| Contributors | p. xi |
| Preface | p. xiii |
| A Brief History of Cancer Chemotherapy | |
| Summary | p. 1 |
| Introduction | p. 1 |
| Genotoxic (Cytotoxic) Therapy | p. 2 |
| Growth Control Pathways | p. 5 |
| Host-Tumor Interactions | p. 7 |
| Conclusions | p. 8 |
| References | p. 9 |
| Novel Targets in the Cell Cycle and Cell Cycle Checkpoints | |
| Summary | p. 13 |
| Introduction | p. 12 |
| Molecular Regulation of Cell Cycle Progression | p. 14 |
| Molecular Regulation of Cell Cycle Checkpoints | p. 15 |
| Rationale for Targeting Cyclin-Dependent Kinases and Cell Cycle Checkpoint Pathways | p. 17 |
| Agents and Strategies for Therapeutic Interference | p. 19 |
| Conclusions | p. 24 |
| References | p. 25 |
| Growth Factor and Signal Transduction Targets for Cancer Therapy | |
| Summary | p. 31 |
| Introduction | p. 31 |
| The ErbB Family of Receptor Tyrosine Kinases (RTKs) | p. 32 |
| The Ras-Raf-MEK-ERK Signaling Pathway | p. 34 |
| c-Src Kinase, Signal Transduction, Transformation, and Cancer | p. 37 |
| Akt | p. 38 |
| Nuclear Hormone Receptors as Targets for Cancer Therapy | p. 40 |
| Implications for Drug Discovery and Development | p. 43 |
| References | p. 44 |
| Cell Death Pathways as Targets for Anticancer Drugs | |
| Summary | p. 55 |
| Introduction | p. 56 |
| Two Main Pathways for Drug-Induced Apoptosis | p. 56 |
| Modulation of Drug-Induced Cell Death by Bcl-2 and Related Proteins | p. 58 |
| The Central Role of Caspases in Drug-Induced Apoptosis | p. 61 |
| Synergy between Death Receptors and Cytotoxic Drugs | p. 64 |
| The Rel/NF-kB/lkB Proteins | p. 69 |
| Conclusion | p. 70 |
| References | p. 70 |
| Drug Resistance Pathways as Targets | |
| Summary | p. 77 |
| Introduction | p. 77 |
| Targeting Drug Transport | p. 78 |
| Targeting Cellular Stress Responses | p. 81 |
| Targeting DNA Repair Systems | p. 85 |
| Conclusions | p. 86 |
| References | p. 86 |
| Role of Matrix Metalloproteinases and Plasminogen Activators in Cancer Invasion and Metastasis: Therapeutic Strategies | |
| Summary | p. 91 |
| Introduction | p. 92 |
| The Extracellular Matrix | p. 92 |
| Cancer Invasion and Metastasis | p. 92 |
| Cell Adhesion in Cancer | p. 94 |
| Cancer Cell Motility | p. 95 |
| Inflammatory Response to Cancer | p. 95 |
| Proteolytic Enzymes Implicated in Cancer Invasion | p. 96 |
| MMPIs as Novel Anticancer Agents | p. 104 |
| Sheddases | p. 111 |
| The uPA System: Proteolytic Control of MMP Activation | p. 111 |
| References | p. 116 |
| Tumor Vasculature as a Target | |
| Summary | p. 123 |
| Introduction | p. 123 |
| How to Inhibit Tumor Angiogenesis | p. 127 |
| Concluding Remarks | p. 131 |
| References | p. 131 |
| Gene-Directed Enzyme Prodrug Therapy | |
| Summary | p. 137 |
| Introduction | p. 137 |
| Background | p. 138 |
| Enzyme-Prodrug Systems | p. 138 |
| Tailored Prodrugs for GDEPT | p. 140 |
| The Activation Process | p. 148 |
| Augmenting the Effect | p. 149 |
| Exploiting the Bystander Effect and Acquired Immunity | p. 150 |
| Conclusions | p. 151 |
| References | p. 152 |
| Tumor Antigens as Targets for Anticancer Drug Development | |
| Summary | p. 157 |
| Introduction | p. 157 |
| Antigen Targets for Cancer Vaccines | p. 158 |
| Tumor Antigens as Targets for Antibody-Based Therapeutics | p. 164 |
| References | p. 168 |
| Structure-Based Drug Design and Its Contributions to Cancer Chemotherapy | |
| Summary | p. 171 |
| Introduction | p. 171 |
| Antimetabolites | p. 173 |
| Protease Inhibitors | p. 176 |
| Protein Kinase Inhibitors | p. 179 |
| Other Targets | p. 181 |
| Novel Methods in Structure-Based Drug Design | p. 182 |
| Conclusions and Current Questions | p. 183 |
| References | p. 183 |
| The Contribution of Synthetic Organic Chemistry to Anticancer Drug Development | |
| Summary | p. 187 |
| Introduction | p. 188 |
| Early Rationality | p. 188 |
| The Random Screening Era: Directly from Screen to Clinic | p. 188 |
| Organic Synthesis Catches Up: Development of National Product Leads | p. 189 |
| Development of Synthetic Compounds: Structure-Activity Relationships | p. 190 |
| Immunotoxins: Synthetic Organic Chemistry Applied to Large Molecules | p. 191 |
| Organic Synthesis in Rational Design: Tumor-Activated Prodrugs of Cytokines | p. 191 |
| Early Genomics: Inhibitors of Transmembrane Tyrosine Kinases | p. 194 |
| The Genomics/Proteomics Era: Combinatorial Chemistry | p. 195 |
| Conclusion | p. 198 |
| References | p. 199 |
| Biosynthetic Products for Anticancer Drug Design and Treatment: The Bryostatins | |
| Summary | p. 203 |
| Introduction | p. 203 |
| Background to the Bryostatins | p. 204 |
| Comprehensive Review of Bryostatin Scientific and Medical Reports | p. 205 |
| References | p. 220 |
| DNA-Encoded Peptide Libraries and Drug Discovery | |
| Summary | p. 237 |
| Introduction | p. 237 |
| Methods for DNA-Encoded Peptide Display | p. 237 |
| Applications for DNA-Encoded Peptide Libraries | p. 241 |
| Conclusions | p. 246 |
| References | p. 246 |
| Mechanism-Based High-Throughput Screening for Novel Anticancer Drug Discovery | |
| Summary | p. 249 |
| Importance of Mechanism-Based Targets in Postgenomic Drug Discovery | p. 250 |
| High-Throughput Screening | p. 251 |
| Assay Technologies | p. 255 |
| Assay Performance and Downstream Evaluation of Bits | p. 259 |
| Compounds for HTS | p. 260 |
| Examples of Compounds Identified Through Screening Approaches | p. 261 |
| Future HTS Developments | p. 263 |
| Concluding Remarks | p. 264 |
| References | p. 264 |
| Tumor Cell Cultures in Drug Development | |
| Summary | p. 269 |
| Introduction | p. 269 |
| Growth Inhibition Assays | p. 270 |
| Clongenic Assays | p. 274 |
| Three-Dimensional Cell Cultures: Modeling Extravascular Drug Transport | p. 275 |
| Modeling of in Vivo Activity by in Vitro Assays | p. 278 |
| Perspective | p. 280 |
| References | p. 280 |
| Screening Using Animal Systems | |
| Summary | p. 285 |
| Introduction | p. 285 |
| Choice of in Vivo Systems for Large-Scale Drug Development | p. 286 |
| Combined in Vitro/in Vivo Testing Procedure Using Human Tumor Xenografts--The Freiburg Experience | p. 289 |
| Use of Transgenic Animals in the Search for New Drugs | p. 293 |
| Screening for Angiogenesis Inhibitors | p. 295 |
| References | p. 297 |
| Relevance of Preclinical Pharmacology and Toxicology to Phase I Trial Extrapolation Techniques: Relevance of Animal Toxicology | |
| Summary | p. 301 |
| Introduction | p. 302 |
| Historical Perspective | p. 302 |
| Special Toxicity Evaluations | p. 303 |
| Recent Examples of Drug Development at NCI | p. 303 |
| Predictability of Nonclinical Animal Data | p. 320 |
| Conclusions | p. 323 |
| References | p. 323 |
| Clinical Trial Design: Incorporation of Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic Principles | |
| Summary | p. 329 |
| Introduction | p. 330 |
| Rationale for Chemotherapy Optimization | p. 330 |
| Pharmacokinetic-Pharmacodynamic Relationships | p. 332 |
| Pharmacogenetics | p. 335 |
| Strategies to Improve Therapeutic Index | p. 340 |
| Conclusion and Perspectives | p. 347 |
| References | p. 348 |
| Tumor Imaging Applications in the Testing of New Drugs | |
| Summary | p. 353 |
| Introduction | p. 353 |
| Positron Emission Tomography | p. 354 |
| PET in New Drug Evaluation | p. 355 |
| Conclusions | p. 365 |
| References | p. 365 |
| Mechanistic Approaches to Phase I Clinical Trials | |
| Summary | p. 371 |
| Introduction | p. 371 |
| Mechanism-Based Studies of Established Anticancer Agents to Assess Target Inhibition | p. 373 |
| Mechanistic Trial Perspectives on Anticancer Agents with Novel Mechanisms | p. 373 |
| Potential of PET Scanning in the Assessment of Pharmacodynamic End Points | p. 381 |
| Conclusion | p. 381 |
| References | p. 381 |
| Index | p. 385 |
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