Meyer Vascular Disruptive Agents for the Treatment of Cancer

1. Auflage 2010
ISBN: 978-1-4419-6609-4
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Wasserzeichen (»Systemvoraussetzungen)

E-Book, Englisch, 256 Seiten

Angiogenesis (formation of new vessels from pre-existing ones) is a crucial early event in the process of tumor development. New vessels supply the tumor with nutrients that are needed for further local growth and enable distant metastases (Folkman 1995). Judah Folkman (1971) highlighted the potential therapeutic imp- cations of tumor angiogenesis. He hypothesized that if tumor angiogenesis is inhibited, then tumor growth and metastasis will be impaired greatly or even impossible. The subsequent quest for endogenous and exogenous inhibitors of angiogenesis has yielded a variety of promising therapeutic agents that block one or more angiogenic pathways, a few of which have been approved by the FDA (e. g. , bevacizumab, sorafenib, sunitinib) for use as single agents or in combination with chemotherapy in specific populations of cancer patients (Sessa et al. 2008). There has also been a dramatic expansion in the exploration of novel anti-angiogenic agents pre-clinically and in clinical trials (Ferrara 2002). Some of the most promising data comes from the development of agents that inhibit one of the key growth factors involved in tumor angiogenesis - vascular endothelial growth factor (VEGF) (Ferrara et al. 2003). Bevacizumab is a monoclonal antibody against VEGF that was the first an- angiogenic agent that improved significantly the overall survival of patients with colorectal and non-squamous non-small cell lung cancer (Ferrara et al. 2005). Various agents that target tumor angiogenesis are currently under investigation in different cancer types in many clinical trials (Ferrara and Kerbel 2005).

Dr. Tim Meyer is a Senior Lecturer in Medical Oncology at the UCL Cancer Institute in London where he specialises in gastrointestinal cancers and drug development. He trained in medicine at UCL and obtained his PhD from London University, after which he completed specialist training in medical oncology. His major research focus is antibody-based vascular targeting.

Autoren/Hrsg.

Meyer, Tim

Inhaltsverzeichnis

1;Vascular Disruptive Agentsfor the Treatment of Cancer;3
1.1;Contents;5
1.2;Contributors;7
1.3;Development of Vascular Disrupting Agents;10
1.3.1;1 Introduction;10
1.3.2;2 Early Studies Supporting the Development of Vascular Disrupting Cancer Therapies;14
1.3.2.1;2.1 Testicular Torsion;14
1.3.2.2;2.2 William Henry Woglom;15
1.3.2.3;2.3 Tumor Clamping Studies;15
1.3.2.4;2.4 Coley’s Toxins;16
1.3.3;3 Vascular Disrupting Therapies Employing High Molecular Weight Agents;17
1.3.3.1;3.1 Engineered Ligands;17
1.3.3.2;3.2 Antibody-Based Approaches;18
1.3.3.3;3.3 Gene Therapy;19
1.3.4;4 Small Molecule Vascular Disrupting Agents;21
1.3.4.1;4.1 Metals and Metalloids;21
1.3.4.2;4.2 Flavonoids/Xanthenones;21
1.3.4.3;4.3 N-Cadherin Antagonists;22
1.3.4.4;4.4 Colchicine;22
1.3.4.5;4.5 Novel Vascular Disrupting Tubulin Depolymerizing Agents;23
1.3.5;5 Combining VDAs with Other Therapies;25
1.3.6;6 Clinical Experience with VDAs;26
1.3.7;7 Concluding Remarks;28
1.3.8;References;28
1.4;Part I Pre-Clinical Development;37
1.4.1;The Discovery and Characterisation of Tumour Endothelial Markers;38
1.4.1.1;1 Vascular Tumor Targeting: Concepts and Definitions;38
1.4.1.2;2 Methodologies for the Discovery of Vascular Tumor Targets;39
1.4.1.3;3 Ligand-Based Pharmacodelivery Applications;42
1.4.1.4;4 Validated Vascular Tumor Targets;43
1.4.1.4.1;4.1 EDA and EDB Domains of Fibronectin;43
1.4.1.4.2;4.2 Extra Domains of Within Tenascin-C;44
1.4.1.4.3;4.3 Endoglin;44
1.4.1.4.4;4.4 Prostate-Specific Membrane Antigen;45
1.4.1.4.5;4.5 Annexin A1;45
1.4.1.4.6;4.6 Phosphatidylserine Phospholipids;45
1.4.1.4.7;4.7 VEGF-A and VEGF Receptors;46
1.4.1.4.8;4.8 Integrins;46
1.4.1.4.9;4.9 Robo4;46
1.4.1.4.10;4.10 Other TEM’s Endosialin/TEM1 and TEM7;47
1.4.1.5;5 Products in Clinical Development and Concluding Remarks;47
1.4.1.6;References;49
1.4.2;The Use of Animal Models in the Assessment of Tumour Vascular Disrupting Agents (VDAs);56
1.4.2.1;1 Introduction;56
1.4.2.2;2 Animal Models;57
1.4.2.2.1;2.1 General Considerations;57
1.4.2.2.2;2.2 Subcutaneous and Other Ectopic Models;58
1.4.2.2.3;2.3 Orthotopic and Metastatic Models;59
1.4.2.2.4;2.4 Autochthonous Tumour Models;59
1.4.2.2.5;2.5 Isolated Limb Perfusion in Rats;60
1.4.2.2.6;2.6 Transgenic Knockout Mice;60
1.4.2.2.7;2.7 Zebrafish;61
1.4.2.3;3 Assays for Vascular Function;62
1.4.2.3.1;3.1 General Considerations;62
1.4.2.3.2;3.2 Blood Flow Rate;62
1.4.2.3.3;3.3 High Frequency Micro-ultrasound;63
1.4.2.3.4;3.4 Doppler Optical Coherence Tomography (DOCT);65
1.4.2.3.5;3.5 Laser Doppler Flowmetry and Near Infrared Spectroscopy;65
1.4.2.3.6;3.6 Multifluorescence Microscopy;65
1.4.2.3.7;3.7 Matrigel Plug Assay;67
1.4.2.3.8;3.8 Intravital Video Microscopy;68
1.4.2.4;4 Assays for Vascular Morphology;69
1.4.2.4.1;4.1 Microvascular Corrosion Casting of Tumour Architecture;69
1.4.2.4.2;4.2 Transmission Electron Microscopy (TEM);69
1.4.2.4.3;4.3 Confocal Laser Scanning Microscopy (CLSM) and Multi-Photon Fluorescence Microscopy (MPFM);70
1.4.2.5;5 Non-invasive Imaging;71
1.4.2.5.1;5.1 General Considerations;71
1.4.2.5.2;5.2 Bioluminescence/Fluorescence Imaging;71
1.4.2.5.3;5.3 Nuclear Magnetic Resonance Spectroscopy (MRS) and Imaging (MRI);72
1.4.2.5.4;5.4 Positron Emission Tomography (PET);75
1.4.2.5.5;5.5 Scintigraphic Imaging of Tumour Hypoxia;75
1.4.2.6;6 Other Assays;76
1.4.2.6.1;6.1 Hollow Fibre Assay;76
1.4.2.6.2;6.2 Wick-in-Needle Method for the Measurement of Interstitial Fluid Pressure (IFP);76
1.4.2.7;References;77
1.4.3;Combination Therapy with Chemotherapy and VDAs;83
1.4.3.1;1 Introduction;83
1.4.3.2;2 Combining VDAs and Chemotherapy;84
1.4.3.2.1;2.1 Complementary Targeting of Different Regions of the Tumor (Spatial Cooperation);84
1.4.3.2.2;2.2 Synergistic Activity on the Same Tumor Compartment;90
1.4.3.2.3;2.3 Combination with Agents That Exploitthe Microenvironmental Changes Induced by VDAs;91
1.4.3.2.4;2.4 Combination with Agents That Potentiate the Activityof VDAs, Reduce Resistance to Them or Limit Their Toxicity;91
1.4.3.2.5;2.5 Modification in Blood Flow: Effects on Cytotoxic Drug Pharmacokinetics;92
1.4.3.3;3 Sequencing and Timing;93
1.4.3.4;4 Toxicity;95
1.4.3.5;5 Conclusions;96
1.4.3.6;References;97
1.4.4;Lessons from Animal Imaging in Preclinical Models;100
1.4.4.1;1 Magnetic Resonance Imaging of Tumour Vasculature;100
1.4.4.2;2 Why Use MRI for VDA Assessment?;101
1.4.4.3;3 Dynamic Contrast-Enhanced MRI;102
1.4.4.3.1;3.1 Preclinical Assessment of ZD6126 Using DCE-MRI;103
1.4.4.3.2;3.2 Preclinical Assessment of CA4P Using DCE-MRI;105
1.4.4.3.3;3.3 Preclinical Assessment of DMXAA Using DCE-MRI;106
1.4.4.3.4;3.4 Preclinical DCE-MRI Summary;107
1.4.4.4;4 Susceptibility Contrast MRI;108
1.4.4.4.1;4.1 Preclinical Assessment of VDAs Using Susceptibility Contrast MRI;108
1.4.4.5;5 Intrinsic Susceptibility MRI;109
1.4.4.5.1;5.1 Preclinical Assessment of VDAs Using Intrinsic Susceptibility MRI;109
1.4.4.6;6 Diffusion-Weighted MRI;111
1.4.4.6.1;6.1 Preclinical Assessment of VDAs Using DW-MRI;111
1.4.4.7;7 Magnetic Resonance Spectroscopy;112
1.4.4.7.1;7.1 Preclinical Assessment of VDAs Using Magnetic Resonance Spectroscopy;113
1.4.4.8;8 Non-MR Imaging Modalities;115
1.4.4.8.1;8.1 Fluorine-18 Fluorodeoxyglucose-Positron Emission Tomography ([18F]-FDG-PET);115
1.4.4.8.2;8.2 Scintigraphic Imaging;116
1.4.4.8.3;8.3 High-Frequency Doppler Ultrasound;116
1.4.4.9;9 Chapter Summary;116
1.4.4.10;References;117
1.4.5;Combining Antiangiogenic Drugs with Vascular Disrupting Agents Rationale and Mechanisms of Action;122
1.4.5.1;1 Introduction and Background;123
1.4.5.2;2 Circulating Endothelial Progenitor Cells in Tumor Angiogenesis;125
1.4.5.2.1;2.1 Induction of Multiple Growth Factors, Cytokines, and Chemokines by Cytotoxic Agents, Including VDAs;130
1.4.5.2.2;2.2 Clinical Studies of Combination Vascular Disruptive Agent and Antiangiogenics;132
1.4.5.2.2.1;2.2.1 Study Design;133
1.4.5.2.2.2;2.2.2 Patient Population;134
1.4.5.2.2.3;2.2.3 Results;134
1.4.5.3;3 Conclusions and Summary;137
1.4.5.4;References;137
1.5;Part II maging in the Development of VascularDisruptive Agents;140
1.5.1;MRI to Assess Vascular Disruptive Agents;141
1.5.1.1;1 Introduction;141
1.5.1.2;2 Imaging the Vascularity of Tissues: Comparison of Methods;143
1.5.1.3;3 MRI for Assessing Tissue Vascularity;144
1.5.1.3.1;3.1 Biological Basis for Observations of Dynamic MRI;145
1.5.1.3.2;3.2 Quantification of DCE-MRI;146
1.5.1.3.3;3.3 Validation of DCE-MRI as a Vascular Biomarker;149
1.5.1.3.4;3.4 DCE-MRI in the Clinical Assessment of Antiangiogenic Agents;149
1.5.1.3.4.1;3.4.1 Phase I Studies;150
1.5.1.3.4.2;3.4.2 Antiangiogenic Agents as Monotherapy;151
1.5.1.3.4.3;3.4.3 Antiangiogenic Agents with Conventional Therapies;152
1.5.1.3.5;3.5 DCE-MRI in Pre-clinical Development of VDAs;152
1.5.1.4;4 DCE-MRI in the Clinical Development of VDAs;154
1.5.1.4.1;4.1 DMXAA;154
1.5.1.4.2;4.2 ZD6126;154
1.5.1.4.3;4.3 CA4P;158
1.5.1.4.4;4.4 CA1P (OXi-4503);160
1.5.1.5;5 VDA Experience with Positron Emission Tomography (PET);161
1.5.1.6;6 VDA Experience with Perfusion ComputedTomography (CT);162
1.5.1.7;7 Conclusions;162
1.5.1.8;References;163
1.5.2;Contrast Ultrasound in Imaging Tumor Angiogenesis;168
1.5.2.1;1 Background;169
1.5.2.2;2 Imaging of Tumor Angiogenesis;170
1.5.2.3;3 Contrast Ultrasound;171
1.5.2.3.1;3.1 Targeted Imaging with Microbubbles-Enhanced Ultrasound;172
1.5.2.3.2;3.2 Imaging Tumor Angiogenesis with Targeted MB and Ultrasound;173
1.5.2.4;4 Conclusions;175
1.5.2.5;References;177
1.6;Part III Clinical Development;183
1.6.1;The Clinical Development of Tubulin Binding Vascular Disrupting Agents;184
1.6.1.1;1 Introduction;184
1.6.1.2;2 Combretastatin A4;185
1.6.1.2.1;2.1 Preclinical Development;185
1.6.1.2.1.1;2.1.1 Structure and Mechanism of Action;185
1.6.1.2.1.2;2.1.2 In Vivo Antitumor Efficacy;186
1.6.1.2.1.2.1;CA4P Single-Agent Activity;186
1.6.1.2.1.2.2;CA4P Combination Activity;187
1.6.1.2.1.3;2.1.3 Preclinical Administration Schedule: Infusion Frequency and Duration;188
1.6.1.2.1.4;2.1.4 Animal Toxicity;189
1.6.1.2.2;2.2 Clinical Development;190
1.6.1.2.2.1;2.2.1 Phase I Trials;190
1.6.1.2.2.2;2.2.2 Trials of CA4P in Combination with Cytotoxic Agents;196
1.6.1.2.2.3;2.2.3 CA4P in Combination with Radiotherapy or Antibodies;199
1.6.1.2.2.4;2.2.4 Toxicity;199
1.6.1.2.2.5;2.2.5 Pharmacokinetics;200
1.6.1.2.2.6;2.2.6 Pharmacodynamics: Imaging the Effects of Vasculature-Targeting Agents;202
1.6.1.2.3;2.3 Conclusion;203
1.6.1.3;3 Other Tubulin Binding VDAs;204
1.6.1.3.1;3.1 ZD6126 (ANG453);204
1.6.1.3.2;3.2 AVE8062;205
1.6.1.3.3;3.3 OXi4503;206
1.6.1.3.4;3.4 Dolastatin-10 (NSC-376128);207
1.6.1.3.5;3.5 Cemadotin (LU103793, NSC D-669356);207
1.6.1.3.6;3.6 TZT-1027;207
1.6.1.3.7;3.7 ILX651;208
1.6.1.3.8;3.8 NPI-2358;209
1.6.1.3.9;3.9 MN-029;209
1.6.1.3.10;3.10 ABT-751;209
1.6.1.3.11;3.11 BNC-105P;210
1.6.1.3.12;3.12 EPC-2407;210
1.6.1.3.13;3.13 LP-261;211
1.6.1.3.14;3.14 CYT-997;211
1.6.1.3.15;3.15 Other Tubulin Binding VDAs in Development;211
1.6.1.4;References;212
1.6.2;ASA404 (DMXAA): New Concepts in Tumour Vascular Targeting Therapy;218
1.6.2.1;1 Introduction;218
1.6.2.2;2 Preclinical Development;219
1.6.2.2.1;2.1 Tumour Vasculature as a Target;220
1.6.2.2.2;2.2 Cytokine Induction as a Target for ASA404;221
1.6.2.2.3;2.3 ASA404 Combination Treatment in Mice;223
1.6.2.3;3 Clinical Development of ASA404;223
1.6.2.3.1;3.1 Biomarkers;225
1.6.2.4;4 Perspective;226
1.6.2.5;References;227
1.6.3;Vascular Disruptive Agents in Combination with Radiotherapy;232
1.6.3.1;1 Introduction;232
1.6.3.2;2 Vascular Effects of Radiation;233
1.6.3.3;3 Rationale for Combining VDAs and Radiotherapy;234
1.6.3.4;4 Tubulin-Binding VDAs and Radiotherapy;236
1.6.3.4.1;4.1 Combretastatin A4 Phosphate;237
1.6.3.4.2;4.2 Other Combretastatins;239
1.6.3.4.3;4.3 ZD6126;240
1.6.3.5;5 Flavonoid VDAs and Radiotherapy;240
1.6.3.5.1;5.1 Flavone Acetic Acid;241
1.6.3.5.2;5.2 5,6-Dimethylxanthenone-4-Acetic Acid;241
1.6.3.6;6 Hyperthermia, VDAs and Radiotherapy;242
1.6.3.7;7 Other Novel Agents in Combination with VDAs and Radiotherapy;244
1.6.3.7.1;7.1 Bioreductive Agents;244
1.6.3.7.2;7.2 Nitric Oxide Synthase Inhibition;244
1.6.3.7.3;7.3 Other Targeted Therapies;245
1.6.3.8;8 Clinical Trials of Combined VDAs and Radiotherapy;246
1.6.3.9;9 Conclusions;246
1.7;Index;252