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[资源] Novel Anticancer Agents: Strategies for Discovery and Clinical Testing

Novel Anticancer Agents: Strategies for Discovery and Clinical Testing
By Alex A. Adjei, John K. Buolamwini
Publisher:  Academic Press
Number Of Pages:  464
Publication Date:  2005-12-13
ISBN / ASIN:  0120885611
EAN:  9780120885619

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Book Description:

This book offers pertinent basic science information on strategies used for the rational design and discovery of novel anticancer agents, and, in addition, translational studies involving clinical trial design and execution with these novel, mostly cytostatic agents. This book covers basic science strategies that are being used in drug discovery and preclinical evaluation focused on novel molecular targets, as well as clinical trial methodology including clinical pharmacokinetics and imaging to address issues of efficacy evaluation of the new, relatively non-cytotoxic anticancer agents.

At present, there is no book that provides such an integration of basic and clinical studies of novel anticancer agents, covering both drug discovery and translational research extensively.

* Addresses the critical issues involved in the development of novel agents for cancer therapy by experts in the field
* Presents drug discovery strategies
* Discusses regulatory issues surrounding drug development
*

I l l
CONTENTS
CONTRIBUTORS XI
PREFACE XV
STRATEGIES FOR DRUG DISCOVERY
A Survey of Novel Molecular Targets for
Anticancer Drug Discovery
JOHN K. BUOLAMWlNI
I. Introduction 1
II. Overview of Growth Factor Induced Mitogenic Signaling
III. Protein Kinases and Phosphatases 4
IV. Adapter Proteins 12
V. GTP-Binding Proteins 12
VI. Oncogenic Transcription Factors 13
VII. Apoptosis, Cell Survival, and Life Span Targets 15
VIII. Angiogenesis and Metastasis Molecular Factors 17
IX. Protein Degradation and Chaperoning Targets 19
X. Chromatin Remodeling Factors 19
XI. Conclusion 20
References 20
V
VI CONTENTS
2 Microarrays: Small Spots Produce Major Advances
in Pharmacogenomics
M. NEESW, . KUSNEZOWA, ND C. D. WOODWORTH
I. Introduction to Microarrays 38
II. Advantages of DNA Microarrays 44
III. Major DNA Array Formats: Something for Everyone 45
IV. What is the Best Way to Interface with Microarrays? 52
V. Microarrays and Pharmacogenomics: Revolutionizing Discovery of New
Drugs and Gene Function 55
VI. What Can Go Wrong in cDNA Microarray Experimentation? 65
VII. Array-Based Proteomics: How to Investigate Protein Complexity 68
VIII. Emerging Microarray Technologies for High-Throughput Proteome
Investigation: A Technical Overview 68
IX. Current and Future Applications of Protein Arrays in Drug Discovery 71
X. How to Deal with all that Data 73
XI. The Future is Only Going to Get Better 74
References 76
3 Strategies to Target Chemotherapeutics to Tumors
CHARLES E ALBRIGHT AND PEARL S. HUANG
I. Background and Rationale 83
II. Antibody-Directed Enzyme Prodrug Technique 84
III. Passive Tumor Targeting 84
IV. Targeting by Binding to Tumor Cell Surface Molecules 85
V. Enzyme-Activated Targeting 85
VI. Summary and Future Directions 90
References 90
4 QSAR and Pharmacophore Mapping Strategies
in Novel Anticancer Drug Discovery
JAMES J. KAMINSKI
I. Introduction 93
II. Pharmacophore Definition
III. Pharmacophore Validation
IV. Conclusions 104
References 104
5 Applications of Nuclear Magnetic Resonance and Mass
Spectrometry t o Anticancer Drug Discovery
ROBERT POWERS AND MARSHALL M. SIEGEL
I. Introduction 107
II. NMR in Anticancer Drug Discovery 109
III. Mass Spectrometry in Anticancer Drug Discovery 140
IV. MS/NMR Screening Assay
V. Conclusions 172
Acknowledgements 172
References 173
162
6 Antisense Strategies for the Development
of Novel Cancer Therapeutics
RUIWEN ZHANG AND HUI WANG
I. Introduction 191
II. Design and Evaluation of Antisence Oligonucleotides
III. Conclusion 202
Acknowledgements 203
References 203
193
7 Antibodies and Vaccines as Novel Cancer Therapeutics
SVETOMIR N. MARKOVIC AND ESTEBAN CELLS
I. Introduction 207
II. Anti-Tumor Antibodies
III. Cancer Vaccines 212
IV. Conclusion 218
References 219
207
8 Inhibitors of Apoptosis as Targets for Cancer Therapy
M. SAEED SHEIKH AND YING HUANG
I. The Inhibitors of Apoptosis
II. Concluding Remarks 229
References 230
223
9 Preclinical Testing and Validation
of Novel Anticancer Agents
LLOYD R. KELLAND
I. Introduction 233
II. Target Validation 234
III. A Generic Cascade for Anticancer Drug Discovery 235
IV. High-Throughput Cell-Free Screens for Activity Against the Target 237
V. In Vitro Cell Line Models 238
VI. In Vivo Testing of Novel Compounds 240
VII. Cassette-Dosing 240
VIII. Pharmaceutical Considerations 241
IX. High-Throughput In Vivo Anti-Tumor Testing: The Hollow Fiber
Assay 241
X. Human Tumor Xenografts 242
XI. Orthotopic, Transgenic, and Other Animal Models 243
V I I I CONTENTS
XII. Pharmacodynamics 244
XIII. Summary 245
Acknowledgements 245
References 245
METHODS FOR CLINICAL TESTING OF NOVEL AGENTS
I 0 Surrogate End Points and Biomarkers for Early Trials
of Novel Anticancer Agents
ALEX A. ADJEI
I. Introduction 249
II. What are Targeted Agents? 250
III. Surrogate Markers or Biomarkers? 250
IV. Biomarkers as Indicators of Drug Effect In Vivo 252
V. Biomarkers as Predictive Factors 252
VI. Biomarkers as Prognostic Factors 253
VII. Technical Issues in the Evaluation of Drug Effects In Vivo
VIII. Lessons for the Future 261
Acknowledgements 261
References 261
II Regulatory Considerations in Clinical Trials
of Novel Anticancer Drugs
GRANT WILLIAMS AND RICHARD PAZDUR
254
I. Introduction 263
II. Overview of Cancer Drug Regulation 264
III. Regulatory Considerations in Early Cancer Drug Development
IV. Regulatory Considerations in Late Drug Development 271
V. Conclusion 283
Acknowledgements 283
References 283
12 Improving the Efficacy and Safety of Anticancer
Agents--The Role of Pharmacogenetics
MARGARET-MARY AMEYAW AND HOWARD L. MCLEOD
267
I. Introduction 286
II. Thiopurine Methyltransferase 286
III. DPD 288
IV. Thymidylate Synthase 289
V. ABC Family of Drug Transporters 291
VI. UDP-Glucuronosyltransferase IAI Pharmacogenetics and Irinotecan
VII. MTHFR Reductase Pharmacogenetics 293
VIII. Cytochrome P4503A Pharmacogenetics 293
IX. Conclusion 293
Acknowledgements 294
References 294
292
13 Imaging of Pharmacodynamic End Points
in Clinical Trials
ERIC O. ABOAGYE, A. R. PADHANI, AND PATRICIA M. PRICE
I. Introduction 300
II. PET 300
III. Evaluation of Cancer Therapeutics with PET 302
IV. MRI Assessment of Microvessel Function 311
V. Conclusions 328
References 328
14 Devising Proof-of-Concept Strategies
in Oncology Clinical Trials
PAUL S. WISSEL
I. Introduction 337
II. Proof-of-Concept 338
III. Elements of "The Concept" 339
IV. Application of Surrogate End Points in Proof-of-Concept Decision
Making 343
V. Selected Statistical Considerations in Proof-of-Concept Studies 349
VI. Pharmacodynamic Proof-of-Concept End Points 352
VII. Pharmacokinetic Proof-of-Concept End Points 356
VIII. Proceeding From Proof-of-Concept Directly to Phase III 359
IX. Guidelines and Summary 360
Acknowledgements 361
References 361
1 5 Clinical Trial Designs for Cytostatic Agents and Agents
Directed at Novel Molecular Targets
EDWARD L. KORN, LARRY V. RUBINSTEIN, SALLY A. HUNSBERGER, ]AMES M. PLUDA,
ELIZABETH EISENHAUER, AND SUSAN G. ARBUCK
I. Introduction 366
II. Phase I Dose-Finding Trials 366
III. Preliminary Efficacy Trials 372
IV. Definitive Randomized Efficacy Trials
V. Conclusions 377
References 377
376
X CONTENTS
16 Cancer Gene Therapy Clinical Trials: From the Bench
to the Clinic
EVANTHIA GALANIS
I. Regulatory Requirements and Good Manufacturing Practices for Gene
Transfer Products 381
II. Preclinical Development of Gene Therapy Vectors/Toxicology Testing 382
III. Federal and Institutional Approval Processes for Clinical Gene Therapy
Trials 383
IV. Gene Therapy Clinical Trial Design 384
V. Correlative End Points 386
References 389
17 Molecular Targets for Radiosensitization
ROGER OVE AND JAMES A. BONNER
I. Introduction 391
II. Growth Factor Receptors 394
III. Ras 399
IV. Modulation of p53 401
V. DNA Damage Recognition and Repair
VI. Other Promising Approaches 405
VII. Conclusions 407
VIII. Addendum 407
Addendum References 409
References 409
18 Patient Accrual to Clinical Trials
SUSAN QUELLA
402
I. Introduction 415
II. Setting Up the Environment
References 425
Index 427
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