Anticancer Drug Development

  • ID: 1757078
  • Book
  • 397 Pages
  • Elsevier Science and Technology
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Here in a single source is a complete spectrum of ideas on the development of new anticancer drugs. Containing concise reviews of multidisciplinary fields of research, this book offers 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 sources for new drugs and methods for testing and clinical trial design are also provided.
  • 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
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Contributors

Preface


Chapter 1 A Brief History of Cancer Chemotherapy


Summary


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 Checkpoints


Summary


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 Pathways


5. Agents and Strategies for Therapeutic Interference


6. Conclusions


References


Chapter 3 Growth Factor and Signal Transduction Targets for Cancer Therapy


Summary


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 Drugs


Summary


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 Targets


Summary


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 Strategies


Summary


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 Target


Summary


1. Introduction


2. How to Inhibit Tumor Angiogenesis


3. Concluding Remarks


References


Chapter 8 Gene-Directed Enzyme Prodrug Therapy


Summary


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 Development


Summary


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 Chemotherapy


Summary


1. Introduction


2. Antimetabolites


3. Protease Inhibitors


4. Protein Kinase Inhibitors


5. Other Targets


6. Novel Methods in Structure-Based Drug Design


7. Conclusions and Current Questions


References


Chapter 11 The Contribution of Synthetic Organic Chemistry to Anticancer Drug Development


Summary


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 Bryostatins


Summary


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 Discovery


Summary


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 Discovery


Summary


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 Development


Summary


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 Systems


Summary


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 Toxicology


Summary


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 Principles


Summary


1. Introduction


2. Rationale for Chemotherapy Optimization


3. 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 Drugs


Summary


1. Introduction


2. Positron Emission Tomography


3. PET in New Drug Evaluation


4. Conclusions


References


Chapter 20 Mechanistic Approaches to Phase I Clinical Trials


Summary


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
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Baguley, Bruce C.
Kerr, David J.
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