Macromolecular Anticancer Therapeutics (eBook)

L. Harivardhan Reddy, Patrick Couvreur (Herausgeber)

eBook Download: PDF

2010 | 2010
X, 500 Seiten
Springer New York (Verlag)
978-1-4419-0507-9 (ISBN)

Infos

In spite of the development of various anticancer drugs, the therapy of cancer has remained challenging for decades. The current therapy of cancer is overwhelmed because of the inability to deliver therapeutics to all regions of a tumor in effective therapeutic concentrations, intrinsic or acquired resistance to the treatment with currently available agents via genetic and epigenetic mechanisms, and toxicity. As a result, cancer therapy using conventional therapeutics and different types of treatment regimens using this therapeutics has not led to a convincing survival benefit of the patients. In this context, Macromolecular therapeutics offer several advantages over conventional low molecular therapeutics by various ways such as, enable the use of larger doses of these agents by limiting the toxicity, by enhanced permeability and retention into tumors, by tumor targeting using tumor-specific antibodies, by specific inhibition of oncogenes using anticancer oligonucleotides etc. Cancer treatment using this macromolecular therapeutics has considerably improved the survival benefit for patients. As a result, various macromolecular therapeutics are already commercialized or are under clinical development. Although we are far from a real magic bullet today, looking at the pace of research and current success in this field of macromolecular therapeutics, it appears that we are approaching a magic bullet for the efficient treatment of cancer. Thus, we believe that the subject of this book is very timely, and that the book will fill an unmet need in the market.

This book is unique and assembles various types and aspects of macromolecular anticancer therapeutics for cancer therapy in one shell and conveys the importance of this interdisciplinary field to the broad audience. Thus, in a nutshell, this book details the basics of cancer, and various therapeutic strategies such as those based on macromolecular therapeutics hence can become an important reference for practitioners, oncologists, medical pharmacologists, medicinal chemists, biomedical scientists, experimental pharmacologists, pharmaceutical technologists, and particularly it can essentially become a handbook of macromolecular therapeutics for cancer therapy for graduates, post-graduates and Ph.D. students in these fields.

L. Harivardhan Reddy is Head of Nanovectors group at Sanofi-aventis, France. He completed Ph.D. in Pharmaceutics and Drug delivery in 2005 from The M.S. University of Baroda, India. He has worked for 4 years in two popular pharmaceutical companies (Sun Pharmaceutical Industries Ltd., and Aristo Pharmaceuticals Ltd.) in India, on drug delivery applications. He worked for 3 years (2005-2008) with anticancer drug delivery specialist Prof. Patrick Couvreur in CNRS lab at Université Paris-Sud, Chatenay-Malabry, France. He is an inventor of 3 patents belonging to macromolecular therapeutics and drug delivery. He has published, as an author and co-author, more than 60 publications in various reputed journals. He is also a reviewer for more than 15 journals of the fields of biomacromolecules, drug delivery, cancer therapy, and pharmacology. He is a member of The European Association for Cancer Research. His principal research interests are supramolecular lipidic prodrug nanomedicines and nanotherapeutics for cancer.

 

Patrick Couvreur is a Full Professor of Pharmacy at the University Paris-Sud, France, and holder of the chair of 'Innovation Technologique' (2009-2010) at the prestigious 'Collège de France'. He is a member of the Academy of Technologies (France), of the Academy of Pharmacy (France) and corresponding member of the Royal Academy of Medicine (Belgium). Prof. Patrick COUVREUR's contributions in the field of drug delivery and targeting are highly recognized and respected around the world. Patrick COUVREUR performed a pioneer work together with Peter SPEISER, and demonstrated for the first time in 1977 that nanoparticles may be used as intracellular carriers for compounds which don't diffuse spontaneously into cells. Patrick COUVREUR's research is primarily on polymer-based and metallic-based nanomedicines, surface engineered nanosystems, and also focuses on lipid-based nanocarriers. He has published as an author and co-author, 341 publications, 109 review articles and book chapters, 6 books as editor, 50 patents, and 193 invited and plenary lectures at national and international congresses. He has received Pharmaceutical Sciences World Congress Award (2004), the 'Marie-Maurice Janot Lecture' (2008) and above all the prestigious 'Host Madsen Medal' (2007) in honour of his outstanding research achievements. He is a Field Editor of 'Pharmaceutical Research', European Editor of the 'Journal of Nanoparticles Research', and is a reviewer of more than 15 high reputed journals in the fields of Drug delivery, cancer research, macromolecules, physical chemistry etc. He is acting or acted as Board of Governors of the Controlled Release Society (CRS), Board of APGI, Expert Member of the Board of Pharmaceutical Sciences, International Pharmaceutical Federation (FIP). His exceptional research has led to two start-up companies BIOALLIANCE and MEDSQUAL dealing with novel therapeutics, in France.

Inhalt

Foreword 6
General References 7
Preface 8
Editors Biography 11
Contents 13
Contributors 15
Part I Classification, Opportunities and Challenges 19
1 Classification of Anticancer Drugs Based on TherapeuticTargets 20
1.1 Introduction 22
1.2 Drugs Directed Against Tumour DNA 24
1.2.1 Drugs Directly Affecting DNA Helix: Alkylators 24
1.2.2 Inhibitors of DNA-Related Proteins 27
1.2.2.1 Topoisomerases Inhibitors 27
1.2.2.2 Antimetabolites 28
1.2.2.3 Histone-Related Enzymes 28
1.2.2.4 Inhibitors of Transcription Factors 29
1.2.3 Specific Genes 29
1.3 Drugs Directed Against Tumour RNA 30
1.4 Drugs Directed Against Proteins in the Tumour Cell 30
1.4.1 Receptors in the Tumour Membrane 30
1.4.2 Intracellular Pathways in Tumour Cells 32
1.4.3 Tubulin 34
1.5 Drugs Acting on the Endothelium 35
1.5.1 Inhibition of Pro-angiogenic Factors 36
1.5.2 Inhibition of Vascular Receptors 38
1.5.3 Inside the Endothelium 39
1.6 Drugs Directed Against Extracellular Matrix 39
1.6.1 Matrix Metalloproteinases Inhibitors 39
1.6.2 Anti-integrin Therapy 40
1.6.3 Copper Chelators 40
1.6.4 L1-CAM Protein 40
1.6.5 Thrombospondin and Others 40
1.7 Immunotherapy 41
1.7.1 Antibody-Based Immunotherapy of Cancer 41
1.7.1.1 Unconjugated Monoclonal Antibodies 41
1.7.1.2 Conjugated Monoclonal Antibodies 41
1.7.1.3 Monoclonal Antibodies as Immunogens 42
1.7.2 Cytokines in Cancer Immunotherapy 42
1.7.3 Cancer Vaccines 42
1.7.3.1 Peptide Vaccines 43
1.7.3.2 Dendritic Cell-Based Cancer Vaccines 43
1.7.3.3 Cellular Vaccines 43
1.7.3.4 DNA Vaccines 44
1.7.3.5 Heat Shock Protein Vaccines 44
1.7.4 Adoptive T-Cell Transfer for Cancer Immunotherapy 44
1.7.5 Natural Killer Cell-Based Immunotherapy 44
1.7.6 Regulatory Cells and Cancer Immunotherapy 45
1.7.7 Toll-Like Receptors 45
1.8 Drugs Acting on Potentially Metastatic Sites and Glands 45
1.9 Conclusion 46
References 46
2 Signal Transduction Pathways as Therapeutic Targetsin Cancer Therapy 53
2.1 Introduction 55
2.2 Protein Tyrosine Kinases (TK) as Therapeutic Targets 58
2.2.1 RTK as Therapeutic Targets: The Paradigm of EGFR Mutations in NSCLC 60
2.3 Cytoplasmic Signaling Intermediates 64
2.3.1 The Ras/Raf/MAPK Pathway 64
2.3.2 The PI3K/AKT/mTOR Pathway 69
2.3.3 Signaling Cross talk 74
2.4 Oncogenic Addiction 76
2.4.1 Oncogenic Shock 80
2.4.2 Oncogene Amnesia 80
2.5 Open Issues in the Clinical Development of Signal Transduction-Targeted Anticancer Agents 82
2.5.1 The Role of ''Early Phases'': Are Phase II Studies Still Necessary? 84
2.5.2 Phase II Randomized Studies: A New Tale with Targeted Agents 85
2.5.3 Targeted Agents: Moving into Phase III 86
References 89
Part II Polymer-Based Anticancer Prodrugs 100
3 HPMA-Anticancer Drug Conjugates 101
3.1 Introduction 103
3.2 Synthesis and Structure of N-(2-Hydroxypropyl) methacrylamide CopolymerDrug Conjugates 108
3.2.1 Synthesis of Linear Polymer--Drug Conjugates 108
3.2.2 Polymer Conjugates with Biologically Active Proteins 110
3.2.3 Polymer Systems Designed for Targeted Drug Delivery 111
3.2.3.1 Passively Targeted HPMA Copolymer--Drug Conjugates 111
3.2.3.2 Actively Targeted HPMA Copolymer--Drug Conjugates 112
3.3 Immunogenicity of HPMA-Based Conjugates 114
3.3.1 The Humoral Response Against HPMA 115
3.3.2 The Cellular Response to HPMA 115
3.3.3 Complement Activation 116
3.3.4 The Chronic Treatment 116
3.3.5 The Decreased Immunogenicity of Proteins Bound to HPMA 116
3.3.6 Decrease of Side Toxicity of HPMA Copolymer Carrier-Bound Drugs 117
3.4 HPMA CopolymerDoxorubicin Conjugates with pH-Controlled Activation 117
3.4.1 Linear Dox0HPMA HYD Conjugates 117
3.4.2 Branched and Grafted Dox0HPMA HYD Conjugates 118
3.4.3 Micellar Dox0HPMA HYD Conjugates 118
3.4.4 Antibody-Targeted Dox0HPMA HYD Conjugates 120
3.4.5 Immunomodulatory Properties of Dox0HPMA HYD Conjugates 120
3.5 HPMA CopolymerDoxorubicin Conjugates with Amide Bond Between the Drug and the Carrier 120
3.5.1 Dox0HPMA AM (PK1) 120
3.5.2 Dox0HPMA AM Conjugate Containing Human Immunoglobulin (HuIg) 121
3.5.2.1 Preclinical Evaluation of Dox-HPMA AM -HuIg 122
3.5.2.2 Pilot Clinical Study with Dox-HPMA AM -HuIg 122
3.5.3 HPMA-Based Polymer Prodrugs in Clinical Trials 123
3.6 Specific Targeting of HPMA Copolymer-Bound Drug Conjugates to Cancer Cells 123
3.6.1 Targeting to Asialoglycoprotein Receptor 124
3.6.2 Targeting Using Lectins 124
3.6.3 Targeting Using Antibodies 124
3.6.4 Targeting to Transferrin Receptor 126
3.6.5 Targeting Using Synthetic Peptides 126
3.7 Intracellular Destiny of Polymeric Conjugates Based on HPMA 126
3.7.1 Lysosomotropic Delivery of the Polymeric Drugs 126
3.7.2 Intracellular Destiny of Polymeric Drugs 127
3.7.3 Effect of a Doxorubicin Derivative 7,8-dehydro-9,10-desacetyldoxorubicinone (D ) in the Detection of Fluorescence 128
3.7.4 The Cleavability of Conjugates 129
3.7.5 Apoptosis, Necrosis, and Cell Signaling 131
3.8 Immunomodulatory Properties of HPMA Copolymer-Bound Doxorubicin 132
References 135
4 Poly-L-Glutamic Acid Anti-cancer Drug 147
4.1 Introduction 149
4.2 CT-2103 (Paclitaxel Poliglumex) 150
4.2.1 Chemistry and Manufacturing 151
4.2.1.1 Technical Issues in the Synthesis of CT-2103 151
4.2.1.2 Synthetic Strategy 153
4.2.1.3 Synthesis Optimization 153
4.2.1.4 Formulation of CT-2103 154
4.2.1.5 Development of Analytic Methods and Characterization of CT-2103 155
4.2.1.6 Setting Molecular Weight and Loading Limits, the Four Corners Approach 157
4.2.2 Preclinical Pharmacology 157
4.2.2.1 Pharmacokinetics 157
4.2.2.2 Tissue Distribution in Rats and Dogs 158
4.2.2.3 Tissue Distribution in Comparison with Paclitaxel in Tumor-Bearing Mice 158
4.2.2.4 Mass Balance in Rat 159
4.2.2.5 Toxicology Studies 160
4.2.3 Cellular Pharmacology 160
4.2.3.1 Cellular Metabolism 160
4.2.3.2 The Role of the Macrophage 161
4.2.3.3 Preclinical Efficacy 162
4.2.3.4 In Vivo Efficacy Studies in Combination with Radiation 162
4.2.3.5 The Effect of Estradiol on CT-2103 164
4.2.4 Preclinical Summary 165
4.2.5 Clinical Studies 166
4.2.5.1 Phase I Studies: Determination of a Safe and Effective Dose 166
4.2.5.2 Phase II Studies 166
4.2.6 Use of CT-2103 as a Radiosensitizer 167
4.2.7 Phase III Programs 168
4.2.7.1 Non-small Cell Lung Cancer (NSCLC) 168
4.2.7.2 Ovarian Cancer 169
4.3 CT-2106 (poly-L-glutamic acid gly-camptothecin) 170
4.3.1 Design and Synthesis 170
4.3.2 Overview of Preclinical Studies 172
4.3.3 Phase I Clinical Studies 172
4.4 Overall Conclusions 173
References 173
5 Polysaccharide-Based Anticancer Prodrugs 176
5.1 Introduction 179
5.2 Chitin and Chitosan 180
5.2.1 Mitomycin C 183
5.2.1.1 Insoluble Suc-Chitosan-MMC Derivatives 183
5.2.1.2 Soluble MMC-Suc-Chitosan Derivatives 184
5.2.1.3 Lactosyl-Suc-Chitosan-MMC Derivatives 185
5.2.2 Epirubicin 187
5.2.3 Doxorubicin 188
5.2.4 1-ß-D-Arabinofuranosylcytosine (Ara-C) 189
5.2.5 5-Fluorouracil 190
5.2.6 Tyr-Ile-Gly-Ser-Arg 191
5.2.7 DNA 191
5.3 Hyaluronic Acid 192
5.3.1 Paclitaxel 194
5.3.2 Doxorubicin 199
5.3.3 Butyric Acid 201
5.3.4 All-Trans Retinoic Acid 203
5.4 Dextran 205
5.4.1 Doxorubicin 207
5.4.2 Daunomycin 211
5.4.3 Mitomycin C 211
5.4.4 Paclitaxel 212
5.4.5 1-ß-D-Arabinofuranosylcytosine 213
5.4.6 Cisplatin 213
5.4.7 Camptothecin 215
5.4.8 Methylprednisolone and Tacrolimus 216
5.4.9 Radionuclides 219
5.4.10 Proteins 219
5.5 Arabinogalactan 220
5.6 Pullulan 221
5.7 Cyclodextrins 222
5.8 Conclusions 224
References 224
6 PEGAnticancer Drugs 233
6.1 Introduction 235
6.1.1 Drug Delivery Using Permanent PEGylation 236
6.1.2 Non-permanently Bonded PEG--Drugs: PEG Prodrugs 237
6.2 PEGAnticancer Drug Conjugates 238
6.2.1 PEG--Paclitaxel 238
6.2.2 PEG--Camptothecin 242
6.2.3 PEG--Doxorubicin 250
6.2.4 PEG--Daunorubicin 258
6.2.5 PEG--Epirubicin 258
6.2.6 PEG--Ara-C 264
6.2.7 PEG--Gemcitabine 265
6.2.8 PEG--Platinum Antitumour Drug 267
6.2.9 PEG--Methotrexate 268
6.3 Concluding Remarks 270
References 271
7 Poly(ethylene glycol)-Protein, Peptide, and EnzymeConjugates 276
7.1 Introduction 278
7.2 PEG-Proteins and Peptides 281
7.2.1 Antibodies and Antibody Fragments 281
7.2.2 Granulocyte Colony-Stimulating Factor 282
7.2.3 Interferons 283
7.2.4 Thrombopoietin or Megakaryocyte Growth and Development Factor 284
7.2.5 Anticancer Peptides 284
7.3 PEG-Enzymes 285
7.3.1 Arginase 286
7.3.2 Arginine Deiminase 287
7.3.3 Asparaginase 288
7.3.4 Methioninase 289
7.3.5 Glutaminase 290
7.3.6 Uricase 290
7.3.7 Other Anticancer Enzymes 291
7.4 Conclusions 292
References 293
Part III Lipid-Based Anticancer Prodrugs 300
8 Lipid-Based Anticancer Prodrugs 301
8.1 Introduction 302
8.2 Lipids Applied in Cancer Treatment 303
8.2.1 Non-Fatty Acids 303
8.2.1.1 Cardiolipin 303
8.2.1.2 Ceramide 305
8.2.2 Fatty Acids 305
8.2.2.1 Essential Fatty Acids (EFAs) 305
8.2.2.2 Omega-3 Fatty Acids 305
8.2.2.3 Conjugated Linoleic Acids 306
8.2.2.4 Olive Oil Constituents 307
8.2.2.5 Miscellaneous Fatty Acids 308
8.3 Anticancer Lipid Prodrugs 309
8.3.1 Antibiotic Anticancer Drug-Lipid Conjugates 309
8.3.1.1 Mitomycin C-Lipid Conjugates 309
8.3.1.2 Doxorubicin-Lipid Conjugates 311
8.3.2 Antimetabolite Anticancer Drug-Lipid Conjugates 311
8.3.2.1 Methotrexate-Lipid Conjugates 311
8.3.2.2 Nucleoside Analog Anticancer Drug-Lipid Conjugates 314
8.3.3 Taxane-Lipid Conjugates 322
8.3.4 Others: Camptothecin Alkaloids-Lipid Conjugates 327
8.4 Conclusion 328
References 328
Part IV Antibody-Directed Cancer Therapy 339
9 AntibodyCytotoxic Compound Conjugates for Oncology 340
9.1 Introduction 341
9.2 Target Selection 343
9.3 Antibody Selection 352
9.4 Cytotoxic Compounds Used in ACCs 355
9.5 AntibodyCytotoxic Compound Linker Strategies 358
9.6 ACCs in Clinical Development 362
9.7 Conclusions and Future Prospects 365
References 367
10 Immunoconjugate Anticancer Therapeutics 379
10.1 Introduction 380
10.2 mAb Forms for Conjugates 380
10.2.1 Radionuclide Conjugates 382
10.2.1.1 Radionuclides for RAIT 382
10.2.1.2 Therapy of Hematological Cancers 383
10.2.1.3 Therapy of Solid Cancers 386
10.2.1.4 Quo Vadis? 388
10.2.2 Antibody--Drug Conjugates 389
10.2.2.1 Drugs 389
10.2.2.2 Cleavable Linker in Drug Conjugate Design 389
10.2.2.3 mAb Conjugates: Homogeneity and Site Specificity 393
10.2.3 Toxin Conjugates 394
10.2.3.1 Plant and Bacterial Toxin Conjugates 394
10.2.3.2 Ribonuclease Conjugates 394
10.3 Conclusions 395
References 395
11 Antibody-Directed Enzyme Prodrug Therapy (ADEPT)for Cancer 401
11.1 Introduction and Principles 402
11.2 Antibodies and Targets 404
11.3 Enzymes 404
11.3.1 Mammalian Enzymes Including Human 405
11.3.2 Non-mammalian Enzymes 405
11.3.3 Catalytic Antibodies 406
11.4 Prodrugs 406
11.5 Carboxypeptidase G2 406
11.5.1 Antibody--Enzyme Conjugates 406
11.5.1.1 Pre-clinical Studies 406
11.5.1.2 Clinical Studies 407
11.5.2 Fusion Proteins 409
11.6 Immunogenicity 409
11.7 Conclusion 410
References 410
12 EGFR-Directed Monoclonal Antibodies 415
12.1 EGFR and Cancer 417
12.2 EGFR Inhibitors as Anticancer Therapy 419
12.3 Anti-EGFR Monoclonal Antibodies (MAbs) 420
12.3.1 Cetuximab (IMC-225) 421
12.3.2 Panitumumab (ABX-EGF) 426
12.3.3 Matuzumab (EMD 72000) 431
12.3.4 Nimotuzumab (hR3) 433
12.3.5 Zalutumumab 434
12.3.6 MDX-447 435
12.3.7 ch806 435
12.4 Conclusion 435
References 436
13 The Biology of the HER Family and Her2/neu Directed-Antibody Therapy 445
13.1 Introduction 447
13.2 The HER Family 448
13.3 HER2 and Downstream Signaling Pathways 449
13.3.1 The PI3k/Akt/Mammalian Target of Rapamycin (mTOR) Pathway 449
13.3.2 HER2 and PTEN 450
13.3.3 The Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) Pathway 450
13.3.4 HER2 and Endocrine Receptors (ER) 450
13.3.5 HER2 and p27 451
13.4 HER2 Targeted Antibodies 451
13.4.1 Trastuzumab 451
13.4.1.1 Trastuzumab and Metastatic Breast Cancer: Single Agent Trastuzumab 452
13.4.1.2 Dosing of Trastuzumab 452
13.4.1.3 Trastuzumab and Chemotherapy for Metastatic Breast Cancer 452
13.4.1.4 Trastuzumab and Aromatase Inhibitors for Metastatic Breast Cancer 453
13.4.1.5 Trastuzumab and Adjuvant Therapy 455
13.4.1.6 Trastuzumab and Neoadjuvant Chemotherapy 456
13.4.1.7 Treating with Trastuzumab Beyond Progression 458
13.4.1.8 Trastuzumab and Cardiotoxicity 460
13.4.1.9 Mechanisms of Resistance 461
13.4.2 HER and PTEN/PI3k/Akt/Mammalian Target of Rapamycin (mTOR) Pathway 461
13.4.3 Insulin-Like Growth Factor-1 Receptor 462
13.4.4 MUC4 Over-Expression 462
13.4.5 HER2 Receptor Truncation or Mutations 462
13.5 Novel HER Family-Directed Antibodies 463
13.5.1 Pertuzumab 463
13.5.2 Trastuzumab-DM1 464
13.5.3 HER2 Monoclonal Antibodies and Nanoparticles in Development 465
13.6 Conclusion 465
References 466
14 Anti-Vascular Endothelial Growth Factor MonoclonalAntibodies 473
14.1 Angiogenesis and Cancer 475
14.1.1 Biologic Relevance of Vascular Endothelial Growth Factor in Tumor Angiogenesis 475
14.1.2 VEGF Family and Receptors 475
14.1.3 VEGF as a Target for Cancer Therapy 477
14.2 VEGF Monoclonal Antibodies and Clinical Experience 477
14.2.1 Bevacizumab 477
14.2.1.1 Pharmacology 477
14.2.1.2 Clinical Experience 478
14.2.1.3 Side Effects 484
14.2.2 VEGF Trap 485
14.2.2.1 Pharmacology 485
14.2.2.2 Clinical Experience 486
14.2.3 HuMV833 487
14.2.3.1 Pharmacology 487
14.2.3.2 Clinical Experience 487
14.3 VEGF Receptor Monoclonal Antibodies 488
14.3.1 IMC-1121b 488
14.3.2 IMC-18F1 488
14.3.3 CDP791 489
14.4 Monoclonal Antibodies to Placental Growth Factor 489
14.5 Current Issues Emerging from Anti-VEGF Therapies 490
14.5.1 Biologic Markers for Dosing and Efficacy 490
14.5.2 Resistance to Anti-VEGF Therapy 492
14.6 Summary 493
References 493
15 Monoclonal Antibody Therapy for Hematologic Malignancies 500
15.1 Introduction 502
15.2 Rituximab 503
15.2.1 Follicular Lymphoma 505
15.2.2 Marginal Zone B-Cell Lymphoma 509
15.2.3 Mantle Cell Lymphoma 510
15.2.4 Diffuse Large B-Cell Lymphoma 512
15.2.5 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 514
15.3 90 Y Ibritumomab Tiuxetan 516
15.4 131 I Tositumomab 517
15.5 Alemtuzumab 517
15.6 Gemtuzumab Ozogamicin 518
15.7 Ofatumumab 519
15.8 AME-133v 519
15.9 Epratuzumab 520
15.10 CMC-544 521
15.11 BL22 522
15.12 Lumiliximab 522
15.13 Galiximab 523
15.14 SGN-40 523
15.15 Bevacizumab 524
15.16 CP-751,871 525
15.17 Zanolimumab 525
15.18 Limtuzumab 525
15.19 IMC-EB10 526
15.20 SGN-30 527
15.21 Chimeric Anti-CD4 Monoclonal Antibody 527
15.22 TRU-016 528
15.23 Milatuzumab 528
15.24 Ipilimumab 529
15.25 Conclusion 529
References 530
Part V Anticancer Oligonucleotide Therapeutics 544
16 Anticancer Oligonucleotides 545
16.1 Introduction 546
16.2 Pre-clinical Studies 547
16.2.1 Antisense Oligonucleotides 547
16.2.1.1 Studies on bcl-2 Proto-oncogene 547
16.2.1.2 Studies on Raf Kinases 549
16.2.1.3 Studies on Ras Proteins 550
16.2.1.4 Studies on PKC- 551
16.2.2 Small Interfering RNA 552
16.2.2.1 Studies on Bcl-2 Proto-oncogene 552
16.2.2.2 Studies on Raf Kinases 553
16.2.2.3 Studies on Ras Proteins and PKC- 553
16.2.3 Decoys 553
16.2.4 Aptamers 554
16.2.5 Ribozymes 554
16.2.5.1 Studies on bcl-2 555
16.2.5.2 Studies on Ras Proteins 555
16.2.5.3 Studies on PKC- 555
16.2.6 Discussion 555
16.2.6.1 Immunostimulation 556
16.2.6.2 Minimal Active Doses 556
16.2.6.3 Selectivity and Off-Target Effects 556
16.3 Clinical Studies 557
16.3.1 Antisense Oligonucleotides 557
16.3.1.1 Clinical Trials on Bcl-2 557
16.3.1.2 Clinical Trials on Raf Kinase 562
16.3.1.3 Clinical Trials on Ras 563
16.3.1.4 Clinical Trials on PKC- 564
16.3.2 Small Interfering RNA 566
16.3.3 Ribozymes 566
16.3.4 Decoys 566
16.3.5 Discussion 567
16.4 Conclusion 567
References 568
Part VI Miscellaneous 575
17 New Molecular Therapeutic Interventions: The Caseof Breast Cancers 576
17.1 Introduction 578
17.2 Estrogens, Phytoestrogens, and Xenoestrogens 580
17.2.1 Biosynthesis of Estrogens 580
17.2.2 Phytoestrogens and Xenoestrogens 580
17.3 Estrogen Receptors 582
17.3.1 Structure 582
17.3.2 The Classical Genomic Transactivation Mechanisms 584
17.3.3 Non-classical Transactivation Systems 586
17.3.4 Nuclear Localization and Nucleocytoplasmic Shuttling 588
17.3.5 Estrogen Receptors Stability 588
17.4 Estrogen Receptors in Breast Cancers 589
17.4.1 Estrogen Receptors in the Normal Mammary Gland 589
17.4.1.1 Estrogen Receptor Isotypes in Breast Cancers 590
17.4.1.2 Classical Anti-hormonal Treatments 590
17.5 Emergence of Innovative Strategies for Specific Targets 595
17.5.1 Apoptosis Induction and Cell Cycle Inhibition 595
17.5.1.1 Apoptosis 595
17.5.1.2 Cdk Inhibitors 596
17.5.1.3 Survivin 596
17.5.1.4 Nuclear Factor-B 597
17.5.1.5 Ubiquitin--Proteasome System 597
17.5.1.6 Histone Deacetylase Inhibitors 597
17.5.1.7 Hsp90 Inhibitors 598
17.5.1.8 p53 599
17.5.1.9 Pi3k/Akt Pathway 599
17.5.1.10 Farnesyl Transferase Inhibitors (FTI) 600
17.5.2 Vascular and Angiogenesis Inhibitors 600
17.5.3 Monoclonal Antibodies and Tyrosine Kinase Inhibitors for EGFR and Erb-B2 601
17.6 Breast Cancer and Stem Cells 602
17.6.1 Implication of Stem Cells in Metastasis 602
17.6.2 Targeting CD44 for Breast Cancer Therapy 603
17.7 Conclusion and Future Perspectives 603
References 604
Author Index 617
Subject Index 619

Produkt-Details

• Erscheint lt. Verlag: 20.3.2010
• Reihe/Serie: Cancer Drug Discovery and Development
• Reihe/Serie: Cancer Drug Discovery and Development
• Zusatzinfo: X, 500 p. 50 illus., 8 illus. in color.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Studium
• Schlagworte: Cancer • Cancer Therapy • Cancer Treatment • Chemistry • classification • Drug • hormones • Imaging • immunotherapy • Oncogene • pharmacology • Research • Toxicity • Tumor • Vaccine
• ISBN-10: 1-4419-0507-3 / 1441905073
• ISBN-13: 978-1-4419-0507-9 / 9781441905079