Teicher Tumor Models in Cancer Research

2. Auflage 2011
ISBN: 978-1-60761-968-0
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 693 Seiten, eBook

Reihe: Cancer Drug Discovery and Development

The past 6 years since the first edition of this book have seen great progress in the development of genetically engineered mouse (GEM) models of cancer. These models are finding an important role in furthering our understanding of the biology of malignant disease. A comfortable position for GEM models in the routine conduct of screening for potential new therapeutics is coming more slowly but is coming. Increasing numbers of genetically engineered mice are available, some with conditional activation of oncogenes, some with multiple genetic changes providing mouse models that are moving closer to the human disease.

Zielgruppe

Research

Autoren/Hrsg.

Teicher, Beverly A.

Inhaltsverzeichnis

1;Tumor Models in Cancer Research;3
1.1;Preface;5
1.2;Contents;7
1.3;Contributors;11
1.4;Part I Introduction;15
1.4.1;Chapter 1: Perspectives on the History and Evolution of Tumor Models;16
1.4.1.1;1.1 Introduction and Statement of the Problem;16
1.4.1.2;1.2 Tumor Models for Cancer Drug Development: Where We Were;18
1.4.1.2.1;1.2.1 Historical Basis;18
1.4.1.2.2;1.2.2 Early Screening Models;19
1.4.1.3;1.3 Novel Screens Beget Novel In Vivo Model Challenges;21
1.4.1.3.1;1.3.1 Non-mammalian Models;21
1.4.1.3.1.1;1.3.1.1 Unicellular;21
1.4.1.3.1.2;1.3.1.2 Multicellular;22
1.4.1.3.2;1.3.2 Technology-Intensive Screening;24
1.4.1.3.2.1;1.3.2.1 High-Throughput Screening;24
1.4.1.3.2.2;1.3.2.2 Chemogenomics;25
1.4.1.3.2.3;1.3.2.3 Proteome and Kinome Screens;25
1.4.1.3.2.4;1.3.2.4 Nanotechnology;25
1.4.1.3.2.5;1.3.2.5 RNA Interference;26
1.4.1.3.3;1.3.3 In Vitro Models;26
1.4.1.4;1.4 Tumor Models for Cancer Drug Development: Where We Need to Be;27
1.4.1.4.1;1.4.1 “In Vitro” Area Under the Concentration × Time Curve for Target Effect;28
1.4.1.4.2;1.4.2 Qualification of Compound for In Vivo Study;28
1.4.1.4.3;1.4.3 Initial Rodent Pharmacology and Model Selection;29
1.4.1.4.4;1.4.4 Sample Size and Randomization of Animals;29
1.4.1.4.5;1.4.5 Correlative Studies;29
1.4.1.4.6;1.4.6 Additional Desirable Studies;29
1.4.1.5;1.5 Conclusion;30
1.4.1.6;References;31
1.5;Part II Transplantable Syngeneic Rodent Tumors;34
1.5.1;Chapter 2: Murine L1210 and P388 Leukemias;35
1.5.1.1;2.1 Introduction;36
1.5.1.2;2.2 Role in Drug Screening;36
1.5.1.3;2.3 Characteristics;37
1.5.1.4;2.4 Sensitivity to Clinical Agents;38
1.5.1.5;2.5 Predictive Value;44
1.5.1.6;2.6 Drug-Resistant Leukemias;46
1.5.1.6.1;2.6.1 Resistance to Alkylating Agents;46
1.5.1.6.2;2.6.2 Resistance to Antimetabolites;48
1.5.1.6.3;2.6.3 Resistance to DNA- and Tubulin-Binding Agents;48
1.5.1.7;2.7 Conclusions;50
1.5.1.8;References;52
1.5.2;Chapter 3: Transplantable Syngeneic Rodent Tumors: Solid Tumors in Mice;54
1.5.2.1;3.1 Introduction;55
1.5.2.2;3.2 Compatibility! Compatibility! Compatibility!;55
1.5.2.3;3.3 Compatible But Not Perfect: Inbred Mice and Genetic Drift;55
1.5.2.4;3.4 Evidence of Tumor–Host Incompatibility and Consequences;56
1.5.2.4.1;3.4.1 No-Takes;56
1.5.2.4.2;3.4.2 Spontaneous Regressions or Tumors that Fail to Progress to Over 1,000-mg Size;58
1.5.2.4.3;3.4.3 Excessive Curability;58
1.5.2.4.4;3.4.4 Lack of Invasion and Metastasis;61
1.5.2.5;3.5 Compatibility Problems Unique to Human Tumors in Immune-deficient Mice;61
1.5.2.6;3.6 Passage of Tumors in Cell Culture: Maintaining Genotype, Histology, Biologic Behavior, and Drug–Response Characteristic;62
1.5.2.7;3.7 Cancer: a Cellular Disease, Take-Rate, Feeder Effect, Implications for Cure;63
1.5.2.8;3.8 Results Tabulation of Chemotherapy Trials: Desired Information from a Tumor Model;72
1.5.2.9;3.9 Characterization of a Tumor Model and Quality-Control Monitoring;80
1.5.2.10;3.10 Summary;81
1.5.2.11;3.11 Methods;82
1.5.2.11.1;3.11.1 Tumor Maintenance;82
1.5.2.11.2;3.11.2 Origins of Mouse Tumors Used or Discussed;82
1.5.2.11.3;3.11.3 Chemotherapy of Leukemias: L1210/0;83
1.5.2.11.4;3.11.4 X-Irradiation of Solid Tumors;83
1.5.2.11.5;3.11.5 Chemotherapy of Solid Tumors;83
1.5.2.11.6;3.11.6 End Points Assessing Antitumor Activity Solid Tumors;84
1.5.2.11.6.1;3.11.6.1 Tumor-Growth Delay (T–C Value);84
1.5.2.11.6.2;3.11.6.2 Percent Increase Life Span;84
1.5.2.11.7;3.11.7 Calculation Tumor-Cell-Kill;84
1.5.2.11.8;3.11.8 Activity Rating Solid Tumors;85
1.5.2.11.8.1;3.11.8.1 Activity Rating for Leukemia L1210/0;85
1.5.2.11.9;3.11.9 Non-quantitative Determination Antitumor Activity Tumor-Growth Inhibition (T/C Value);86
1.5.2.12;References;86
1.5.3;Chapter 4: B16 Murine Melanoma: Historical Perspective on the Development of a Solid Tumor Model;90
1.5.3.1;4.1 Introduction;90
1.5.3.2;4.2 Historical Context;91
1.5.3.3;4.3 B16 Melanoma;95
1.5.3.4;4.4 Conclusions;101
1.5.3.5;4.5 Dedication;105
1.5.3.6;References;105
1.6;Part III Human Tumor Xenografts;107
1.6.1;Chapter 5: Human Tumor Xenograft Efficacy Models;108
1.6.1.1;5.1 Introduction;108
1.6.1.2;5.2 Xenograft Tumor Models for Efficacy Evaluation;111
1.6.1.2.1;5.2.1 Immunodeficient Mice;111
1.6.1.2.2;5.2.2 Cultured Tumor Cells Vs. Tumor Fragments;112
1.6.1.2.3;5.2.3 Subcutaneous Vs. Orthotopic Transplantation;113
1.6.1.2.4;5.2.4 Tumor Metastasis;114
1.6.1.2.5;5.2.5 Monitoring Tumor Progression and Determining Efficacy;115
1.6.1.2.6;5.2.6 Examples of Single Agent and Combination Preclinical Trials;117
1.6.1.3;5.3 Pros and Cons;121
1.6.1.4;5.4 Pharmacology and Pharmacokinetic Correlations;122
1.6.1.5;5.5 Future Perspectives;124
1.6.1.6;References;126
1.6.2;Chapter 6: Imaging the Steps of Metastasis at the Macro and Cellular Level with Fluorescent Proteins in Real Time;134
1.6.2.1;6.1 Introduction;134
1.6.2.2;6.2 The In Vivo Revolution Sparked by Fluorescent Proteins;135
1.6.2.2.1;6.2.1 Isolation of Stable High-Level Expression GFP and/or RFP Expressing Tumor Cell Lines;135
1.6.2.2.1.1;6.2.1.1 Production of GFP Retrovirus;135
1.6.2.2.1.2;6.2.1.2 Production of RFP Retroviral Vector;135
1.6.2.2.1.3;6.2.1.3 Production of Histone H2B-GFP Vector;136
1.6.2.2.1.4;6.2.1.4 GFP or RFP Gene Transduction of Cancer Cells;136
1.6.2.2.1.5;6.2.1.5 Establishment of Dual-Color Cancer Cells;136
1.6.2.2.2;6.2.2 Imaging Sites of Metastasis;137
1.6.2.2.2.1;6.2.2.1 Patterns of Contralateral and Regional Lung Tumor Metastases Visualized by GFP Expression in Orthotopic Models;137
1.6.2.2.2.2;6.2.2.2 GFP-Expressing Bone Metastases of Lung Cancer in Orthotopic Models;137
1.6.2.2.2.3;6.2.2.3 Prostate-Cancer Bone and Visceral Metastasis Visualized by GFP in Orthotopic Models;137
1.6.2.2.2.4;6.2.2.4 GFP-Expressing Melanoma Bone and Organ Metastasis Models;138
1.6.2.2.2.5;6.2.2.5 GFP-Expressing Brain Metastasis in Orthotopic Models;138
1.6.2.2.2.6;6.2.2.6 GFP-Expressing Experimental Multi-organ Metastases in Nude Mice;138
1.6.2.2.3;6.2.3 Whole-Body Fluorescence Optical Tumor Imaging of Tumor Growth and Metastasis;139
1.6.2.2.4;6.2.4 Whole-Body Imaging of RFP Pancreatic Cancer Progression;139
1.6.2.2.5;6.2.5 Whole-Body Imaging of RFP Prostate Cancer Progression;140
1.6.2.2.6;6.2.6 Whole-Body Imaging of GFP Colon Cancer Progression;140
1.6.2.3;6.3 Imaging Bacterial Targeting of Tumors;141
1.6.2.4;6.4 Advantages of GFP Imaging;144
1.6.2.5;6.5 Viral Labeling of Tumors with GFP in Live Animals;146
1.6.2.5.1;6.5.1 Selective In Vivo Tumor Delivery of the Retroviral Green Fluorescent Protein Gene to Report Future Occurrence of Metas;146
1.6.2.5.2;6.5.2 Telomerase-Dependent Adenovirus to Label Tumors In Vivo for Surgical Navigation;147
1.6.2.6;6.6 Color-Coded Imaging of the Tumor Microenvironment;148
1.6.2.6.1;6.6.1 Color-Coded Imaging of the Tumor–Host Interaction Using Colored Host Mice;148
1.6.2.6.1.1;6.6.1.1 Transgenic GFP Nude Mouse;148
1.6.2.6.1.2;6.6.1.2 Transgenic RFP Nude Mouse;149
1.6.2.6.1.3;6.6.1.3 Transgenic CFP Nude Mouse;150
1.6.2.6.2;6.6.2 Color-Coded Imaging in the Tumor Microenvironment;152
1.6.2.6.3;6.6.3 Noninvasive Color-Coded Imaging of the Tumor Microenvironment;152
1.6.2.7;6.7 Imaging the Cell Biology of Metastasis In Vivo;155
1.6.2.7.1;6.7.1 Dynamic Imaging of GFP or RFP-Expressing Cancer Cells in Blood Vessels and Lymphatics;155
1.6.2.7.2;6.7.2 Imaging Cancer Cell Trafficking in Blood Vessels;156
1.6.2.7.3;6.7.3 Imaging Cancer Cell Trafficking in Lymphatic Vessels;157
1.6.2.7.4;6.7.4 Determining Clonality of Metastasis Using Color-Coded Cancer Cells;158
1.6.2.8;6.8 Imaging Lateral Gene Transfer Between Cancer Cells;158
1.6.2.8.1;6.8.1 Color-Coded Imaging of Circulating Cancer Cells;158
1.6.2.8.2;6.8.2 Color-Coded Imaging of Gene Transfer Between Cancer Cells Interacting In Vivo;160
1.6.2.8.3;6.8.3 Color-Coded Imaging of Gene Transfer from High- to Low-Metastatic Osteosarcoma Cells In Vivo;160
1.6.2.9;6.9 Methods;161
1.6.2.9.1;6.9.1 Imaging Apparatus;161
1.6.2.9.1.1;6.9.1.1 In Vivo Imaging with an LED Flashlight and Filters;161
1.6.2.9.1.2;6.9.1.2 Simple Light-Box Imaging;161
1.6.2.9.1.3;6.9.1.3 In Vivo Imaging with a Fluorescence Dissecting Microscope;162
1.6.2.9.1.4;6.9.1.4 In Vivo Cellular Imaging with a Variable Magnification Imaging Chamber;162
1.6.2.9.1.5;6.9.1.5 Imaging Chambers Designed for Whole-Body Imaging;163
1.6.2.10;6.10 Patient-Like Orthotopic Tumor Models;164
1.6.2.10.1;6.10.1 Surgical Orthotopic Implantation;164
1.6.2.10.1.1;6.10.1.1 Ovarian Cancer;164
1.6.2.10.1.2;6.10.1.2 Lung Cancer;165
1.6.2.10.1.3;6.10.1.3 Prostate Cancer;165
1.6.2.10.1.4;6.10.1.4 Colon Cancer;165
1.6.2.10.1.4.1;Colonic Transplantation;165
1.6.2.10.1.4.2;Intrahepatic Transplantation;166
1.6.2.11;6.11 Technical Details;166
1.6.2.11.1;6.11.1 RFP Retrovirus Production;166
1.6.2.11.2;6.11.2 GFP Retrovirus Production;167
1.6.2.11.3;6.11.3 RFP or GFP Gene Transduction of Tumor Cell Lines;168
1.6.2.11.4;6.11.4 Cell Injection to Establish an Experimental Metastasis Model;168
1.6.2.11.5;6.11.5 Surgical Orthotopic Implantation to Establish a Spontaneous Metastasis Model;168
1.6.2.11.6;6.11.6 Imaging;169
1.6.2.11.6.1;6.11.6.1 Fluorescence Microscopy;169
1.6.2.11.6.2;6.11.6.2 Fluorescence Stereomicroscopy;169
1.6.2.11.7;6.11.7 Chamber Imaging Systems;170
1.6.2.11.7.1;6.11.7.1 Olympus OV100;170
1.6.2.11.7.2;6.11.7.2 INDEC FluorVivo;170
1.6.2.11.7.3;6.11.7.3 UVP iBox;170
1.6.2.11.8;6.11.8 Tumor Tissue Sampling;171
1.6.2.11.9;6.11.9 Measurement of GFP-expressing Tumor Blood Vessel Length and Evaluation of Antiangiogenetic Agents;171
1.6.2.11.10;6.11.10 Immunohistochemical Staining;171
1.6.2.12;References;172
1.6.3;Chapter 7: Patient-Derived Tumor Models and Explants;176
1.6.3.1;7.1 Introduction;176
1.6.3.1.1;7.1.1 Historical Perspective;176
1.6.3.1.2;7.1.2 The Strength of Human Models Derived from Patient Explants;177
1.6.3.2;7.2 Materials and Methods;178
1.6.3.2.1;7.2.1 Establishment of Human Tumor Xenografts from Patient Explants;178
1.6.3.2.1.1;7.2.1.1 Animals;180
1.6.3.2.1.2;7.2.1.2 Tumors;180
1.6.3.2.1.3;7.2.1.3 Tumor Growth Measurements;180
1.6.3.2.2;7.2.2 Experimental Design of Drug Testing;180
1.6.3.2.2.1;7.2.2.1 Study Design;180
1.6.3.2.2.2;7.2.2.2 Chemotherapy;181
1.6.3.2.2.3;7.2.2.3 Evaluation Parameters for Tumor Response;182
1.6.3.2.3;7.2.3 Molecular Target Characterization of the Freiburg Patient-Derived Tumor Xenograft Panel;182
1.6.3.2.4;7.2.4 Clonogenic Assay;183
1.6.3.2.4.1;7.2.4.1 Preparation of Single-Cell Suspensions;183
1.6.3.2.4.2;7.2.4.2 Culture Methods;183
1.6.3.2.5;7.2.5 Gene Signatures;184
1.6.3.3;7.3 Results and Discussion;185
1.6.3.3.1;7.3.1 Take Rates and Growth Behavior of Patient Tumor Explants in Nude Mice;185
1.6.3.3.2;7.3.2 Comparison of Drug Response of a Tumor Growing in the Nude Mouse and in the Patient;186
1.6.3.3.2.1;7.3.2.1 Cytotoxic Agents;186
1.6.3.3.2.2;7.3.2.2 Targeted Agents;187
1.6.3.3.3;7.3.3 Clinically Used Cytotoxic Agents Active in the Freiburg Xenograft Panel;187
1.6.3.3.3.1;7.3.3.1 Cytotoxic Drugs;187
1.6.3.3.3.2;7.3.3.2 Clinically Used Targeted Agents;188
1.6.3.3.3.3;7.3.3.3 Comparison of Freiburg Experience to Other Groups;190
1.6.3.3.4;7.3.4 Molecular Characterization of Human Tumor Xenografts for Target-Oriented Drug Discovery;191
1.6.3.3.4.1;7.3.4.1 Significance of Gene Signatures for Anticancer Therapy;191
1.6.3.3.4.2;7.3.4.2 Significance of Tumor Tissue Microarrays;192
1.6.3.3.4.3;7.3.4.3 Target Prevalence in the Freiburg Tumor Collection;193
1.6.3.3.5;7.3.5 Assessment of In Vivo Efficacy of Anticancer Agents Drug Discovery Using the Freiburg Xenograft System;194
1.6.3.3.6;7.3.6 Selected Examples of Anticancer Agents in Clinical Trials Which Have Been Discovered in a Target-Oriented Approach;197
1.6.3.3.7;7.3.7 Possible Future Impact of Patient-Derived Tumor Xenografts and Explants;198
1.6.3.4;7.4 Summary;198
1.6.3.5;References;199
1.6.4;Chapter 8: The Pediatric Preclinical Testing Program;203
1.6.4.1;8.1 Introduction;203
1.6.4.2;8.2 Selection of Preclinical Models;204
1.6.4.3;8.3 Molecular Characterization of Tumor Models;207
1.6.4.3.1;8.3.1 Model Fidelity;209
1.6.4.3.2;8.3.2 Primary Screening;210
1.6.4.3.3;8.3.3 Response Criteria: Solid Tumors;211
1.6.4.3.4;8.3.4 Response Criteria: Acute Lymphoblastic Leukemia Xenograft Models;212
1.6.4.3.4.1;8.3.4.1 Event-Free Survival;212
1.6.4.3.4.2;8.3.4.2 Tumor Growth Delay Value;213
1.6.4.3.4.3;8.3.4.3 Tumor Volume T/C Value;213
1.6.4.3.4.4;8.3.4.4 EFS T/C Value;213
1.6.4.4;8.4 Data Presentation;214
1.6.4.5;8.5 Secondary Screening;216
1.6.4.6;8.6 Combination Drug Testing;217
1.6.4.7;8.7 Secondary Models;218
1.6.4.8;8.8 Integrating Molecular Data with Drug Sensitivity;218
1.6.4.8.1;8.8.1 Submitting Agents to the PPTP;218
1.6.4.9;8.9 Closing Remarks;219
1.6.4.10;References;220
1.6.5;Chapter 9: Imaging Efficacy in Tumor Models;222
1.6.5.1;9.1 Introduction;222
1.6.5.2;9.2 Challenges in Preclinical Imaging;223
1.6.5.3;9.3 Imaging Modalities: Technical Overview and Use in Oncology Models;224
1.6.5.3.1;9.3.1 Magnetic Resonance Imaging;224
1.6.5.3.2;9.3.2 Computed Tomography;225
1.6.5.3.3;9.3.3 Positron Emission Tomography;226
1.6.5.3.4;9.3.4 Single Photon Emission Computed Tomography;227
1.6.5.3.5;9.3.5 In Vivo Optical Imaging;227
1.6.5.3.6;9.3.6 Ultrasound;228
1.6.5.4;9.4 Imaging End Points in Oncology Models;229
1.6.5.4.1;9.4.1 Anatomical Imaging;229
1.6.5.4.1.1;9.4.1.1 Tumor Detection and Staging;229
1.6.5.4.1.2;9.4.1.2 Tumor Burden;230
1.6.5.4.2;9.4.2 Functional Imaging;231
1.6.5.4.2.1;9.4.2.1 Imaging Tumor Metabolism and Metabolite Levels;231
1.6.5.4.2.2;9.4.2.2 Cell Proliferation;234
1.6.5.4.2.3;9.4.2.3 Vascular Imaging, Permeability, and Blood Flow;234
1.6.5.4.2.4;9.4.2.4 Tumor Cellularity and Cell Kill;236
1.6.5.4.2.5;9.4.2.5 Receptor Occupancy and Gene Expression;236
1.6.5.4.2.6;9.4.2.6 Tissue Hypoxia and pH;237
1.6.5.4.2.7;9.4.2.7 Apoptosis;237
1.6.5.4.2.8;9.4.2.8 Imaging of Oncogenic Pathways;238
1.6.5.4.2.9;9.4.2.9 Other Imaging Applications in Oncology;238
1.6.5.5;9.5 Imaging Efficacy in Oncology Models: Future Outlook;239
1.6.5.6;References;239
1.7;Part IV Carcinogen-Induced Tumors;249
1.7.1;Chapter 10: Mammary Cancer in Rats;250
1.7.1.1;10.1 Introduction;250
1.7.1.2;10.2 Historical Perspective;251
1.7.1.2.1;10.2.1 Induction of Mammary Carcinomas Using MNU;252
1.7.1.2.2;10.2.2 Carcinogen Dose and Age of Administration;253
1.7.1.2.3;10.2.3 Typical Animal Protocols;254
1.7.1.2.3.1;10.2.3.1 Chemoprevention Protocol;254
1.7.1.2.3.2;10.2.3.2 Therapeutic Protocol;256
1.7.1.2.4;10.2.4 Biological Characteristic of Mammary Carcinomas Induced by MNU;256
1.7.1.2.5;10.2.5 Value of this Model Relative to Genetically Engineered Models for Mammary Cancer;258
1.7.1.3;References;258
1.8;Part V Disease and Target-Specific Models;261
1.8.1;Chapter 11: Animal Models of Melanoma;262
1.8.1.1;11.1 Introduction;262
1.8.1.2;11.2 Xiphophorus Species;263
1.8.1.3;11.3 South American Opossum;264
1.8.1.4;11.4 Canine Melanoma;266
1.8.1.5;11.5 Sinclair Swine;267
1.8.1.6;11.6 Murine Models;269
1.8.1.6.1;11.6.1 Induction with Physical Agents;269
1.8.1.6.2;11.6.2 Tumors Arising in Transgenic Mice;271
1.8.1.6.3;11.6.3 Spontaneously Arising Murine Melanomas;274
1.8.1.6.3.1;11.6.3.1 Models Employing the B16 Cell Line;274
1.8.1.6.4;11.6.4 Tumor Models that Employ Immunodeficient Mice;277
1.8.1.6.4.1;11.6.4.1 Nude Mouse Models;279
1.8.1.6.4.2;11.6.4.2 SCID Mouse Models;280
1.8.1.7;References;282
1.8.2;Chapter 12: Experimental Animal Models for Investigating Renal Cell Carcinoma Pathogenesis and Preclinical Therapeutic Approac;289
1.8.2.1;12.1 Introduction;289
1.8.2.2;12.2 Murine Syngeneic Renal Adenocarcinoma: The Renca Model;290
1.8.2.3;12.3 Rat Renal Carcinoma Models;296
1.8.2.3.1;12.3.1 The Wistar–Lewis Rat Renal Adenocarcinoma;296
1.8.2.3.2;12.3.2 The Eker Rat Model;297
1.8.2.4;12.4 Xenografts of Human RCC Tumor Cell Linesin Immunodeficient Mice;298
1.8.2.5;References;302
1.8.3;Chapter 13: Animal Models of Mesothelioma;308
1.8.3.1;13.1 Introduction;308
1.8.3.2;13.2 Asbestos-Induced Mesothelioma in Animal Models;309
1.8.3.2.1;13.2.1 Types of Asbestos Fibers;309
1.8.3.2.2;13.2.2 Asbestos-Induced Animal Models of Mesothelioma: General Comments;310
1.8.3.2.3;13.2.3 Intraperitoneal Asbestos Injection;311
1.8.3.2.4;13.2.4 Intraperitoneal Asbestos Injection: Rats;311
1.8.3.2.5;13.2.5 Intraperitoneal Asbestos Injection: Mice;312
1.8.3.2.6;13.2.6 Intrapleural Asbestos Injection;313
1.8.3.2.7;13.2.7 Intrapleural Asbestos Injection: Rat;313
1.8.3.2.8;13.2.8 Inhalation of Asbestos in Animal Models;314
1.8.3.2.8.1;13.2.8.1 Inhalation Studies in Rats;314
1.8.3.2.8.2;13.2.8.2 Inhalation Studies: Guinea Pig;314
1.8.3.2.8.3;13.2.8.3 Intratracheal Asbestos Administration;314
1.8.3.2.8.4;13.2.8.4 Intratracheal Asbestos Administration: Syrian Golden Hamster;315
1.8.3.3;13.3 Spontaneous Models of Mesothelioma;315
1.8.3.4;13.4 Other Agents for Animal Production of Mesothelioma;315
1.8.3.4.1;13.4.1 Chemical;315
1.8.3.4.2;13.4.2 Man-Made Fibers;316
1.8.3.5;13.5 Novel Viral-Induced and Transgenic Knockout Models of Mesothelioma;317
1.8.3.5.1;13.5.1 SV40 Viral Hamster Models;317
1.8.3.5.2;13.5.2 SV40 Transgenic Mouse Models;319
1.8.3.5.3;13.5.3 Transgenic Murine Models, Utilizing Nf2, Ink4a/ARF, and P53 Knockout Mice;319
1.8.3.6;13.6 Orthotopic Transplants and Xenograft;320
1.8.3.7;13.7 Conclusions;322
1.8.3.8;References;322
1.8.4;Chapter 14: The Use of Mouse Models to Study Leukemia/Lymphoma and Assess Therapeutic Approaches;326
1.8.4.1;14.1 Introduction;326
1.8.4.1.1;14.1.1 Models of Myeloid Leukemia;328
1.8.4.1.2;14.1.2 Models of Acute Lymphocytic Leukemia;331
1.8.4.1.3;14.1.3 Chronic Lymphocytic Leukemia;333
1.8.4.1.4;14.1.4 HTLV-Related T Cell Leukemia/Lymphoma;335
1.8.4.2;14.2 Models of Hodgkin’s Lymphoma;335
1.8.4.3;14.3 Models of Non-Hodgkin’s Lymphoma;337
1.8.4.4;14.4 Models of Multiple Myeloma;340
1.8.4.5;14.5 Conclusions;342
1.8.4.6;References;343
1.8.5;Chapter 15: Spontaneous Companion Animal (Pet) Cancers;353
1.8.5.1;15.1 Introduction;353
1.8.5.2;15.2 Overview of Cancer in Companion Animal Species;354
1.8.5.2.1;15.2.1 Cancer Incidence and Availability of Veterinary Medical Care;354
1.8.5.2.2;15.2.2 Genetic and Molecular Basis of Cancer in Pet Dogs;355
1.8.5.3;15.3 Potential Opportunities/Advantages of Including Companion Animals with Cancer as Models;358
1.8.5.4;15.4 Caveats to Inclusion of Pet Dogs with Cancer as Models;362
1.8.5.5;15.5 The Vested Communities;364
1.8.5.6;15.6 Study Design Issues Specific to Companion Species Trials;366
1.8.5.7;15.7 Conclusions;368
1.8.5.8;References;369
1.9;Part VI Genetically Engineered Mouse Models of Cancer;374
1.9.1;Chapter 16: Genetically Engineered Mouse Models of Pancreatic Ductal Adenocarcinoma;375
1.9.1.1;16.1 Pancreas Anatomy, Physiology, and Development;376
1.9.1.2;16.2 Histological and Molecular Characteristics of Human PDAC;377
1.9.1.3;16.3 Modeling PDAC;378
1.9.1.4;16.4 Transgenic Expression of Oncogenes in the Pancreas;379
1.9.1.5;16.5 Viral Delivery of Oncogenes;380
1.9.1.6;16.6 Compound Inducible Mutants;380
1.9.1.6.1;16.6.1 Cooperation Between Kras and Tumor Suppressors in PDAC;382
1.9.1.6.2;16.6.2 Preclinical Studies;384
1.9.1.7;16.7 Ongoing and Future Modeling Efforts;386
1.9.1.8;16.8 Conclusions;388
1.9.1.9;References;388
1.9.2;Chapter 17: Transgenic Adenocarcinoma of the Mouse Prostate: A Validated Model for the Identification and Characterization of M;394
1.9.2.1;17.1 Introduction;394
1.9.2.2;17.2 Generation of the TRAMP Model and Phenotypic Characterization;396
1.9.2.3;17.3 Gene Expression Profiling Studies;398
1.9.2.4;17.4 Epigenetic Regulation of Gene Expression;400
1.9.2.5;17.5 Validating and Elucidating Gene Function Through Additional Genetic Engineering;403
1.9.2.6;17.6 Testing of Known and Putative Therapeutic Agents;404
1.9.2.7;17.7 Summary, Conclusions, and Future Directions;411
1.9.2.8;References;412
1.9.3;Chapter 18: The Utility of Transgenic Mouse Models for Cancer Prevention Research;419
1.9.3.1;18.1 Introduction;419
1.9.3.2;18.2 Cancer Prevention in Transgenic Mice: Lessons Learned from Commonly Used Models;420
1.9.3.2.1;18.2.1 Mutant Mouse Models for Prostate Cancer Prevention;420
1.9.3.2.1.1;18.2.1.1 PTEN Mutant Mouse Models;420
1.9.3.2.1.2;18.2.1.2 c-Myc Transgenic Mice;421
1.9.3.2.1.3;18.2.1.3 Viral Oncogene Models;421
1.9.3.2.2;18.2.2 Mutant Mouse Models for Mammary Cancer Prevention;423
1.9.3.2.2.1;18.2.2.1 TGFa Models;423
1.9.3.2.2.2;18.2.2.2 ErbB-2/HER2/neu Models;423
1.9.3.2.2.3;18.2.2.3 SV40 T-antigen Transgenic Models;424
1.9.3.2.2.4;18.2.2.4 p53-mutant Mouse Models;424
1.9.3.2.2.5;18.2.2.5 MMTV-Wnt-1 Transgenic Mouse Model;425
1.9.3.2.2.6;18.2.2.6 Ras Mutant Models;426
1.9.3.2.2.7;18.2.2.7 c-myc Transgenic Mice;426
1.9.3.2.2.8;18.2.2.8 Cyclin D1 Transgenic Mice;426
1.9.3.2.2.9;18.2.2.9 Inducible Models;427
1.9.3.2.2.10;18.2.2.10 Examples of Dietary or Chemopreventive Studies Using Transgenic Mouse Models of Mammary Cancer;427
1.9.3.2.2.10.1;Selective Estrogen Receptor Modulators;427
1.9.3.2.2.10.2;Aromatase Inhibitors;428
1.9.3.2.2.10.3;Retinoids;428
1.9.3.2.2.10.4;Tyrosine Kinase Inhibitors;428
1.9.3.2.2.10.5;Nonsteroidal Anti-Inflammatory Drugs/Cyclooxygenase-2 Inhibitors;429
1.9.3.2.2.10.6;Energy Balance Interventions;429
1.9.3.2.3;18.2.3 Apc-Deficient Models for Intestinal Cancer Prevention Studies;429
1.9.3.2.4;18.2.4 Emerging Models of Pancreatic Cancer;430
1.9.3.3;18.3 Summary and Conclusions;432
1.9.3.4;References;433
1.10;Part VII Metastasis Models;440
1.10.1;Chapter 19: Models for Evaluation of Targeted Therapies of Invasive and Metastatic Disease;441
1.10.1.1;19.1 Introduction;441
1.10.1.2;19.2 Therapeutic Strategies for Targeting Metastases;443
1.10.1.2.1;19.2.1 Target Identification and Validation;443
1.10.1.2.2;19.2.2 Molecular Targets;444
1.10.1.2.2.1;19.2.2.1 Oncogenic Receptor Tyrosine Kinase Signaling Pathways;444
1.10.1.2.2.2;19.2.2.2 HSP90 Chaperone;456
1.10.1.2.2.3;19.2.2.3 Chemokine Receptors;456
1.10.1.2.2.4;19.2.2.4 BCr-Abl: A Paradigm for Tumor-Specific Therapy;457
1.10.1.2.2.5;19.2.2.5 Hedgehog (Hh);457
1.10.1.2.2.6;19.2.2.6 Wnt Pathway;458
1.10.1.2.2.7;19.2.2.7 Combination Therapies;458
1.10.1.2.3;19.2.3 Processes Linked to Metastasis;458
1.10.1.2.3.1;19.2.3.1 Angiogenesis and Hypoxia;458
1.10.1.2.3.2;19.2.3.2 Proteolysis in Invasion and Angiogenesis;460
1.10.1.2.3.3;19.2.3.3 Intravasation and Extravasation;460
1.10.1.2.3.4;19.2.3.4 The Premetastatic Niche;461
1.10.1.2.4;19.2.4 Resistance to Therapy;461
1.10.1.2.4.1;19.2.4.1 Cancer Stem-Like Cells;461
1.10.1.2.4.2;19.2.4.2 Dormant Metastases;462
1.10.1.2.5;19.2.5 Immunological Approaches;463
1.10.1.2.5.1;19.2.5.1 Antibody-Based Therapies;463
1.10.1.2.5.2;19.2.5.2 Vaccines, Cytokines, and Cell-Mediated Immunotherapy;463
1.10.1.2.5.3;19.2.5.3 Targeting Using Vectors or Peptides with Tumor Selectivity;464
1.10.1.3;19.3 Detection and Quantitation of Metastases and Determination of Therapeutic Benefit;464
1.10.1.4;19.4 Animal Models for Evaluating Targeted Therapy of Metastasis;466
1.10.1.4.1;19.4.1 Syngeneic Rodent Tumor Models;466
1.10.1.4.2;19.4.2 Human Tumor Xenograft Models;466
1.10.1.4.3;19.4.3 Organ Colonization and Site-Selective Metastases;468
1.10.1.4.3.1;19.4.3.1 Lung Metastases;468
1.10.1.4.3.2;19.4.3.2 Liver Metastasis;469
1.10.1.4.3.3;19.4.3.3 Brain Metastasis;469
1.10.1.4.3.4;19.4.3.4 Bone Metastasis;469
1.10.1.4.4;19.4.4 Spontaneous Metastasis Models;470
1.10.1.4.4.1;19.4.4.1 Orthotopic Implantation Models;471
1.10.1.4.4.2;19.4.4.2 Lymph Node Metastases;471
1.10.1.4.5;19.4.5 Transgenic Models;472
1.10.1.5;19.5 Summary and Conclusions;474
1.10.1.6;References;475
1.11;Part VIII Normal Tissue Response Models;490
1.11.1;Chapter 20: Animal Models of Toxicities Caused by Anti-Neoplastic Therapy;491
1.11.1.1;20.1 Introduction;491
1.11.1.2;20.2 Models of Oral Mucositis Induced by Anti-Neoplastic Drugs and Radiation;492
1.11.1.2.1;20.2.1 Overview of the Condition;492
1.11.1.2.2;20.2.2 The Biology of Mucositis;493
1.11.1.2.3;20.2.3 Objectives of Animal Models of Mucositis;494
1.11.1.2.4;20.2.4 Current Models;494
1.11.1.2.4.1;20.2.4.1 Screening Models for the Enablement of Pharmaceuticalsand Biologicals;496
1.11.1.2.4.1.1;Background;496
1.11.1.2.4.1.2;History of Radiation Model Development in Hamsters;496
1.11.1.2.4.2;20.2.4.2 The Hamster Model for Acute Radiation-Induced Mucositis;496
1.11.1.2.4.3;20.2.4.3 Non-Clinical Endpoints;1
1.11.1.2.4.4;20.2.4.4 The Hamster Model for Fractionated Radiation-Induced Mucositis;500
1.11.1.2.4.5;20.2.4.5 Hamster Models for Chemotherapy-Induced Mucositis Withor Without Concomitant Radiation;500
1.11.1.2.4.6;20.2.4.6 Chemotherapy-Induced Oral Mucositis;500
1.11.1.2.4.7;20.2.4.7 Concomitant Chemotherapy and Radiation;501
1.11.1.3;20.3 Chemotherapy-Induced Mucositis of the GI Tract;501
1.11.1.3.1;20.3.1 Models of Intestinal Mucositis;501
1.11.1.3.1.1;20.3.1.1 Use of Endoscopy to Assess Chemotherapy-Induced Mucosal Injury;502
1.11.1.4;20.4 Radiation-Induced Proctitis;503
1.11.1.4.1;20.4.1 Overview of the Condition;503
1.11.1.4.2;20.4.2 The Biology of Radiation-Induced Proctitis;503
1.11.1.4.3;20.4.3 Animal Model of Radiation-Induced Proctitis;504
1.11.1.4.3.1;20.4.3.1 Radiation-Induced Dermatitis;504
1.11.1.4.3.1.1;Overview of the Condition;504
1.11.1.4.4;20.4.4 The Biology of Radiation-Induced Dermatitis;505
1.11.1.4.5;20.4.5 Animal Model of Radiation-Induced Dermatitis;505
1.11.1.4.6;20.4.6 Bisphosphonate-Related Osteonecrosis of the Jaws;507
1.11.1.4.6.1;20.4.6.1 Introduction;507
1.11.1.4.6.2;20.4.6.2 Rat Model for Bisphosphonate-Associated Osteonecrosis of the Jaws;508
1.11.1.5;References;509
1.11.2;Chapter 21: Bone Marrow as a Critical Normal Tissuethat Limits Drug Dose/Exposure in Preclinical Models and the Clinic1;512
1.11.2.1;21.1 Introduction;513
1.11.2.2;21.2 Blood Cytopenia as a Quantifiable Dose-Limiting Toxicity in the Oncology Clinic;514
1.11.2.3;21.3 Cancer Therapeutics as Toxicants to Highly Proliferative Hematopoietic Cells;516
1.11.2.4;21.4 Bone Marrow as a Critical Normal Tissue that Sets Maximum Human Dose/Exposure and Therefore Should Restrict Dose/Exposur;521
1.11.2.5;21.5 Using Hematotoxicology to Limit Treatment of Mouse Models to Tolerated Human Doses/Exposures;523
1.11.2.5.1;21.5.1 Method 1: Treating Mouse Models at Maximum Tolerated Human Dose, Predicted Using CFU-GM Assays;524
1.11.2.5.2;21.5.2 Method 2: Treating Mouse Models at Maximum Tolerated Human Dose/Exposure Determined Empirically Using NOD/SCID Mice En;528
1.11.2.6;21.6 Concluding Thoughts on Improving the Predictive Accuracy of Mouse Efficacy Models Using Human Hematotoxicology Data;536
1.11.2.7;References;538
1.11.3;Chapter 22: Anesthetic Considerations for the Study of Murine Tumor Models;544
1.11.3.1;22.1 Overview;544
1.11.3.2;22.2 Rationale and Requirements for Animal Anesthesia in Cancer Research;544
1.11.3.2.1;22.2.1 Humane Reasons;545
1.11.3.2.2;22.2.2 To Control Motion;545
1.11.3.3;22.3 Special Requirements for Anesthesia in Cancer Research;545
1.11.3.3.1;22.3.1 Non-Survival Surgery;545
1.11.3.3.2;22.3.2 Survival Surgery;545
1.11.3.3.3;22.3.3 Functional Studies;546
1.11.3.3.4;22.3.4 Controlled Delivery of Anticancer Treatment;546
1.11.3.3.5;22.3.5 Assessment of Anesthetic Depth in Rodents;547
1.11.3.4;22.4 Animal Support;547
1.11.3.4.1;22.4.1 Body Temperature;547
1.11.3.4.2;22.4.2 Respiration;548
1.11.3.4.3;22.4.3 Hydration;549
1.11.3.4.4;22.4.4 Analgesia;549
1.11.3.4.5;22.4.5 Inhalable Anesthetics;549
1.11.3.5;22.5 Isoflurane;550
1.11.3.5.1;22.5.1 Background About the Drug;550
1.11.3.5.2;22.5.2 Anesthetic Properties;551
1.11.3.5.3;22.5.3 Typical Applications;551
1.11.3.5.4;22.5.4 Required Equipment;552
1.11.3.5.5;22.5.5 Protocol for Isoflurane in Mice and Rats;552
1.11.3.5.6;22.5.6 Induction of Anesthesia in Rats with Isoflurane, Followed by Injectable Anesthesia;552
1.11.3.6;22.6 Injectible Anesthetics;553
1.11.3.6.1;22.6.1 Ketamine HCl with Xylazine;553
1.11.3.6.1.1;22.6.1.1 Background and Biochemistry;553
1.11.3.6.1.2;22.6.1.2 Anesthetic Properties in Rodents;553
1.11.3.6.1.3;22.6.1.3 Impact of Ketamine on Rodent Physiology;554
1.11.3.6.1.4;22.6.1.4 Anesthesia Protocol of Mice Using Ketamine/Xylazine Anesthesia;554
1.11.3.6.1.4.1;Preparation;554
1.11.3.6.1.4.2;Protocol;554
1.11.3.7;22.7 Pentobarbital;555
1.11.3.7.1;22.7.1 Background and Biochemistry;555
1.11.3.7.2;22.7.2 Anesthetic Properties in Rodents;555
1.11.3.7.3;22.7.3 Physiological Impact of Pentobarbital;556
1.11.3.7.4;22.7.4 Applications;556
1.11.3.7.5;22.7.5 Protocol for Pentobarbital Anesthesia in Mice;556
1.11.3.7.5.1;22.7.5.1 Preparation;556
1.11.3.7.5.2;22.7.5.2 Protocol;557
1.11.3.7.6;22.7.6 Other Injectibles;557
1.11.3.8;22.8 Summary;557
1.11.3.9;References;558
1.12;Part IX Experimental Methods and Endpoints;560
1.12.1.1;23.1 Introduction;1
1.12.1.2;23.2 Ascites Tumors;562
1.12.1.3;23.3 Solid Tumors;564
1.12.1.4;23.4 Combination Treatments;568
1.12.1.5;23.5 Therapeutic Index;576
1.12.1.6;23.6 In Vivo/Ex Vivo Assay of Primary and Metastatic Disease;577
1.12.1.7;23.7 In Vivo Resistant Tumors;579
1.12.1.8;23.8 Drug Penetration into Tumor;580
1.12.1.9;23.9 Conclusion;587
1.12.1.10;References;588
1.12.2;Chapter 24: Tumor Cell Survival;596
1.12.2.1;24.1 Introduction;597
1.12.2.2;24.2 Selection of Tumor–Host Systems;598
1.12.2.3;24.3 Cell Survival Assays;600
1.12.2.3.1;24.3.1 Implications of Clonogenic Cell Survival;600
1.12.2.3.2;24.3.2 Measuring Clonogenicity;600
1.12.2.3.2.1;24.3.2.1 Identifying Clonogenic Cells;601
1.12.2.3.2.2;24.3.2.2 Motion Artifacts;603
1.12.2.3.2.3;24.3.2.3 Cell Density Problems;603
1.12.2.3.2.4;24.3.2.4 Colony Density Problems;604
1.12.2.3.2.5;24.3.2.5 Counting the Colonies;604
1.12.2.3.3;24.3.3 Tumor Cell Suspensions;605
1.12.2.3.3.1;24.3.3.1 Preparing the Suspension;605
1.12.2.3.3.2;24.3.3.2 Counting the Cells;606
1.12.2.3.3.3;24.3.3.3 The Importance of Single-Cell Suspensions;606
1.12.2.3.4;24.3.4 Scheduling Problems in Clonogenic Assays;607
1.12.2.4;24.4 Analysis of Cell Survival Data;609
1.12.2.5;24.5 Conclusions;611
1.12.2.6;References;611
1.12.3;Chapter 25: Apoptosis In Vivo;614
1.12.3.1;25.1 Introduction;614
1.12.3.2;25.2 Recognition and Quantification of Apoptosis;615
1.12.3.2.1;25.2.1 Morphological Assessment In Vivo;615
1.12.3.2.2;25.2.2 Quantification of Apoptosis In Vitro;616
1.12.3.3;25.3 Apoptosis in Tumor Biology;617
1.12.3.3.1;25.3.1 The Role of Apoptosis in Tumor Development;617
1.12.3.3.2;25.3.2 Genetic Regulation of Apoptosis;618
1.12.3.4;25.4 Apoptosis in Cancer Therapy;620
1.12.3.4.1;25.4.1 Response of Normal Tissue to Cytotoxic Therapy;620
1.12.3.4.2;25.4.2 Apoptosis in Tumors Responding to Cytotoxic Therapy;621
1.12.3.4.3;25.4.3 In Vivo Imaging of Apoptosis;624
1.12.3.5;25.5 Summary and Conclusions;625
1.12.3.6;References;625
1.12.4;Chapter 26: Transparent Window Models and Intravital Microscopy: Imaging Gene Expression, Physiological Function and Therapeuti;630
1.12.4.1;26.1 Introduction;630
1.12.4.2;26.2 Chronic Window Preparations;633
1.12.4.2.1;26.2.1 Procedures;635
1.12.4.2.1.1;26.2.1.1 Rabbit Ear Chamber;635
1.12.4.2.1.2;26.2.1.2 Dorsal Skin Chamber Preparation;636
1.12.4.2.1.3;26.2.1.3 Mammary Fat Pad Chamber Preparation;637
1.12.4.2.1.4;26.2.1.4 Cranial Window Preparation;637
1.12.4.2.1.5;26.2.1.5 Angiogenesis Gel Assay and Tissue Engineered Vessel Model;638
1.12.4.3;26.3 Acute (Exteriorized) Preparations;641
1.12.4.3.1;26.3.1 Procedures;641
1.12.4.3.1.1;26.3.1.1 Mesentery;641
1.12.4.3.1.2;26.3.1.2 Liver Tumor Preparation;641
1.12.4.3.1.3;26.3.1.3 Pancreatic Tumor Preparation;642
1.12.4.3.1.4;26.3.1.4 Mammary Fat Pad Tumor Preparation;643
1.12.4.4;26.4 In Situ Preparations;643
1.12.4.4.1;26.4.1 Procedures;644
1.12.4.4.1.1;26.4.1.1 Corneal Pocket Assay;644
1.12.4.4.1.2;26.4.1.2 Chick Chorioallantoic Membrane;644
1.12.4.4.1.3;26.4.1.3 Tail Lymphatics;645
1.12.4.4.1.4;26.4.1.4 Ear Model;645
1.12.4.5;26.5 Intravital Microscopy and Image Analysis;647
1.12.4.5.1;26.5.1 Intravital Microscopy Work Station;647
1.12.4.5.1.1;26.5.1.1 Conventional Single-Photon Microscopy;647
1.12.4.5.1.2;26.5.1.2 Multiphoton Laser-Scanning Microscopy;647
1.12.4.5.1.3;26.5.1.3 Optical Frequency Domain Imaging;647
1.12.4.5.2;26.5.2 Tumor Growth and Regression;649
1.12.4.5.3;26.5.3 Vascular Parameters;649
1.12.4.5.3.1;26.5.3.1 Angiogenesis and Hemodynamics;649
1.12.4.5.3.1.1;Single-Photon Microscopy Procedure;650
1.12.4.5.3.1.2;Multiphoton Laser-Scanning Microscopy Procedure;650
1.12.4.5.3.2;26.5.3.2 Vascular Permeability;651
1.12.4.5.3.2.1;Single-Photon Microscopy Procedure;651
1.12.4.5.3.2.2;Multiphoton Laser-Scanning Microscopy Procedure;651
1.12.4.5.3.3;26.5.3.3 Leukocyte Endothelial Interactions;652
1.12.4.5.3.3.1;Single-Photon Microscopy Procedure [92];652
1.12.4.5.3.3.2;Multiphoton Laser-Scanning Microscopy Procedure [80];652
1.12.4.5.4;26.5.4 Extravascular Parameters;653
1.12.4.5.4.1;26.5.4.1 Interstitial pH Measurements;653
1.12.4.5.4.2;26.5.4.2 Interstitial and Microvascular pO2 Measurements;654
1.12.4.5.4.3;26.5.4.3 Tissue Nitric Oxide Distribution;654
1.12.4.5.4.4;26.5.4.4 Interstitial Diffusion, Convection, and Bindings;655
1.12.4.5.4.4.1;Single-Photon Fluorescence Recovery After Photobleaching Procedures;655
1.12.4.5.4.4.2;Multiphoton Fluorescence Recovery After Photobleaching Procedures [101];656
1.12.4.5.4.4.3;Multiphoton Fluorescence Correlation Spectroscopy Procedures [102];656
1.12.4.5.4.5;26.5.4.5 Gene Expression: Promoter Activity via GFP Imaging;657
1.12.4.6;26.6 Novel Insights;658
1.12.4.7;26.7 Future Perspectives;660
1.12.4.8;References;660
1.13;Index;669

Über Autor(innen)

Dr. Beverly A. Teicher is Senior Scientific Director in Cancer Research at Genzyme Molecular Oncology and Genzyme Corporation, Framingham, Massachusetts. She has authored or co-authored more than 400 scientific publications, has edited five books, senior editor for the journal Clinical Cancer Research and is series editor for the Cancer Drug Discovery and Development book series.