Anticancer Drug Development

Edited by Bruce C. Baguley and David J. Kerr

"..this is a really extensive and comprehensive book on the drug development process. ...There is very little overlap between chapters and all are written by experts in the field. Hundreds of useful references are included for those wanting to go further. ...Very good value...and essential reading for both the scientist and Ph.D. student. Definately one for the library to stock." --Paul Loadman, University of Bradford, UK for BRITISH JOURNAL OF CANCER, 2002"Well-referenced and indexed...this text would be a useful addition to the clinic, research laboratory and institution library." --P. Parsons, Queensland Institute of Medical Research for CANCER FORUM, 2002

• Contributors PrefaceChapter 1 A Brief History of Cancer ChemotherapySummary 1. Introduction 2. Genotoxic (Cytotoxic) Therapy 3. Growth Control Pathways 4. Host–Tumor Interactions 5. Conclusions References Chapter 2 Novel Targets in the Cell Cycle and Cell Cycle CheckpointsSummary 1. Introduction 2. Molecular Regulation of Cell Cycle Progression 3. Molecular Regulation of Cell Cycle Checkpoints 4. Rationale for Targeting Cyclin-Dependent Kinases and Cell Cycle Checkpoint Pathways5. Agents and Strategies for Therapeutic Interference 6. Conclusions References Chapter 3 Growth Factor and Signal Transduction Targets for Cancer TherapySummary 1. Introduction 2. The ErbB Family of Receptor Tyrosine Kinases (RTKs) 3. The Ras-Raf-MEK-ERK Signaling Pathway 4. c-Src Kinase, Signal Transduction, Transformation, and Cancer 5. Akt 6. Nuclear Hormone Receptors as Targets for Cancer Therapy 7. Implications for Drug Discovery and Development References Chapter 4 Cell Death Pathways as Targets for Anticancer DrugsSummary 1. Introduction 2. Two Main Pathways for Drug-Induced Apoptosis 3. Modulation of Drug-Induced Cell Death by Bcl-2 and Related Proteins 4. The Central Role of Caspases in Drug-Induced Apoptosis 5. Synergy between Death Receptors and Cytotoxic Drugs 6. The Rel/NF-kB/IkB Proteins 7. Conclusion References Chapter 5 Drug Resistance Pathways as TargetsSummary 1. Introduction 2. Targeting Drug Transport 3. Targeting Cellular Stress Responses 4. Targeting DNA Repair Systems 5. Conclusions References Chapter 6 Role of Matrix Metalloproteinases and Plasminogen Activators in Cancer Invasion and Metastasis: Therapeutic StrategiesSummary 1. Introduction 2. The Extracellular Matrix 3. Cancer Invasion and Metastasis 4. Cell Adhesion in Cancer 5. Cancer Cell Motility 6. Inflammatory Response to Cancer 7. Proteolytic Enzymes Implicated in Cancer Invasion 8. MMPIs as Novel Anticancer Agents 9. Sheddases 10. The uPA System: Proteolytic Control of MMP Activation References Chapter 7 Tumor Vasculature as a TargetSummary 1. Introduction 2. How to Inhibit Tumor Angiogenesis 3. Concluding Remarks References Chapter 8 Gene-Directed Enzyme Prodrug TherapySummary 1. Introduction 2. Background 3. Enzyme-Prodrug Systems 4. Tailored Prodrugs for GDEPT 5. The Activation Process 6. Augmenting the Effect 7. Exploiting the Bystander Effect and Acquired Immunity 8. Conclusions References Chapter 9 Tumor Antigens as Targets for Anticancer Drug DevelopmentSummary 1. Introduction 2. Antigen Targets for Cancer Vaccines 3. Tumor Antigens as Targets for Antibody-Based Therapeutics References Chapter 10 Structure-Based Drug Design and its Contributions to Cancer ChemotherapySummary 1. Introduction2. Antimetabolites 3. Protease Inhibitors 4. Protein Kinase Inhibitors 5. Other Targets6. Novel Methods in Structure-Based Drug Design 7. Conclusions and Current Questions References Chapter 11 The Contribution of Synthetic Organic Chemistry to Anticancer Drug DevelopmentSummary 1. Introduction 2. Early Rationality 3. The Random Screening Era: Directly from Screen to Clinic 4. Organic Synthesis Catches Up: Development of National Product Leads 5. Development of Synthetic Compounds: Structure–Activity Relationships 6. Immunotoxins: Synthetic Organic Chemistry Applied to Large Molecules 7. Organic Synthesis in Rational Design: Tumor-Activated Prodrugs of Cytokines 8. Early Genomics: Inhibitors of Transmembrane Tyrosine Kinases 9. The Genomics/Proteomics Era: Combinatorial Chemistry 10. Conclusion References Chapter 12 Biosynthetic Products for Anticancer Drug Design and Treatment: The BryostatinsSummary 1. Introduction 2. Background to the Bryostatins 3. Comprehensive Review of Bryostatin Scientific and Medical Reports References Chapter 13 DNA-Encoded Peptide Libraries and Drug DiscoverySummary 1. Introduction 2. Methods for DNA-Encoded Peptide Display 3. Applications for DNA-Encoded Peptide Libraries 4. Conclusions References Chapter Mechanism-Based Highthroughput Screening for Novel Anticancer Drug DiscoverySummary 1. Importance of Mechanism-Based Targets in Postgenomic Drug Discovery 2. High-Throughput Screening 3. Assay Technologies 4. Assay Performance and Downstream Evaluation of Bits 5. Compounds for HTS 6. Examples of Compounds Identified Through Screening Approaches 7. Future HTS Developments 8. Concluding Remarks References Chapter 15 Tumor Cell Cultures in Drug DevelopmentSummary 1. Introduction 2. Growth Inhibition Assays 3. Clonogenic Assays 4. Three-Dimensional Cell Cultures: Modeling Extravascular Drug Transport 5. Modeling of in Vivo Activity by in Vitro Assays 6. Perspective References Chapter 16 Screening Using Animal SystemsSummary 1. Introduction 2. Choice of in Vivo Systems for Large-Scale Drug Development 3. Combined in Vitro/in Vivo Testing Procedure Using Human Tumor Xenografts—The Freiburg Experience 4. Use of Transgenic Animals in the Search for New Drugs 5. Screening for Angiogenesis Inhibitors References Chapter 17 Relevance of Preclinical Pharmacology and Toxicology to Phase I Trial Extrapolation Techniques: Elevance of Animal ToxicologySummary 1. Introduction 2. Historical Perspective 3. Special Toxicity Evaluations 4. Recent Examples of Drug Development at NCI 5. Predictability of Nonclinical Animal Data 6. Conclusions References Chapter 18 Clinical Trial Design: Incorporation of Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic PrinciplesSummary 1. Introduction 2. Rationale for Chemotherapy Optimization3. Pharmacokinetic–Pharmacodynamic Relationships 4. Pharmacogenetics 5. Strategies to Improve Therapeutic Index 6. Conclusion and Perspectives References Chapter 19 Tumor Imaging Applications in the Testing of New DrugsSummary 1. Introduction 2. Positron Emission Tomography 3. PET in New Drug Evaluation 4. Conclusions References Chapter 20 Mechanistic Approaches to Phase I Clinical TrialsSummary 1. Introduction 2. Mechanism-Based Studies of Established Anticancer Agents to Assess Target Inhibition 3. Mechanistic Trial Perspectives on Anticancer Agents with Novel Mechanisms 4. Potential of PET Scanning in the Assessment of Pharmacodynamic End Points 5. Conclusion References Index