1;1 Introduction;62
6.2;2 Approaches in Anticancer Drug Therapy;63
6.2.1;2.1 Drug Development Paradigms for Molecularly Targeted Agents;63
6.2.1.1;2.1.1 Facilitating Apoptosis;65
6.2.1.2;2.1.2 Inhibiting Metastasis;66
6.2.1.3;2.1.3 Inhibiting Angiogenesis;66
6.2.1.4;2.1.4 Antibodies Against Tumor-Specific Antigens;66
6.2.2;2.2 Pharmacogenetics and Metabolomics;67
6.2.3;2.3 Modulators, Sensitizers, and Supportive Cancer-Care Agents;69
6.3;3 Anticancer Drug Development Process;70
6.3.1;3.1 Historical Background;73
6.3.2;3.2 Discovery of Potential Drug Candidates;73
6.3.3;3.3 Preclinical Evaluation;74
6.3.3.1;3.3.1 Preclinical Efficacy Screening;75
6.3.3.2;3.3.2 Preclinical Toxicity Studies;78
6.3.4;3.4 Clinical Testing;79
6.3.4.1;3.4.1 Dose Escalation Studies;80
6.3.4.2;3.4.2 Inter-patient Variability and Dose Normalization;81
6.3.4.3;3.4.3 Microdosing in Human Clinical Trials;82
6.3.4.4;3.4.4 Drug Combinations and Dosing Strategies;83
6.3.4.5;3.4.5 Adverse Effects and Toxicities of Anticancer Drugs;85
6.3.4.6;3.4.6 Special Patient Populations;86
6.3.4.7;3.4.7 Phase II and III Clinical Trials;87
6.3.4.8;3.4.8 Trial Design;88
6.3.4.9;3.4.9 End Points of Cancer Clinical Trials;89
6.4;4 Potentials and Practices in Anticancer Drug Delivery;90
6.5;5 Regulatory Considerations;96
6.6;6 Conclusions;98
6.7;References;100
7;Tumor-Targeted Macromolecular Drug Delivery Based on the Enhanced Permeability and Retention Effect in Solid Tumor;106
7.1;1 Introduction;106
7.1.1;1.1 Status Quo;106
7.1.2;1.2 Problems;107
7.1.3;1.3 Population Dynamics of Cancer Cells and Recurrence of Cancer;108
7.1.4;1.4 Proof of Evidence and Forward;109
7.2;2 Mechanisms of the EPR Effect;111
7.2.1;2.1 Pathophysiology and Architecture of Neovasculature of Cancer;111
7.2.2;2.2 Factors That Mediate EPR Effect;114
7.2.2.1;2.2.1 Bradykinin (kinin);114
7.2.2.2;2.2.2 Nitric Oxide;114
7.2.2.3;2.2.3 VEGF;117
7.2.2.4;2.2.4 Others;118
7.3;3 Development of EPR Effect: Past and Future;118
7.3.1;3.1 Background;118
7.3.2;3.2 Augmentation of EPR Effect: Development for Future;119
7.3.2.1;3.2.1 Under Angiotensin (AT)-II-Induced Hypertension;119
7.3.2.2;3.2.2 Local Increase of Bradykinin Level by ACE Inhibitor;120
7.3.2.3;3.2.3 By Using Prostacyclin Agonists;120
7.3.2.4;3.2.4 Increasing NO Concentration in Tumor by Use of NO-Releasing Agents;120
7.4;4 Important Issues on Nanomedicine: Intracellular Uptake of Macromolecular Drugs, Drug Release Rate from the Complex, and Drug Resistance;121
7.4.1;4.1 Access to Tumor and Intracellular Uptake, and to the Molecular Target;121
7.4.1.1;4.1.1 Free Drug Diffusion;121
7.4.1.2;4.1.2 Cellular Uptake;122
7.4.1.3;4.1.3 Access to Submolecular Target;122
7.4.2;4.2 Against Multidrug Resistance;123
7.5;5 Recent Developments of Macromolecular Anticancer Agents for Tumor-Targeted Delivery Utilizing EPR Effect: Potential Drugs for Future;123
7.5.1;5.1 OPAXIOtrade, Poly(l-Glutamic Acid)-Paclitaxel Conjugates;123
7.5.2;5.2 NK012, SN-38-Encapsulated Micelles;124
7.5.3;5.3 NK105, Paclitaxel-Encapsulated Micelle;124
7.5.4;5.4 NC6004, Cisplatin-Encapsulated Micelle and MBP-426, Oxaliplatin Containing Transferrin-Coated Stealth Liposomes;124
7.5.5;5.5 Camptothecin Conjugates;125
7.5.6;5.6 PEG- and SMA-Conjugated Zinc Protoporphyrin IX;126
7.6;6 Conclusions;127
7.7;References;127
8;Multidrug Resistance in Solid Tumor and Its Reversal;134
8.1;1 Introduction;134
8.2;2 Multidrug Resistance Mediated by ATP-Binding Cassette (ABC) Transporters;135
8.2.1;2.1 ABC Transporters - Classification, Structure, and Drug Efflux Mechanism;135
8.2.2;2.2 P-glycoprotein (P-gp);138
8.2.3;2.3 Other ABC Transporters Related to MDR;139
8.3;3 Therapeutic Strategies Reversing Multidrug Resistance;140
8.3.1;3.1 MDR Reversal Agents Targeting ABC Transporters;140
8.3.2;3.2 Reversal of MDR with Drug Carrier of Nano- or Micro-meter Size;142
8.3.2.1;3.2.1 Intrinsic MDR Reversal Activities of Drug Carriers;143
8.3.2.2;3.2.2 Encapsulation and Delivery of MDR Reversal Agents;144
8.3.2.3;3.2.3 Delivery of Combinational Therapy or Unconventional Anticancer Agents;145
8.3.2.4;3.2.4 Bypassing Membrane Transporter Resistance Mechanism by Endocytosis;146
8.4;4 New Perspectives on Overcoming Multidrug Resistance in Solid Tumors;150
8.4.1;4.1 Cancer Progenitor/Stem Cells and Multidrug Resistance;150
8.4.2;4.2 Other Molecular Pathways and Multidrug Resistance;151
8.4.3;4.3 Solid Tumors and Multidrug Resistance;152
8.5;5 Conclusion and Future Directions;153
8.6;References;153
9;Targeting of Apoptosis Signaling Pathways and Their Mediators for Cancer Therapy;162
9.1;1 Introduction;162
9.2;2 Apoptosis Pathways;164
9.2.1;2.1 The Extrinsic Pathway;164
9.2.2;2.2 The Intrinsic Pathway;165
9.3;3 Targeting of the Extrinsic Pathway;166
9.4;4 Caspases and Strategies for Targeting Their Activation;168
9.5;5 Inhibitors of Apoptosis as Potential Targets for Therapeutic Intervention;171
9.6;6 The Anti-apoptotic BCL-2 Family of Proteins as Targets for Anti-cancer Strategies;175
9.7;7 P53 and Strategies Targeting Its Functional Activation;181
9.8;8 Novel and Emerging Apoptosis Transducers as Targets for Anti-cancer Strategies;182
9.8.1;8.1 Nur77/TR3;182
9.8.2;8.2 CARP-1/CCAR1;184
9.9;9 Concluding Remarks;188
9.10;References;188
10;Role of Telomerase in Cancer Therapeutics;202
10.1;1 Introduction;202
10.2;2 Human Telomeres Act as a Mitotic Clock;202
10.3;3 Telomerase Extends Cellular Lifespan;203
10.4;4 Telomerase Expression in Normal and Cancerous Tissues;205
10.5;5 Telomerase Inhibitors in Cancer Therapy;206
10.5.1;5.1 Telomerase Inhibition and the Viability of Cancer Cells;206
10.5.2;5.2 GRN163L, a First Telomerase Inhibitor;207
10.5.3;5.3 Clinical and Preclinical Studies of GRN163L;208
10.6;6 Challenges in the Clinical Application of Telomerase Inhibitors;209
10.6.1;6.1 Measuring the Effects on Recurrences After Conventional Therapy;209
10.6.2;6.2 Targeting the Cancer Stem Cells;210
10.6.3;6.3 Impact of Telomerase Inhibitors on Normal Renewal Tissues;211
10.6.4;6.4 Development of Resistance to Antitelomerase Therapy;213
10.6.5;6.5 Development of New Antitelomerase Compounds;213
10.7;7 Concluding Remarks;214
10.8;References;215
11;Polymeric Carriers for Anticancer Drugs;219
11.1;1 Introduction;219
11.2;2 Polymeric Drug Carriers;219
11.2.1;2.1 Conjugates;219
11.2.2;2.2 Dendrimers and Hyperbranched Polymers;220
11.2.3;2.3 Micelles;221
11.2.4;2.4 Nanoparticles;222
11.2.5;2.5 Nanogels;222
11.2.6;2.6 Polymersomes;223
11.2.7;2.7 Depot Systems;224
11.3;3 Solubility;224
11.4;4 Biodistribution;225
11.4.1;4.1 Long Circulation;225
11.4.2;4.2 Distribution Volume;226
11.4.3;4.3 Toxicity Profile;226
11.4.4;4.4 EPR Effect;227
11.5;5 Triggered Release;228
11.5.1;5.1 pH-Responsive Delivery;229
11.5.2;5.2 Temperature-Responsive Delivery;231
11.5.3;5.3 Ultrasound-Responsive Drug Delivery;232
11.5.4;5.4 Enzyme-Responsive Delivery;233
11.6;6 Cytosolic Delivery;234
11.6.1;6.1 Active Targeting;234
11.6.2;6.2 Endosomolysis;236
11.7;7 Multidrug Resistance;238
11.8;8 Challenges;243
11.9;9 Conclusion;244
11.10;References;244
12;Application of Nanobiotechnology in Cancer Therapeutics;256
12.1;1 Introduction;256
12.2;2 Nanotechnology for Detection of Cancer Biomarkers;256
12.2.1;2.1 Basics of Cancer Biomarkers;256
12.2.2;2.2 Nucleoprotein Nanodevices for Detection of Cancer Biomarkers;257
12.3;3 Nanoparticles for Combined Cancer Diagnosis and Therapy;258
12.3.1;3.1 Gold Nanoparticles;258
12.3.2;3.2 Silver Nanoparticles;258
12.3.3;3.3 Quantum Dots;259
12.3.4;3.4 Nanotubes;260
12.3.5;3.5 Multifunctional Nanoparticles;260
12.4;4 Nanotechnology-Based Imaging for Management of Cancer;261
12.4.1;4.1 Nanoparticle CT Scan;261
12.4.2;4.2 Nanoparticles Designed for Dual-Mode Imaging of Cancer;262
12.5;5 Nanobiotechnology-Based Anticancer Drug Development;262
12.6;6 Nanobiotechnology-Based Drug Delivery in Cancer;263
12.7;7 Nanoparticles for Targeted Delivery of Drugs in Cancer;265
12.7.1;7.1 Innovations in Dendrimers for Anticancer Drug Delivery;265
12.7.2;7.2 Nanoparticles for Enhancing Tumor Targeting by Antibodies;266
12.7.3;7.3 Nanocarriers to Improve Cancer-Targeting Therapy;267
12.7.4;7.4 Gold Nanoparticles for Targeted Drug Delivery in Cancer;267
12.7.5;7.5 Carbon Nanotubes for Targeted Drug Delivery to Cancer Cells;268
12.7.6;7.6 Polymersomes for Targeted Cancer Drug Delivery;268
12.7.7;7.7 Polymer Nanoparticles for Targeted Drug Delivery in Prostate Cancer;269
12.7.8;7.8 Use of Nanoparticles for Drug Delivery in Glioblastoma Multiforme;269
12.7.9;7.9 Nanoparticle-Based Anticancer Drug Delivery to Overcome MDR;270
12.8;8 Nanoparticles Adjuncts to Physical Methods of Cancer Therapy;270
12.8.1;8.1 Nanoparticles as Adjuncts to Photodynamic Therapy of Cancer;271
12.8.2;8.2 Ultrasonic Tumor Imaging and Targeted Chemotherapy by Nanobubbles;271
12.8.3;8.3 Nanobomb for Cancer;272
12.8.4;8.4 Thermotherapy of Prostate Cancer Using Magnetic Nanoparticles;272
12.8.5;8.5 Application of Nanoparticles in Boron Neutron Capture Therapy;273
12.9;9 Nanobiotechnology-Based Aids to Cancer Surgery;274
12.9.1;9.1 Lymph Node Mapping in Cancer;274
12.9.2;9.2 Nanotechnology-Based Devices as Aids to the Detection of Cancer During Surgery;275
12.10;10 Nanobiotechnology for the Management of Metastatic Cancer;275
12.11;11 Role of Nanobiotechnology in Personalized Cancer Therapy;275
12.12;12 Concluding Remarks and Future Prospects;276
12.13;References;277
13;Receptor-Mediated Delivery of Proteins and Peptides to Tumors;280
13.1;1 Introduction;280
13.2;2 Protein Expression and Chemical Modifications, Cleavability;280
13.2.1;2.1 Recombinant Fusion Proteins;281
13.2.2;2.2 Chemical Conjugates;281
13.2.3;2.3 Designing the Bond;282
13.3;3 Delivery Strategies;283
13.3.1;3.1 Direct Delivery;283
13.3.2;3.2 PEGylation;283
13.3.3;3.3 Polymers, Scaffolds, Nanoparticles;284
13.4;4 Targeting Strategies;285
13.4.1;4.1 Proteoglycans and Cationic Ligands;286
13.4.2;4.2 Integrins and Other Targets on Tumor Endothelium;287
13.4.3;4.3 Transferrin Receptor;287
13.4.4;4.4 EGF Receptor;289
13.4.5;4.5 Folate Receptor;289
13.4.6;4.6 Other Targeting Strategies;289
13.5;5 Intracellular Fate;290
13.5.1;5.1 Direct Membrane Passage (Protein Transduction);291
13.5.2;5.2 Endosomal Release;291
13.6;6 Protein/Peptide Therapeutics;292
13.6.1;6.1 Membrane-Lytic Peptides;292
13.6.2;6.2 Peptides Influencing Intracellular Functions of Tumor Cells;293
13.6.3;6.3 Ribosome-Inactivating Proteins (RIP);293
13.6.4;6.4 Ribonucleases;294
13.6.5;6.5 Bacterial Toxins;295
13.6.6;6.6 Therapeutic Antibodies;295
13.7;7 Clinical Applications and Challenges of Protein and Peptide Therapeutics;297
13.8;8 Conclusions and Future Directions;299
13.9;References;300
14;Protein Transduction Domain-Mediated Delivery of Anticancer Proteins;307
14.1;1 Introduction;307
14.2;2 PTD as a Transducer of Macromolecules into Living Cells;308
14.3;3 Characteristics and Categories of PTD;309
14.4;4 Mechanism of PTD-Mediated Protein Transduction into Living Cells;310
14.5;5 Kinetics and Tissue Distribution of PTD-Fused Protein in Living Animals;312
14.6;6 Development of PTD-Mediated Anticancer Protein Drugs;312
14.6.1;6.1 Application of a HIF-1alpha ODD Domain; Development of Hypoxia-Targeting Protein Drugs;314
14.6.2;6.2 Restoration and Activation of p53 Function;316
14.6.3;6.3 Modification of Apoptotic Pathway;318
14.6.4;6.4 Modification of IGF-I Signaling Pathway;320
14.6.5;6.5 Modification of ErbB2 (HER-2/neu) Expression;320
14.6.6;6.6 Application to Dendritic Cell (DC) Vaccines;321
14.6.7;6.7 PTD-Mediated Modulation of Deregulated Cell Cycle of Cancer Cells;321
14.6.8;6.8 Specific Delivery of PTD-Conjugated Macromolecules to Cancer Cells;323
14.7;7 Conclusions and Perspectives;323
14.8;References;324
15;Pharmaceutical Perspectives of Cancer Therapeutics: Current Therapeutic Uses of Monoclonal Antibodies;330
15.1;1 Introduction;330
15.2;2 History;331
15.3;3 Antibody Structure and Function;333
15.3.1;3.1 Antibody Structure;333
15.3.2;3.2 Antibody Production;335
15.3.3;3.3 Antibody Function;337
15.3.3.1;3.3.1 Targeting Ligands and Receptors;337
15.3.3.2;3.3.2 Recruitment of Host Immune Functions;338
15.3.3.2.1;FcgammaR and Fc Interactions;338
15.3.3.2.2;ADCC ;338
15.3.3.2.3;CMC;339
15.3.3.3;3.3.3 Prior to Delivery of Lethal Payload;339
15.4;4 Clinical Uses of Monoclonal Antibodies;340
15.4.1;4.1 Nontherapeutic Uses of Monoclonal Antibodies;340
15.4.2;4.2 Therapeutic Uses of Antibodies in Other Fields;342
15.4.3;4.3 Therapeutic Uses of Antibodies in Oncology;342
15.4.3.1;4.3.1 Hematologic Malignancies;346
15.4.3.1.1;Rituximab;346
15.4.3.1.2;Yttrium-90 Ibritumomab Tiuxetan and Iodine-131 Tositumomab;347
15.4.3.1.3;Gemtuzumab Ozogamicin;350
15.4.3.1.4;Alemtuzumab;350
15.4.3.2;4.3.2 Solid Tumors: ;351
15.4.3.2.1;Trastuzumab;351
15.4.3.2.2;Cetuximab;353
15.4.3.2.3;Panitumumab;355
15.4.3.2.4;Bevacizumab;355
15.4.4;4.4 Characterizing ‘‘Targeted Therapy’’: Comparing Monoclonal Antibodies and Small Molecule Kinase Inhibitors;358
15.5;5 Toxicities and Limitations of Monoclonal Antibodies;359
15.5.1;5.1 Infusion Reactions;359
15.5.2;5.2 Drug Delivery;360
15.6;6 Areas of Current and Future Development;361
15.6.1;6.1 Antibody Engineering;361
15.6.2;6.2 Targets;361
15.6.3;6.3 Economics;363
15.7;References;364
16;Cancer Vaccines;373
16.1;1 Introduction;373
16.2;2 Cell-Based Vaccines;375
16.2.1;2.1 Adoptive T Cell Transfer (ACT);375
16.2.1.1;2.1.1 T Cell Differentiation Status;375
16.2.1.2;2.1.2 T Cell Subtype;376
16.2.1.3;2.1.3 Improving ACT by Lymphodepletion and IL-2 Treatment of Recipients;376
16.2.1.4;2.1.4 Modification of Transferred T Cells or the Host Environment;378
16.2.2;2.2 Dendritic Cell Vaccines;379
16.2.2.1;2.2.1 Ex Vivo Generation of Autologous DC;380
16.2.2.2;2.2.2 Antigen Loading In Vitro;381
16.2.2.2.1;Exogenous Antigens;381
16.2.2.2.2;Endogenous Antigens;382
16.2.2.3;2.2.3 Delivery of DC Vaccines;383
16.2.3;2.3 Tumour Cell: DC Hybrids;383
16.3;3 Antigen Vaccines;383
16.3.1;3.1 Peptide- and Protein-Based Vaccines, Adjuvants;383
16.3.2;3.2 Recombinant Viral Vector Vaccines;385
16.4;4 Immune Response Modifiers;385
16.4.1;4.1 Adjuvants;386
16.4.2;4.2 Cytokines;387
16.4.3;4.3 Antibodies and Ligands with Immunological Targets;388
16.5;5 Combination of Cancer Vaccines with Chemo- and Radiotherapy;389
16.5.1;5.1 Combined Chemo-immunotherapy;389
16.5.2;5.2 Combined Radio-immunotherapy;391
16.6;6 Ongoing Phase III Cancer Immunotherapy Trials;393
16.6.1;6.1 Cancer Vaccines;393
16.6.1.1;6.1.1 Sipuleucel-T (APC8015);393
16.6.1.2;6.1.2 Stimuvax;394
16.6.1.3;6.1.3 TroVax;394
16.6.1.4;6.1.4 Prostvac (TM);395
16.6.1.5;6.1.5 GVAX;395
16.6.1.6;6.1.6 Lucanix;396
16.6.1.7;6.1.7 Telovac (GV1001);396
16.6.2;6.2 Biological Therapies;397
16.6.2.1;6.2.1 Oncophage;397
16.6.2.2;6.2.2 Ipilimumab;398
16.7;7 Summary;398
16.8;Abbreviations;399
16.9;References;400
17;RNA Interference for Cancer Therapy;406
17.1;1 Introduction;406
17.2;2 RNA Interference Mechanism and Limitations for In Vivo Application;407
17.2.1;2.1 Mechanism of RNAi;407
17.2.2;2.2 siRNA Design;409
17.2.3;2.3 siRNA Versus shRNA;410
17.2.4;2.4 Virus-Based shRNA Expression Vector;412
17.2.5;2.5 Limitations of siRNA Therapeutic Application;413
17.3;3 Screening for Therapeutic Targets in Malignancy;416
17.3.1;3.1 Gene KnockDown Cells;417
17.3.2;3.2 Transfected Cell Array;418
17.3.3;3.3 RNAi Barcode Screens;419
17.4;4 siRNA Gene Targets Involved in Carcinogenesis;421
17.4.1;4.1 Genes Involved in Tumorgenesis;421
17.4.2;4.2 Genes Involved in Tumor-Host Interactions;421
17.5;5 Nonviral Delivery Systems for siRNA;425
17.5.1;5.1 Components of the Delivery System for siRNA;425
17.5.2;5.2 Cationic Lipids and Polymers;427
17.5.2.1;5.2.1 Cationic Lipid;427
17.5.2.2;5.2.2 Poly(ethyleneimine);427
17.5.2.3;5.2.3 Chitosan;428
17.5.2.4;5.2.4 Dendrimer;429
17.5.3;5.3 Cell-Penetrating Peptide;430
17.5.4;5.4 Cyclodextrin;431
17.5.5;5.5 Atelocollagen;432
17.6;6 Ligand-Targeted Delivery of siRNA to Tumor Cells;433
17.6.1;6.1 Antibodies;433
17.6.2;6.2 Transferrin;434
17.6.3;6.3 Folic Acid;435
17.6.4;6.4 Arginine-Glycine-Aspartic Acid (RGD) Peptide;436
17.6.5;6.5 Aptamer;436
17.7;7 Perspectives;438
17.8;References;439
18;MicroRNAs as Therapeutic Targets for Cancer;448
18.1;1 Introduction;448
18.2;2 Gene Regulation;449
18.2.1;2.1 Type of Nucleic Acids Used for Gene Modulation;449
18.2.2;2.2 RNA Interference;450
18.2.3;2.3 miRNA Versus siRNA;450
18.3;3 Identification of miRNA Targets;452
18.4;4 Roles of miRNAs in Cancer;454
18.4.1;4.1 miRNA Profile in Cancer;454
18.4.2;4.2 miRNA Roles in Tumorigenesis;459
18.4.3;4.3 miRNAs as Oncogenes;462
18.4.4;4.4 miRNAs as Tumor Suppressors;464
18.5;5 miRNA for Diagnosis and Prognosis in Cancer Patients;466
18.6;6 Therapeutic Implication of miRNAs;467
18.6.1;6.1 miRNA Inhibition;467
18.6.1.1;6.1.1 miRNA Inhibition Using Modified Antisense Oligonucleotide;468
18.6.1.2;6.1.2 Targeting miRNAs Processing Using Antisense Oligonucleotide;471
18.6.2;6.2 miRNA Replacement;471
18.7;7 Concluding Remarks;472
18.8;References;473
19;Targeted Therapies for Malignant Brain Tumors;482
19.1;1 Introduction;482
19.2;2 Current and Novel Chemotherapies for Brain Tumors;483
19.2.1;2.1 Targeting Growth Factor Signaling Axes in Brain Tumors;484
19.2.1.1;2.1.1 Targeting Cell Proliferation: EGFR Axis;485
19.2.1.2;2.1.2 Targeting Angiogenesis: VEGFR Axis;486
19.2.1.3;2.1.3 Intracellular Effectors in Growth Cascades;486
19.3;3 Barriers in the CNS and Novel Approaches in Delivering Drugs to Brain Tumors;487
19.3.1;3.1 Inhibiting Drug Transporters;490
19.3.2;3.2 Invasive Drug Delivery to Brain Tumors;490
19.3.2.1;3.2.1 CSF Delivery;491
19.3.2.2;3.2.2 Blood-Brain Barrier Disruption and Intra-Arterial Delivery;491
19.3.2.3;3.2.3 Intratumoral and Intracavitary Delivery;492
19.3.2.3.1;Polymer-Laden Drug Delivery;492
19.3.2.3.2;Convection-Enhanced Delivery;494
19.4;4 Targeted Biological Therapy for Brain Tumors;496
19.4.1;4.1 Antibody-Based Drugs and Recombinant Proteins: Active Targeting of Brain Tumors;496
19.4.2;4.2 Vector Therapy;498
19.4.2.1;4.2.1 Non-Viral Vector Delivery;498
19.4.2.2;4.2.2 Viral Vector Delivery;500
19.4.3;4.3 Immunotherapy;502
19.4.3.1;4.3.1 Non-Cell-Based Immunotherapy;505
19.4.3.1.1;Generating Tumor-Specific Immunity: Peptide Vaccines;505
19.4.3.1.2;Immunomodulatory Strategies;506
19.4.3.2;4.3.2 Cell-Based Immunotherapy;507
19.4.3.2.1;Dendritic Cell-Based Strategies;507
19.4.3.2.2;Adoptive Transfer Immunotherapy;509
19.4.3.2.3;Lymphokine-Activated Killer Cells;509
19.5;5 Conclusions;512
19.6;References;513
20;The Complexity of the HIF-1-Dependent Hypoxic Response in Breast Cancer Presents Multiple Avenues for Therapeutic Intervention;527
20.1;1 Introduction to the HIF-1alpha Pathway and Its Relevance to Breast Cancer;527
20.1.1;1.1 Relevance of Hypoxia to Tumorigenesis;527
20.1.2;1.2 Overview of the HIF-1 Pathway;529
20.1.3;1.3 Use of Mouse Models to Understand HIF-1 Function;531
20.1.3.1;1.3.1 Conditional Knockout of HIF-1alpha During Normal Mammary Gland Development;531
20.1.3.2;1.3.2 Conditional Knockout of HIF-1alpha in a Mouse Model of Breast Cancer Reveals that HIF-1alpha Is a Key Mediator of Metastasis;532
20.1.3.3;1.3.3 Limitations of Animal Models;533
20.1.4;1.4 Oxygen-Independent, Growth Factor Receptor Tyrosine Kinase Regulation of HIF-1: A Key Role for the EGFR Family?;534
20.1.5;1.5 HIF-1alpha and Angiogenesis;536
20.1.5.1;1.5.1 VEGF Therapies and Intratumor Hypoxia;536
20.1.5.2;1.5.2 Relevance of Angiogenesis to Breast Cancer;536
20.1.5.3;1.5.3 Role of HIF-1alpha in Angiogenesis Is Microenvironment-Context Specific;537
20.1.6;1.6 HIF-1alpha and Tumor Metabolism;537
20.1.6.1;1.6.1 HIF-1alpha Is a Key Regulator of Glycolytic Energy Production;538
20.1.6.2;1.6.2 Importance of Glycolysis in the Breast;538
20.1.7;1.7 HIF-1alpha and Metastasis;538
20.1.7.1;1.7.1 HIF-1alpha Targets Are Key Mediators of Metastasis;539
20.1.7.2;1.7.2 Role of HIF-1alpha in EMT;540
20.1.7.3;1.7.3 HIF-1alpha and Osteopontin Regulation, a Plasma Biomarker of Poor Prognosis;540
20.1.8;1.8 Hypoxia, HIF-1, and Cancer Stem Cells;541
20.1.8.1;1.8.1 Impact of Hypoxia/HIF-1 on Cancer Stem Cells;541
20.1.8.2;1.8.2 Connections Between Hypoxia, HIF, and Cancer Stem Cell Behavior;541
20.1.8.3;1.8.3 Overview of Profiling for Breast Cancer Stem Cells;542
20.1.8.4;1.8.4 Relevance of Notch and Wnt/beta -Catenin Pathways in Stem Cell Biology;543
20.1.8.5;1.8.5 Interactions Between NOTCH, HIF-1alpha, and FIH-1 in Cancer Cells;543
20.1.8.6;1.8.6 The Wnt/beta -Catenin Pathway in Breast Cancer and Interactions Between HIF-1alpha and beta -Catenin in Hypoxic Cancer Cells;544
20.2;2 HIF-1 and Therapeutic Resistance in Breast Cancer;545
20.2.1;2.1 HIF-1alpha and Radiation Resistance;545
20.2.2;2.2 HIF-1alpha and Chemotherapy Resistance;546
20.2.3;2.3 HIF-1alpha and the Estrogen Receptor;546
20.3;3 Therapeutic Strategies That Modulate HIF-1alpha;547
20.3.1;3.1 Overview of HIF-1alpha Inhibitors;547
20.3.1.1;3.1.1 Inhibitors of Receptor Tyrosine Kinases and the PI3K/Akt/mTOR Pathway;547
20.3.1.2;3.1.2 DNA Modification Inhibitors;548
20.3.1.3;3.1.3 Inhibitors of Hsp90;548
20.3.1.4;3.1.4 Other Small Molecule HIF Inhibitors;549
20.3.1.5;3.1.5 Glycolytic Inhibitors;549
20.3.2;3.2 Limitations of Current Anti-HIF Therapies;550
20.4;4 Summary: Challenges for the Future;550
20.5;References;552
21;Cancer Stem Cells: Potential Mediators of Therapeutic Resistance and Novel Targets of Anti-cancer Treatments;565
21.1;1 Introduction;565
21.2;2 Cancer Stem Cells;566
21.2.1;2.1 Definition;566
21.2.2;2.2 Identification;569
21.2.2.1;2.2.1 Marker-Based Analysis;569
21.2.2.2;2.2.2 Side Population (SP) Analysis;570
21.2.2.3;2.2.3 Sphere Formation Assays;570
21.2.2.4;2.2.4 Label-Retaining Properties;570
21.2.2.5;2.2.5 Clonal Assay;571
21.2.3;2.3 CSC Niche;571
21.3;3 Chemotherapy and Drug Resistance;572
21.4;4 CSCs in Chemoresistance and Radioresistance;573
21.5;5 Novel Cancer Therapies by Targeting CSCs and Their Microenvironment;574
21.5.1;5.1 CSC-Targeted Therapy;575
21.5.1.1;5.1.1 Anti-ABC Transporters;575
21.5.1.2;5.1.2 Inhibiting DNA Repair Capacity;575
21.5.1.3;5.1.3 Promoting Apoptosis;576
21.5.1.4;5.1.4 Sensitizing Dormant CSCs to Anti-proliferative Agents;576
21.5.1.5;5.1.5 Inducing CSCs into Dormancy;576
21.5.1.6;5.1.6 Promoting Differentiation of CSCs;577
21.5.2;5.2 CSC Niche-Targeted Therapy;577
21.5.3;5.3 Combination Therapy Strategy;578
21.6;6 Conclusions and Future Directions;579
21.7;References;580
22;Image-Guided Photodynamic Cancer Therapy;586
22.1;1 Introduction;586
22.2;2 Photodynamic Therapy;586
22.3;3 Bifunctional Polymer Conjugates;589
22.4;4 Non-invasive Imaging of Pharmacokinetics of Polymer Conjugates;592
22.5;5 Cancer Treatment with Contrast-Enhanced MRI-Guided Photodynamic Therapy;597
22.6;6 Non-invasive Assessment of Tumor Response with Dynamic Contrast-Enhanced MRI;598
22.7;7 Concluding Remarks;600
22.8;References;600
23;Functional Imaging of Multidrug Resistance and Its Applications;605
23.1;1 Introduction;605
23.2;2 ABC Transporters and Drug Resistance;606
23.2.1;2.1 Clinical Relevance;608
23.2.2;2.2 Therapeutic Strategies to Overcome Drug Resistance;608
23.2.3;2.3 Detection of ABC Transporters in Tumors;610
23.2.4;2.4 Functional Assays Using Radiolabeled Molecules;610
23.3;3 Functional Imaging of MDR;611
23.3.1;3.1 SPECT Imaging Agents;611
23.3.1.1;3.1.1 [99mTc]Sestamibi;611
23.3.1.1.1;Clinical Studies with [99mTc]MIBI;620
23.3.1.2;3.1.2 [99mTc]Tetrofosmin;628
23.3.1.2.1;Clinical Studies with [99mTc]Tetrofosmin;629
23.3.2;3.2 PET Imaging Agents;630
23.3.2.1;3.2.1 11C-Labeled Compounds;630
23.3.2.2;3.2.2 18F-Labeled Compounds;633
23.3.2.3;3.2.3 67Ga/68Ga-Radiopharmaceuticals;637
23.4;4 Conclusions;638
23.5;References;640
24;Gene Expression Microarrays in Cancer Research;648
24.1;1 Introduction;648
24.2;2 A DNA Microarray Technology Overview;648
24.2.1;2.1 Oligonucleotide Array Dominant Technology Platforms;649
24.2.1.1;2.1.1 cDNA Arrays;650
24.2.1.2;2.1.2 Oligonucleotide Arrays;650
24.2.2;2.2 Reliability and Reproducibility Issues in DNA Microarray Assays;651
24.2.3;2.3 Experimental Design for Microarray Assays;652
24.2.3.1;2.3.1 Biological and Technical Replication;652
24.2.3.2;2.3.2 Sample Pooling;653
24.2.3.3;2.3.3 Confounding Factors and Bias;653
24.2.3.4;2.3.4 Special Considerations with Two-Channel Microarrays;653
24.2.4;2.4 Data Analysis;654
24.2.4.1;2.4.1 Primary Data Analysis;654
24.2.4.1.1;Data Preprocessing;654
24.2.4.1.2;Differentially Expressed Gene Identification;655
24.2.4.1.3;Classification;656
24.2.4.2;2.4.2 Integrated Data Analysis;656
24.2.4.2.1;Meta-Analysis;656
24.2.4.2.2;Modular/Pathway Analysis;657
24.2.4.2.3;Gene Network Analysis;658
24.2.5;2.5 Data Validation;659
24.3;3 Characterization of Cancer Using Expression Signatures;659
24.3.1;3.1 Tumor Individuality;660
24.3.2;3.2 Molecular Classification of Cancer;660
24.3.3;3.3 Common Transcriptional Programs for Tumor Development;661
24.3.4;3.4 Cancer Prognostic Prediction;663
24.3.5;3.5 Cancer Therapeutic Response Prediction;663
24.4;4 Toward Systems Biology of Cancer;664
24.4.1;4.1 System Control;665
24.4.2;4.2 Fail-Safe (Alternative);666
24.4.3;4.3 Modularity;666
24.4.4;4.4 Decoupling;667
24.5;5 Drug Discovery Through Signature Screening;667
24.5.1;5.1 Signature Screening in Laboratory: Gene Expression-Based, High-Throughput Screening;667
24.5.2;5.2 Signature Screening In Silico-Connectivity Map;669
24.5.3;5.3 Module Screening In Silico-Module Map;670
24.6;6 Future Directions and Conclusions;670
24.7;References;672
25;Clinical Trials and Translational Applications in Cancer Therapy;676
25.1;1 Introduction;676
25.2;2 Classic Clinical Trial Design for New Cancer Drugs;676
25.2.1;2.1 Phase 0 Trials: Exploratory Studies;677
25.2.2;2.2 Phase I Trials: Toxicity, Pharmacokinetics, and Pharmacodynamic Studies;677
25.2.3;2.3 Phase II Trials: Response Rates and Toxicity Studies;678
25.2.4;2.4 Phase III Trials: Efficacy Studies;679
25.2.5;2.5 Phase IV Trials: Long-Term Toxicity Studies;680
25.3;3 Study Endpoints;680
25.3.1;3.1 Common Endpoints;680
25.3.2;3.2 Response Evaluation Criteria in Solid Tumors (RECIST);681
25.3.3;3.3 Survival;681
25.4;4 Eligibility;681
25.4.1;4.1 Defining the Study Population;681
25.4.2;4.2 Inclusion and Exclusion Criteria;681
25.5;5 Statistical Considerations;682
25.5.1;5.1 Randomized Control Trials (RCTs);682
25.5.2;5.2 Sample Size, Power, and Significance;682
25.5.3;5.3 The Null Hypothesis;683
25.6;6 Ethical Considerations;684
25.6.1;6.1 The Ethical Basis for Clinical Trials;684
25.6.2;6.2 Special and Vulnerable Populations;684
25.7;7 Challenges and Future Prospects for Translation of Clinical Trials;685
25.8;References;685
26;Index;687