Anticancer Drug Development

By: David J Kerr

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Hardcover | 15 October 2001

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397 Pages

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27.94 x 20.96 x 1.91

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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.

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

"..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)

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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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Anticancer Drug Development

At a Glance

Hardcover

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