Reddy / Couvreur Macromolecular Anticancer Therapeutics

1. Auflage 2010
ISBN: 978-1-4419-0507-9
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 500 Seiten

Reihe: Cancer Drug Discovery and Development

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.

Autoren/Hrsg.

Couvreur, Patrick

Reddy, L. Harivardhan

Inhaltsverzeichnis

1;Foreword;6
1.1;General References;7
2;Preface;8
3;Editors Biography;11
4;Contents;13
5;Contributors;15
6;Part I Classification, Opportunities and Challenges;19
6.1;1 Classification of Anticancer Drugs Based on TherapeuticTargets;20
6.1.1;1.1 Introduction;22
6.1.2;1.2 Drugs Directed Against Tumour DNA;24
6.1.2.1;1.2.1 Drugs Directly Affecting DNA Helix: Alkylators;24
6.1.2.2;1.2.2 Inhibitors of DNA-Related Proteins;27
6.1.2.2.1;1.2.2.1 Topoisomerases Inhibitors;27
6.1.2.2.2;1.2.2.2 Antimetabolites;28
6.1.2.2.3;1.2.2.3 Histone-Related Enzymes;28
6.1.2.2.4;1.2.2.4 Inhibitors of Transcription Factors;29
6.1.2.3;1.2.3 Specific Genes;29
6.1.3;1.3 Drugs Directed Against Tumour RNA;30
6.1.4;1.4 Drugs Directed Against Proteins in the Tumour Cell;30
6.1.4.1;1.4.1 Receptors in the Tumour Membrane;30
6.1.4.2;1.4.2 Intracellular Pathways in Tumour Cells;32
6.1.4.3;1.4.3 Tubulin;34
6.1.5;1.5 Drugs Acting on the Endothelium;35
6.1.5.1;1.5.1 Inhibition of Pro-angiogenic Factors;36
6.1.5.2;1.5.2 Inhibition of Vascular Receptors;38
6.1.5.3;1.5.3 Inside the Endothelium;39
6.1.6;1.6 Drugs Directed Against Extracellular Matrix;39
6.1.6.1;1.6.1 Matrix Metalloproteinases Inhibitors;39
6.1.6.2;1.6.2 Anti-integrin Therapy;40
6.1.6.3;1.6.3 Copper Chelators;40
6.1.6.4;1.6.4 L1-CAM Protein;40
6.1.6.5;1.6.5 Thrombospondin and Others;40
6.1.7;1.7 Immunotherapy;41
6.1.7.1;1.7.1 Antibody-Based Immunotherapy of Cancer;41
6.1.7.1.1;1.7.1.1 Unconjugated Monoclonal Antibodies;41
6.1.7.1.2;1.7.1.2 Conjugated Monoclonal Antibodies;41
6.1.7.1.3;1.7.1.3 Monoclonal Antibodies as Immunogens;42
6.1.7.2;1.7.2 Cytokines in Cancer Immunotherapy;42
6.1.7.3;1.7.3 Cancer Vaccines;42
6.1.7.3.1;1.7.3.1 Peptide Vaccines;43
6.1.7.3.2;1.7.3.2 Dendritic Cell-Based Cancer Vaccines;43
6.1.7.3.3;1.7.3.3 Cellular Vaccines;43
6.1.7.3.4;1.7.3.4 DNA Vaccines;44
6.1.7.3.5;1.7.3.5 Heat Shock Protein Vaccines;44
6.1.7.4;1.7.4 Adoptive T-Cell Transfer for Cancer Immunotherapy;44
6.1.7.5;1.7.5 Natural Killer Cell-Based Immunotherapy;44
6.1.7.6;1.7.6 Regulatory Cells and Cancer Immunotherapy;45
6.1.7.7;1.7.7 Toll-Like Receptors;45
6.1.8;1.8 Drugs Acting on Potentially Metastatic Sites and Glands;45
6.1.9;1.9 Conclusion;46
6.1.10;References;46
6.2;2 Signal Transduction Pathways as Therapeutic Targetsin Cancer Therapy;53
6.2.1;2.1 Introduction;55
6.2.2;2.2 Protein Tyrosine Kinases (TK) as Therapeutic Targets;58
6.2.2.1;2.2.1 RTK as Therapeutic Targets: The Paradigm of EGFR Mutations in NSCLC;60
6.2.3;2.3 Cytoplasmic Signaling Intermediates;64
6.2.3.1;2.3.1 The Ras/Raf/MAPK Pathway;64
6.2.3.2;2.3.2 The PI3K/AKT/mTOR Pathway;69
6.2.3.3;2.3.3 Signaling Cross talk;74
6.2.4;2.4 Oncogenic Addiction;76
6.2.4.1;2.4.1 Oncogenic Shock;80
6.2.4.2;2.4.2 Oncogene Amnesia;80
6.2.5;2.5 Open Issues in the Clinical Development of Signal Transduction-Targeted Anticancer Agents;82
6.2.5.1;2.5.1 The Role of ''Early Phases'': Are Phase II Studies Still Necessary?;84
6.2.5.2;2.5.2 Phase II Randomized Studies: A New Tale with Targeted Agents;85
6.2.5.3;2.5.3 Targeted Agents: Moving into Phase III;86
6.2.6;References;89
7;Part II Polymer-Based Anticancer Prodrugs;100
7.1;3 HPMA-Anticancer Drug Conjugates;101
7.1.1;3.1 Introduction;103
7.1.2;3.2 Synthesis and Structure of N-(2-Hydroxypropyl) methacrylamide CopolymerDrug Conjugates;108
7.1.2.1;3.2.1 Synthesis of Linear Polymer--Drug Conjugates;108
7.1.2.2;3.2.2 Polymer Conjugates with Biologically Active Proteins;110
7.1.2.3;3.2.3 Polymer Systems Designed for Targeted Drug Delivery;111
7.1.2.3.1;3.2.3.1 Passively Targeted HPMA Copolymer--Drug Conjugates;111
7.1.2.3.2;3.2.3.2 Actively Targeted HPMA Copolymer--Drug Conjugates;112
7.1.3;3.3 Immunogenicity of HPMA-Based Conjugates;114
7.1.3.1;3.3.1 The Humoral Response Against HPMA;115
7.1.3.2;3.3.2 The Cellular Response to HPMA;115
7.1.3.3;3.3.3 Complement Activation;116
7.1.3.4;3.3.4 The Chronic Treatment;116
7.1.3.5;3.3.5 The Decreased Immunogenicity of Proteins Bound to HPMA;116
7.1.3.6;3.3.6 Decrease of Side Toxicity of HPMA Copolymer Carrier-Bound Drugs;117
7.1.4;3.4 HPMA CopolymerDoxorubicin Conjugates with pH-Controlled Activation;117
7.1.4.1;3.4.1 Linear Dox0HPMA HYD Conjugates;117
7.1.4.2;3.4.2 Branched and Grafted Dox0HPMA HYD Conjugates;118
7.1.4.3;3.4.3 Micellar Dox0HPMA HYD Conjugates;118
7.1.4.4;3.4.4 Antibody-Targeted Dox0HPMA HYD Conjugates;120
7.1.4.5;3.4.5 Immunomodulatory Properties of Dox0HPMA HYD Conjugates;120
7.1.5;3.5 HPMA CopolymerDoxorubicin Conjugates with Amide Bond Between the Drug and the Carrier;120
7.1.5.1;3.5.1 Dox0HPMA AM (PK1);120
7.1.5.2;3.5.2 Dox0HPMA AM Conjugate Containing Human Immunoglobulin (HuIg);121
7.1.5.2.1;3.5.2.1 Preclinical Evaluation of Dox-HPMA AM -HuIg;122
7.1.5.2.2;3.5.2.2 Pilot Clinical Study with Dox-HPMA AM -HuIg;122
7.1.5.3;3.5.3 HPMA-Based Polymer Prodrugs in Clinical Trials;123
7.1.6;3.6 Specific Targeting of HPMA Copolymer-Bound Drug Conjugates to Cancer Cells;123
7.1.6.1;3.6.1 Targeting to Asialoglycoprotein Receptor;124
7.1.6.2;3.6.2 Targeting Using Lectins;124
7.1.6.3;3.6.3 Targeting Using Antibodies;124
7.1.6.4;3.6.4 Targeting to Transferrin Receptor;126
7.1.6.5;3.6.5 Targeting Using Synthetic Peptides;126
7.1.7;3.7 Intracellular Destiny of Polymeric Conjugates Based on HPMA;126
7.1.7.1;3.7.1 Lysosomotropic Delivery of the Polymeric Drugs;126
7.1.7.2;3.7.2 Intracellular Destiny of Polymeric Drugs;127
7.1.7.3;3.7.3 Effect of a Doxorubicin Derivative 7,8-dehydro-9,10-desacetyldoxorubicinone (D ) in the Detection of Fluorescence;128
7.1.7.4;3.7.4 The Cleavability of Conjugates;129
7.1.7.5;3.7.5 Apoptosis, Necrosis, and Cell Signaling;131
7.1.8;3.8 Immunomodulatory Properties of HPMA Copolymer-Bound Doxorubicin;132
7.1.9;References;135
7.2;4 Poly-L-Glutamic Acid Anti-cancer Drug;147
7.2.1;4.1 Introduction;149
7.2.2;4.2 CT-2103 (Paclitaxel Poliglumex);150
7.2.2.1;4.2.1 Chemistry and Manufacturing;151
7.2.2.1.1;4.2.1.1 Technical Issues in the Synthesis of CT-2103;151
7.2.2.1.2;4.2.1.2 Synthetic Strategy;153
7.2.2.1.3;4.2.1.3 Synthesis Optimization;153
7.2.2.1.4;4.2.1.4 Formulation of CT-2103;154
7.2.2.1.5;4.2.1.5 Development of Analytic Methods and Characterization of CT-2103;155
7.2.2.1.6;4.2.1.6 Setting Molecular Weight and Loading Limits, the Four Corners Approach;157
7.2.2.2;4.2.2 Preclinical Pharmacology;157
7.2.2.2.1;4.2.2.1 Pharmacokinetics;157
7.2.2.2.2;4.2.2.2 Tissue Distribution in Rats and Dogs;158
7.2.2.2.3;4.2.2.3 Tissue Distribution in Comparison with Paclitaxel in Tumor-Bearing Mice;158
7.2.2.2.4;4.2.2.4 Mass Balance in Rat;159
7.2.2.2.5;4.2.2.5 Toxicology Studies;160
7.2.2.3;4.2.3 Cellular Pharmacology;160
7.2.2.3.1;4.2.3.1 Cellular Metabolism;160
7.2.2.3.2;4.2.3.2 The Role of the Macrophage;161
7.2.2.3.3;4.2.3.3 Preclinical Efficacy;162
7.2.2.3.4;4.2.3.4 In Vivo Efficacy Studies in Combination with Radiation;162
7.2.2.3.5;4.2.3.5 The Effect of Estradiol on CT-2103;164
7.2.2.4;4.2.4 Preclinical Summary;165
7.2.2.5;4.2.5 Clinical Studies;166
7.2.2.5.1;4.2.5.1 Phase I Studies: Determination of a Safe and Effective Dose;166
7.2.2.5.2;4.2.5.2 Phase II Studies;166
7.2.2.6;4.2.6 Use of CT-2103 as a Radiosensitizer;167
7.2.2.7;4.2.7 Phase III Programs;168
7.2.2.7.1;4.2.7.1 Non-small Cell Lung Cancer (NSCLC);168
7.2.2.7.2;4.2.7.2 Ovarian Cancer;169
7.2.3;4.3 CT-2106 (poly-L-glutamic acid gly-camptothecin);170
7.2.3.1;4.3.1 Design and Synthesis;170
7.2.3.2;4.3.2 Overview of Preclinical Studies;172
7.2.3.3;4.3.3 Phase I Clinical Studies;172
7.2.4;4.4 Overall Conclusions;173
7.2.5;References;173
7.3;5 Polysaccharide-Based Anticancer Prodrugs;176
7.3.1;5.1 Introduction;179
7.3.2;5.2 Chitin and Chitosan;180
7.3.2.1;5.2.1 Mitomycin C;183
7.3.2.1.1;5.2.1.1 Insoluble Suc-Chitosan-MMC Derivatives;183
7.3.2.1.2;5.2.1.2 Soluble MMC-Suc-Chitosan Derivatives;184
7.3.2.1.3;5.2.1.3 Lactosyl-Suc-Chitosan-MMC Derivatives;185
7.3.2.2;5.2.2 Epirubicin;187
7.3.2.3;5.2.3 Doxorubicin;188
7.3.2.4;5.2.4 1-ß-D-Arabinofuranosylcytosine (Ara-C);189
7.3.2.5;5.2.5 5-Fluorouracil;190
7.3.2.6;5.2.6 Tyr-Ile-Gly-Ser-Arg;191
7.3.2.7;5.2.7 DNA;191
7.3.3;5.3 Hyaluronic Acid;192
7.3.3.1;5.3.1 Paclitaxel;194
7.3.3.2;5.3.2 Doxorubicin;199
7.3.3.3;5.3.3 Butyric Acid;201
7.3.3.4;5.3.4 All-Trans Retinoic Acid;203
7.3.4;5.4 Dextran;205
7.3.4.1;5.4.1 Doxorubicin;207
7.3.4.2;5.4.2 Daunomycin;211
7.3.4.3;5.4.3 Mitomycin C;211
7.3.4.4;5.4.4 Paclitaxel;212
7.3.4.5;5.4.5 1-ß-D-Arabinofuranosylcytosine;213
7.3.4.6;5.4.6 Cisplatin;213
7.3.4.7;5.4.7 Camptothecin;215
7.3.4.8;5.4.8 Methylprednisolone and Tacrolimus;216
7.3.4.9;5.4.9 Radionuclides;219
7.3.4.10;5.4.10 Proteins;219
7.3.5;5.5 Arabinogalactan;220
7.3.6;5.6 Pullulan;221
7.3.7;5.7 Cyclodextrins;222
7.3.8;5.8 Conclusions;224
7.3.9; References ;224
7.4;6 PEGAnticancer Drugs;233
7.4.1;6.1 Introduction;235
7.4.1.1;6.1.1 Drug Delivery Using Permanent PEGylation;236
7.4.1.2;6.1.2 Non-permanently Bonded PEG--Drugs: PEG Prodrugs;237
7.4.2;6.2 PEGAnticancer Drug Conjugates;238
7.4.2.1;6.2.1 PEG--Paclitaxel;238
7.4.2.2;6.2.2 PEG--Camptothecin;242
7.4.2.3;6.2.3 PEG--Doxorubicin;250
7.4.2.4;6.2.4 PEG--Daunorubicin;258
7.4.2.5;6.2.5 PEG--Epirubicin;258
7.4.2.6;6.2.6 PEG--Ara-C;264
7.4.2.7;6.2.7 PEG--Gemcitabine;265
7.4.2.8;6.2.8 PEG--Platinum Antitumour Drug;267
7.4.2.9;6.2.9 PEG--Methotrexate;268
7.4.3;6.3 Concluding Remarks;270
7.4.4;References;271
7.5;7 Poly(ethylene glycol)-Protein, Peptide, and EnzymeConjugates;276
7.5.1;7.1 Introduction;278
7.5.2;7.2 PEG-Proteins and Peptides;281
7.5.2.1;7.2.1 Antibodies and Antibody Fragments;281
7.5.2.2;7.2.2 Granulocyte Colony-Stimulating Factor;282
7.5.2.3;7.2.3 Interferons;283
7.5.2.4;7.2.4 Thrombopoietin or Megakaryocyte Growth and Development Factor;284
7.5.2.5;7.2.5 Anticancer Peptides;284
7.5.3;7.3 PEG-Enzymes;285
7.5.3.1;7.3.1 Arginase;286
7.5.3.2;7.3.2 Arginine Deiminase;287
7.5.3.3;7.3.3 Asparaginase;288
7.5.3.4;7.3.4 Methioninase;289
7.5.3.5;7.3.5 Glutaminase;290
7.5.3.6;7.3.6 Uricase;290
7.5.3.7;7.3.7 Other Anticancer Enzymes;291
7.5.4;7.4 Conclusions;292
7.5.5; References;293
8;Part III Lipid-Based Anticancer Prodrugs;300
8.1;8 Lipid-Based Anticancer Prodrugs;301
8.1.1;8.1 Introduction;302
8.1.2;8.2 Lipids Applied in Cancer Treatment;303
8.1.2.1;8.2.1 Non-Fatty Acids;303
8.1.2.1.1;8.2.1.1 Cardiolipin;303
8.1.2.1.2;8.2.1.2 Ceramide;305
8.1.2.2;8.2.2 Fatty Acids;305
8.1.2.2.1;8.2.2.1 Essential Fatty Acids (EFAs);305
8.1.2.2.2;8.2.2.2 Omega-3 Fatty Acids;305
8.1.2.2.3;8.2.2.3 Conjugated Linoleic Acids;306
8.1.2.2.4;8.2.2.4 Olive Oil Constituents;307
8.1.2.2.5;8.2.2.5 Miscellaneous Fatty Acids;308
8.1.3;8.3 Anticancer Lipid Prodrugs;309
8.1.3.1;8.3.1 Antibiotic Anticancer Drug-Lipid Conjugates;309
8.1.3.1.1;8.3.1.1 Mitomycin C-Lipid Conjugates;309
8.1.3.1.2;8.3.1.2 Doxorubicin-Lipid Conjugates;311
8.1.3.2;8.3.2 Antimetabolite Anticancer Drug-Lipid Conjugates;311
8.1.3.2.1;8.3.2.1 Methotrexate-Lipid Conjugates;311
8.1.3.2.2;8.3.2.2 Nucleoside Analog Anticancer Drug-Lipid Conjugates;314
8.1.3.3;8.3.3 Taxane-Lipid Conjugates;322
8.1.3.4;8.3.4 Others: Camptothecin Alkaloids-Lipid Conjugates;327
8.1.4;8.4 Conclusion;328
8.1.5;References;328
9;Part IV Antibody-Directed Cancer Therapy;339
9.1;9 AntibodyCytotoxic Compound Conjugates for Oncology;340
9.1.1;9.1 Introduction;341
9.1.2;9.2 Target Selection;343
9.1.3;9.3 Antibody Selection;352
9.1.4;9.4 Cytotoxic Compounds Used in ACCs;355
9.1.5;9.5 AntibodyCytotoxic Compound Linker Strategies;358
9.1.6;9.6 ACCs in Clinical Development;362
9.1.7;9.7 Conclusions and Future Prospects;365
9.1.8;References;367
9.2;10 Immunoconjugate Anticancer Therapeutics;379
9.2.1;10.1 Introduction;380
9.2.2;10.2 mAb Forms for Conjugates;380
9.2.2.1;10.2.1 Radionuclide Conjugates;382
9.2.2.1.1;10.2.1.1 Radionuclides for RAIT;382
9.2.2.1.2;10.2.1.2 Therapy of Hematological Cancers;383
9.2.2.1.3;10.2.1.3 Therapy of Solid Cancers;386
9.2.2.1.4;10.2.1.4 Quo Vadis?;388
9.2.2.2;10.2.2 Antibody--Drug Conjugates;389
9.2.2.2.1;10.2.2.1 Drugs;389
9.2.2.2.2;10.2.2.2 Cleavable Linker in Drug Conjugate Design;389
9.2.2.2.3;10.2.2.3 mAb Conjugates: Homogeneity and Site Specificity;393
9.2.2.3;10.2.3 Toxin Conjugates;394
9.2.2.3.1;10.2.3.1 Plant and Bacterial Toxin Conjugates;394
9.2.2.3.2;10.2.3.2 Ribonuclease Conjugates;394
9.2.3;10.3 Conclusions;395
9.2.4;References;395
9.3;11 Antibody-Directed Enzyme Prodrug Therapy (ADEPT)for Cancer;401
9.3.1;11.1 Introduction and Principles;402
9.3.2;11.2 Antibodies and Targets;404
9.3.3;11.3 Enzymes;404
9.3.3.1;11.3.1 Mammalian Enzymes Including Human;405
9.3.3.2;11.3.2 Non-mammalian Enzymes;405
9.3.3.3;11.3.3 Catalytic Antibodies;406
9.3.4;11.4 Prodrugs;406
9.3.5;11.5 Carboxypeptidase G2;406
9.3.5.1;11.5.1 Antibody--Enzyme Conjugates;406
9.3.5.1.1;11.5.1.1 Pre-clinical Studies;406
9.3.5.1.2;11.5.1.2 Clinical Studies;407
9.3.5.2;11.5.2 Fusion Proteins;409
9.3.6;11.6 Immunogenicity;409
9.3.7;11.7 Conclusion;410
9.3.8;References;410
9.4;12 EGFR-Directed Monoclonal Antibodies;415
9.4.1;12.1 EGFR and Cancer;417
9.4.2;12.2 EGFR Inhibitors as Anticancer Therapy;419
9.4.3;12.3 Anti-EGFR Monoclonal Antibodies (MAbs);420
9.4.3.1;12.3.1 Cetuximab (IMC-225);421
9.4.3.2;12.3.2 Panitumumab (ABX-EGF);426
9.4.3.3;12.3.3 Matuzumab (EMD 72000);431
9.4.3.4;12.3.4 Nimotuzumab (hR3);433
9.4.3.5;12.3.5 Zalutumumab;434
9.4.3.6;12.3.6 MDX-447;435
9.4.3.7;12.3.7 ch806;435
9.4.4;12.4 Conclusion;435
9.4.5;References;436
9.5;13 The Biology of the HER Family and Her2/neu Directed-Antibody Therapy;445
9.5.1;13.1 Introduction;447
9.5.2;13.2 The HER Family;448
9.5.3;13.3 HER2 and Downstream Signaling Pathways;449
9.5.3.1;13.3.1 The PI3k/Akt/Mammalian Target of Rapamycin (mTOR) Pathway;449
9.5.3.2;13.3.2 HER2 and PTEN;450
9.5.3.3;13.3.3 The Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) Pathway;450
9.5.3.4;13.3.4 HER2 and Endocrine Receptors (ER);450
9.5.3.5;13.3.5 HER2 and p27;451
9.5.4;13.4 HER2 Targeted Antibodies;451
9.5.4.1;13.4.1 Trastuzumab;451
9.5.4.1.1;13.4.1.1 Trastuzumab and Metastatic Breast Cancer: Single Agent Trastuzumab;452
9.5.4.1.2;13.4.1.2 Dosing of Trastuzumab;452
9.5.4.1.3;13.4.1.3 Trastuzumab and Chemotherapy for Metastatic Breast Cancer;452
9.5.4.1.4;13.4.1.4 Trastuzumab and Aromatase Inhibitors for Metastatic Breast Cancer;453
9.5.4.1.5;13.4.1.5 Trastuzumab and Adjuvant Therapy;455
9.5.4.1.6;13.4.1.6 Trastuzumab and Neoadjuvant Chemotherapy;456
9.5.4.1.7;13.4.1.7 Treating with Trastuzumab Beyond Progression;458
9.5.4.1.8;13.4.1.8 Trastuzumab and Cardiotoxicity;460
9.5.4.1.9;13.4.1.9 Mechanisms of Resistance;461
9.5.4.2;13.4.2 HER and PTEN/PI3k/Akt/Mammalian Target of Rapamycin (mTOR) Pathway;461
9.5.4.3;13.4.3 Insulin-Like Growth Factor-1 Receptor;462
9.5.4.4;13.4.4 MUC4 Over-Expression;462
9.5.4.5;13.4.5 HER2 Receptor Truncation or Mutations;462
9.5.5;13.5 Novel HER Family-Directed Antibodies;463
9.5.5.1;13.5.1 Pertuzumab;463
9.5.5.2;13.5.2 Trastuzumab-DM1;464
9.5.5.3;13.5.3 HER2 Monoclonal Antibodies and Nanoparticles in Development;465
9.5.6;13.6 Conclusion;465
9.5.7;References;466
9.6;14 Anti-Vascular Endothelial Growth Factor MonoclonalAntibodies;473
9.6.1;14.1 Angiogenesis and Cancer;475
9.6.1.1;14.1.1 Biologic Relevance of Vascular Endothelial Growth Factor in Tumor Angiogenesis;475
9.6.1.2;14.1.2 VEGF Family and Receptors;475
9.6.1.3;14.1.3 VEGF as a Target for Cancer Therapy;477
9.6.2;14.2 VEGF Monoclonal Antibodies and Clinical Experience;477
9.6.2.1;14.2.1 Bevacizumab;477
9.6.2.1.1;14.2.1.1 Pharmacology;477
9.6.2.1.2;14.2.1.2 Clinical Experience;478
9.6.2.1.3;14.2.1.3 Side Effects;484
9.6.2.2;14.2.2 VEGF Trap;485
9.6.2.2.1;14.2.2.1 Pharmacology;485
9.6.2.2.2;14.2.2.2 Clinical Experience;486
9.6.2.3;14.2.3 HuMV833;487
9.6.2.3.1;14.2.3.1 Pharmacology;487
9.6.2.3.2;14.2.3.2 Clinical Experience;487
9.6.3;14.3 VEGF Receptor Monoclonal Antibodies;488
9.6.3.1;14.3.1 IMC-1121b;488
9.6.3.2;14.3.2 IMC-18F1;488
9.6.3.3;14.3.3 CDP791;489
9.6.4;14.4 Monoclonal Antibodies to Placental Growth Factor;489
9.6.5;14.5 Current Issues Emerging from Anti-VEGF Therapies;490
9.6.5.1;14.5.1 Biologic Markers for Dosing and Efficacy;490
9.6.5.2;14.5.2 Resistance to Anti-VEGF Therapy;492
9.6.6;14.6 Summary;493
9.7; References ;493
9.8;15 Monoclonal Antibody Therapy for Hematologic Malignancies;500
9.8.1;15.1 Introduction;502
9.8.2;15.2 Rituximab;503
9.8.2.1;15.2.1 Follicular Lymphoma;505
9.8.2.2;15.2.2 Marginal Zone B-Cell Lymphoma;509
9.8.2.3;15.2.3 Mantle Cell Lymphoma;510
9.8.2.4;15.2.4 Diffuse Large B-Cell Lymphoma;512
9.8.2.5;15.2.5 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma;514
9.8.3;15.3 90 Y Ibritumomab Tiuxetan;516
9.8.4;15.4 131 I Tositumomab;517
9.8.5;15.5 Alemtuzumab;517
9.8.6;15.6 Gemtuzumab Ozogamicin;518
9.8.7;15.7 Ofatumumab;519
9.8.8;15.8 AME-133v;519
9.8.9;15.9 Epratuzumab;520
9.8.10;15.10 CMC-544;521
9.8.11;15.11 BL22;522
9.8.12;15.12 Lumiliximab;522
9.8.13;15.13 Galiximab;523
9.8.14;15.14 SGN-40;523
9.8.15;15.15 Bevacizumab;524
9.8.16;15.16 CP-751,871;525
9.8.17;15.17 Zanolimumab;525
9.8.18;15.18 Limtuzumab;525
9.8.19;15.19 IMC-EB10;526
9.8.20;15.20 SGN-30;527
9.8.21;15.21 Chimeric Anti-CD4 Monoclonal Antibody;527
9.8.22;15.22 TRU-016;528
9.8.23;15.23 Milatuzumab;528
9.8.24;15.24 Ipilimumab;529
9.8.25;15.25 Conclusion;529
9.8.26;References;530
10;Part V Anticancer Oligonucleotide Therapeutics;544
10.1;16 Anticancer Oligonucleotides;545
10.1.1;16.1 Introduction;546
10.1.2;16.2 Pre-clinical Studies;547
10.1.2.1;16.2.1 Antisense Oligonucleotides;547
10.1.2.1.1;16.2.1.1 Studies on bcl-2 Proto-oncogene;547
10.1.2.1.2;16.2.1.2 Studies on Raf Kinases;549
10.1.2.1.3;16.2.1.3 Studies on Ras Proteins;550
10.1.2.1.4;16.2.1.4 Studies on PKC-;551
10.1.2.2;16.2.2 Small Interfering RNA;552
10.1.2.2.1;16.2.2.1 Studies on Bcl-2 Proto-oncogene;552
10.1.2.2.2;16.2.2.2 Studies on Raf Kinases;553
10.1.2.2.3;16.2.2.3 Studies on Ras Proteins and PKC-;553
10.1.2.3;16.2.3 Decoys;553
10.1.2.4;16.2.4 Aptamers;554
10.1.2.5;16.2.5 Ribozymes;554
10.1.2.5.1;16.2.5.1 Studies on bcl-2;555
10.1.2.5.2;16.2.5.2 Studies on Ras Proteins;555
10.1.2.5.3;16.2.5.3 Studies on PKC-;555
10.1.2.6;16.2.6 Discussion;555
10.1.2.6.1;16.2.6.1 Immunostimulation;556
10.1.2.6.2;16.2.6.2 Minimal Active Doses;556
10.1.2.6.3;16.2.6.3 Selectivity and Off-Target Effects;556
10.1.3;16.3 Clinical Studies;557
10.1.3.1;16.3.1 Antisense Oligonucleotides;557
10.1.3.1.1;16.3.1.1 Clinical Trials on Bcl-2;557
10.1.3.1.2;16.3.1.2 Clinical Trials on Raf Kinase;562
10.1.3.1.3;16.3.1.3 Clinical Trials on Ras;563
10.1.3.1.4;16.3.1.4 Clinical Trials on PKC-;564
10.1.3.2;16.3.2 Small Interfering RNA;566
10.1.3.3;16.3.3 Ribozymes;566
10.1.3.4;16.3.4 Decoys;566
10.1.3.5;16.3.5 Discussion;567
10.1.4;16.4 Conclusion;567
10.1.5;References;568
11;Part VI Miscellaneous;575
11.1;17 New Molecular Therapeutic Interventions: The Caseof Breast Cancers;576
11.1.1;17.1 Introduction;578
11.1.2;17.2 Estrogens, Phytoestrogens, and Xenoestrogens;580
11.1.2.1;17.2.1 Biosynthesis of Estrogens;580
11.1.2.2;17.2.2 Phytoestrogens and Xenoestrogens;580
11.1.3;17.3 Estrogen Receptors;582
11.1.3.1;17.3.1 Structure;582
11.1.3.2;17.3.2 The Classical Genomic Transactivation Mechanisms;584
11.1.3.3;17.3.3 Non-classical Transactivation Systems;586
11.1.3.4;17.3.4 Nuclear Localization and Nucleocytoplasmic Shuttling;588
11.1.3.5;17.3.5 Estrogen Receptors Stability;588
11.1.4;17.4 Estrogen Receptors in Breast Cancers;589
11.1.4.1;17.4.1 Estrogen Receptors in the Normal Mammary Gland;589
11.1.4.1.1;17.4.1.1 Estrogen Receptor Isotypes in Breast Cancers;590
11.1.4.1.2;17.4.1.2 Classical Anti-hormonal Treatments;590
11.1.5;17.5 Emergence of Innovative Strategies for Specific Targets;595
11.1.5.1;17.5.1 Apoptosis Induction and Cell Cycle Inhibition;595
11.1.5.1.1;17.5.1.1 Apoptosis;595
11.1.5.1.2;17.5.1.2 Cdk Inhibitors;596
11.1.5.1.3;17.5.1.3 Survivin;596
11.1.5.1.4;17.5.1.4 Nuclear Factor-B;597
11.1.5.1.5;17.5.1.5 Ubiquitin--Proteasome System;597
11.1.5.1.6;17.5.1.6 Histone Deacetylase Inhibitors;597
11.1.5.1.7;17.5.1.7 Hsp90 Inhibitors;598
11.1.5.1.8;17.5.1.8 p53;599
11.1.5.1.9;17.5.1.9 Pi3k/Akt Pathway;599
11.1.5.1.10;17.5.1.10 Farnesyl Transferase Inhibitors (FTI);600
11.1.5.2;17.5.2 Vascular and Angiogenesis Inhibitors;600
11.1.5.3;17.5.3 Monoclonal Antibodies and Tyrosine Kinase Inhibitors for EGFR and Erb-B2;601
11.1.6;17.6 Breast Cancer and Stem Cells;602
11.1.6.1;17.6.1 Implication of Stem Cells in Metastasis;602
11.1.6.2;17.6.2 Targeting CD44 for Breast Cancer Therapy;603
11.1.7;17.7 Conclusion and Future Perspectives;603
11.1.8;References;604
12;Author Index;617
13;Subject Index;619