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397 Pages
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KEY FEATURES:
* One work that can be consulted for all aspects of anticancer drug development
* Concise reviews of research fields, combined with practical scientific detail, written by internationally respected experts
* A wealth of ideas on current and future molecular targets for drug design, including signal transduction, the cell division cycle, and programmed cell death
* Detailed descriptions of the sources of new anticancer drugs, including combinatorial chemistry, phage display, and natural products
* Discussion of how new drugs can be tested in preclinical systems, including the latest technology of robotic assay systems, cell culture, and experimental animal techniques
* Hundreds of references that allow the reader to access relevant scientific and medical literature
* Clear illustrations, some in color, that provide both understanding of the field and material for teaching
Industry Reviews
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 |
Table of Contents provided by Syndetics. All Rights Reserved. |
ISBN: 9780120726516
ISBN-10: 0120726513
Published: 15th October 2001
Format: Hardcover
Language: English
Number of Pages: 397
Audience: Professional and Scholarly
Publisher: Academic Press
Country of Publication: US
Dimensions (cm): 27.94 x 20.96 x 1.91
Weight (kg): 1.18
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