Attacking a tumor's supportive blood vessel network may offer novel means of improving cancer cure rates. The vasculature is critical to tumor development, survival, growth and metastatic spread. However, tumor blood vessels are abnormal, both morphologically and functionally, and display characteristics that distinguish them from normal vasculature. It is these inherent differences between blood vessels associated with tumors and those associated with normal tissues that provide a variety of unique targets for the design of novel therapeutics and treatment strategies highly selective for the…mehr
Attacking a tumor's supportive blood vessel network may offer novel means of improving cancer cure rates. The vasculature is critical to tumor development, survival, growth and metastatic spread. However, tumor blood vessels are abnormal, both morphologically and functionally, and display characteristics that distinguish them from normal vasculature. It is these inherent differences between blood vessels associated with tumors and those associated with normal tissues that provide a variety of unique targets for the design of novel therapeutics and treatment strategies highly selective for the cancer.
Vascular-disrupting strategies aim to cause a rapid and catastrophic shutdown in the established vessel networks of solid tumors. This arrests the blood flow and induces tumor cell death as a result of oxygen and nutrient deprivation and build up of waste products. Biological vascular-disrupting approaches include targeted gene therapy, antibodies to neovascular antigens and ligand-directed therapies targeting endothelial cell receptors and extracellular matrix proteins. Small molecule drug approaches have focused primarily on flavenoids and tubulin-binding agents. This book examines the fundamental bases of both these approaches. Emphasis is placed on target development, preclinical assessment, use in combination with conventional treatment regimens and the current clinical status of these therapies.
This book is intended for cancer researchers and clinical oncologists. Its goal is to review the potential of vascular-targeting strategies in cancer management and to foster an understanding of the key differences between these therapeutic approaches and conventional anticancer treatments. Though more research is required to establish the clinical efficacy and ideal application of vascular-disrupting strategies, this developing anticancer approach continues to generate great research interest and clinical optimism.Hinweis: Dieser Artikel kann nur an eine deutsche Lieferadresse ausgeliefert werden.
Dietmar W. Siemann is the editor of Vascular-Targeted Therapies in Oncology , published by Wiley.
Inhaltsangabe
Preface xiii List of Contributors xv 1 Tumor Vasculature: a Target for Anticancer Therapies 1 Dietmar W. Siemann 1.1 Introduction 1 1.2 Tumor vasculature 1 1.3 Impact of tumor microenvironments on cancer management 2 1.4 Vascular-targeting therapies 3 1.5 Combinations with conventional anticancer therapies 4 1.6 Combinations of antiangiogenic and vascular-disrupting agents 5 1.7 Conclusions 5 Acknowledgments 6 References 6 2 Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors 9 Peter Vaupel 2.1 Introduction 9 2.2 Basic principles of blood vessel formation in tumors 10 2.3 Tumor lymphangiogenesis 13 2.4 Tumor vascularity and blood fl ow 13 2.5 Volume and composition of the tumor interstitial space 17 2.6 Fluid pressure and convective currents in the interstitial space of tumors 18 2.7 Evidence, characterization and pathogenesis of tumor hypoxia 18 2.8 Tumor pH 23 2.9 The 'crucial Ps' characterizing the hostile metabolic microenvironment of solid tumors 25 Acknowledgment 27 References 27 3 The Role of Microvasculature in Metastasis Formation 31 Oliver Stoeltzing and Lee M. Ellis 3.1 Introduction 31 3.2 Regulators of angiogenesis in solid tumors 34 3.3 Angiogenesis and metastasis formation 47 3.4 Summary 53 References 53 4 Development of Agents that Selectively Disrupt Tumor Vasculature: a Historical Perspective 63 David J. Chaplin and Sally A. Hill 4.1 Introduction 63 4.2 Early history 65 4.3 Formulation of the VDA concept 67 4.4 Effects of vascular occlusion on tumor cell survival 68 4.5 Rational development of VDA therapeutics 68 4.6 Development of small-molecule VDAs 70 4.7 Combretastatin A4 phosphate 73 4.8 The viable rim 76 4.9 Conclusions 76 References 77 5 Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models 81 Mumtaz V. Rojiani and Amyn M. Rojiani 5.1 Introduction 82 5.2 Animal models 82 5.3 Morphologic and morphometric analysis 84 5.4 Effects of treatment 85 Acknowledgments 92 References 92 6 Molecular Recognition of the Colchicine Binding Site as a Design Paradigm for the Discovery and Development of Vascular Disrupting Agents 95 Kevin G. Pinney 6.1 Introductory comments 95 6.2 Colchicine binding site on tubulin 96 6.3 Brief overview of tubulin biology 97 6.4 Small-molecule inhibitors of tubulin assembly 100 6.5 Design paradigm for small-molecule vascular disrupting agents 105 6.6 Concluding remarks 113 Acknowledgments 114 References 114 7 Combined Modality Approaches Using Vasculature disrupting Agents 123 Wenyin Shi, Michael R. Horsman and Dietmar W. Siemann 7.1 Tumor vasculature 123 7.2 Vascular-disrupting strategies 124 7.3 VDAs and chemotherapy 125 7.4 VDAs and radiation therapy 128 7.5 VDAs and antiangiogenic agents 131 7.6 Summary 131 Acknowledgments 132 References 132 8 Vasculature-targeting Therapies and Hyperthermia 137 Michael R. Horsman and Rumi Murata 8.1 Introduction 137 8.2 Enhancing hyperthermia 140 8.3 Enhancing thermoradiotherapy 148 8.4 Conclusions and clinical relevance 151 Acknowledgments 152 References 152 9 Flavones and Xanthenones as Vascular-disrupting Agents 159 Bronwyn G. Siim and Bruce C. Baguley 9.1 Development of FAA and DMXAA 159 9.2 Antivascular activity of FAA and DMXAA 161 9.3 Cytokine induction by FAA and DMXAA 162 9.4 Molecular target 163 9.5 Preclinical studies: DMXAA as a single agent 164 9.6 Preclinical studies: combination treatments 165 9.7 Species differences 169 9.8 Clinical studies 171 References 172 10 Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer 179 Adam W. Beck, Rolf Brekken and Philip E. Thorpe 10.1 Vascular targeting 179 10.2 Pancreatic cancer: the clinical need 180 10.3 Phosphatidylserine 181 10.4 Proof of concept studies 183 10.5 Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model 185 10.6 Mechanism of action 188 10.7 Conclusion 191 References 191 11 Cadherin Antagonists as Vasculature-targeting Agents 195 Orest Blaschuk and Tracey M. Rowlands 11.1 Pericytes as regulators of blood vessel stability 195 11.2 Cadherins 196 11.3 Cadherins and the vasculature 197 11.4 Tumor vasculature 199 11.5 Manipulation of the tumor vasculature with cadherin antagonists 200 11.6 Summary and future directions 201 Acknowledgment 201 References 201 12 Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells 205 Carolyn A. Staton and Claire Lewis 12.1 Introduction 205 12.2 Discovery of alphastatin 207 12.3 Development of alphastatin 210 12.4 Conclusions 218 References 218 13 Cationic Lipid Complexes to Target Tumor Endothelium 221 Uwe Michaelis and Michael Teifel 13.1 Introduction 221 13.2 Tumor vascular targeting by cationic liposomes 222 13.3 Potential targets for cationic lipid complexes on tumor endothelial cells 225 13.4 Cationic liposomes as drug carriers 227 13.5 Side-effects of intravenously administered cationic lipid complexes 230 13.6 Preclinical data 232 13.7 Clinical data 238 13.8 Conclusion 239 Acknowledgments 240 References 240 14 Development of Vasculature-targeting Cancer Gene Therapy 247 Graeme J. Dougherty, Peter D. Davis and Shona T. Dougherty 14.1 Introduction 247 14.2 Advantages of tumor vasculature as a target in cancer gene therapy 248 14.3 Genes of value in vascular-targeted cancer gene therapy 249 14.4 Targeting gene therapy to tumor vasculature 249 14.5 Concluding remarks 256 Acknowledgment 256 References 257 15 Vasculature-disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors 261 G-One Ahn and J. Martin Brown 15.1 Hypoxia and necrosis as a selective target for cancer therapy 261 15.2 Use of Clostridia as hypoxia/necrotic selective cancer therapy 262 15.3 Advantage of CDEPT over ADEPT and GDEPT 265 15.4 Combination of CDEPT with vascular-disrupting agents 267 15.5 Clinical signifi cance 272 References 273 16 Imaging the Effects of Vasculature-targeting Agents 277 Susan M. Galbraith 16.1 Introduction 277 16.2 Methods for imaging tissue blood fl ow rate 278 16.3 Central volume theorem 279 16.4 Kety model 280 16.5 Fraction of cardiac output or 'fi rst-pass' methods 286 16.6 Color Doppler ultrasonography 286 16.7 Imaging hypoxia 287 16.8 Imaging glucose metabolism 288 16.9 Preclinical experience of imaging vascular-disrupting agents 290 16.10 Clinical experience of imaging vascular-disrupting agents 293 16.11 Conclusions 296 References 298 17 Clinical Progress in Tumor Vasculature-disrupting Therapies 305 Andrew M. Gaya and Gordon J. S. Rustin 17.1 Introduction 305 17.2 Potential clinical advantages of vascular-disrupting agents 306 17.3 Biological (ligand-directed) VDAs 306 17.4 Small-molecule VDAs 307 17.5 Potential surrogate markers of CA4P activity 314 17.6 Combination therapy with VDAs 317 17.7 VDAs in non-malignant diseases 318 17.8 Conclusions 319 References 319 18 Use of Vasculature-disrupting Agents in Non-Oncology Indications 323 Joseph C. Randall and Scott L. Young 18.1 Background 323 18.2 Age-related macular degeneration (AMD) 325 18.3 Myopic macular degeneration 327 18.4 Retinopathy of prematurity 330 18.5 Proliferative diabetic retinopathy 331 18.6 Pediatric hemangiomas 332 18.7 Arthritis 333 18.8 Psoriasis 334 18.9 Conclusions 336 References 336 Index 341
Preface xiii List of Contributors xv 1 Tumor Vasculature: a Target for Anticancer Therapies 1 Dietmar W. Siemann 1.1 Introduction 1 1.2 Tumor vasculature 1 1.3 Impact of tumor microenvironments on cancer management 2 1.4 Vascular-targeting therapies 3 1.5 Combinations with conventional anticancer therapies 4 1.6 Combinations of antiangiogenic and vascular-disrupting agents 5 1.7 Conclusions 5 Acknowledgments 6 References 6 2 Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors 9 Peter Vaupel 2.1 Introduction 9 2.2 Basic principles of blood vessel formation in tumors 10 2.3 Tumor lymphangiogenesis 13 2.4 Tumor vascularity and blood fl ow 13 2.5 Volume and composition of the tumor interstitial space 17 2.6 Fluid pressure and convective currents in the interstitial space of tumors 18 2.7 Evidence, characterization and pathogenesis of tumor hypoxia 18 2.8 Tumor pH 23 2.9 The 'crucial Ps' characterizing the hostile metabolic microenvironment of solid tumors 25 Acknowledgment 27 References 27 3 The Role of Microvasculature in Metastasis Formation 31 Oliver Stoeltzing and Lee M. Ellis 3.1 Introduction 31 3.2 Regulators of angiogenesis in solid tumors 34 3.3 Angiogenesis and metastasis formation 47 3.4 Summary 53 References 53 4 Development of Agents that Selectively Disrupt Tumor Vasculature: a Historical Perspective 63 David J. Chaplin and Sally A. Hill 4.1 Introduction 63 4.2 Early history 65 4.3 Formulation of the VDA concept 67 4.4 Effects of vascular occlusion on tumor cell survival 68 4.5 Rational development of VDA therapeutics 68 4.6 Development of small-molecule VDAs 70 4.7 Combretastatin A4 phosphate 73 4.8 The viable rim 76 4.9 Conclusions 76 References 77 5 Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models 81 Mumtaz V. Rojiani and Amyn M. Rojiani 5.1 Introduction 82 5.2 Animal models 82 5.3 Morphologic and morphometric analysis 84 5.4 Effects of treatment 85 Acknowledgments 92 References 92 6 Molecular Recognition of the Colchicine Binding Site as a Design Paradigm for the Discovery and Development of Vascular Disrupting Agents 95 Kevin G. Pinney 6.1 Introductory comments 95 6.2 Colchicine binding site on tubulin 96 6.3 Brief overview of tubulin biology 97 6.4 Small-molecule inhibitors of tubulin assembly 100 6.5 Design paradigm for small-molecule vascular disrupting agents 105 6.6 Concluding remarks 113 Acknowledgments 114 References 114 7 Combined Modality Approaches Using Vasculature disrupting Agents 123 Wenyin Shi, Michael R. Horsman and Dietmar W. Siemann 7.1 Tumor vasculature 123 7.2 Vascular-disrupting strategies 124 7.3 VDAs and chemotherapy 125 7.4 VDAs and radiation therapy 128 7.5 VDAs and antiangiogenic agents 131 7.6 Summary 131 Acknowledgments 132 References 132 8 Vasculature-targeting Therapies and Hyperthermia 137 Michael R. Horsman and Rumi Murata 8.1 Introduction 137 8.2 Enhancing hyperthermia 140 8.3 Enhancing thermoradiotherapy 148 8.4 Conclusions and clinical relevance 151 Acknowledgments 152 References 152 9 Flavones and Xanthenones as Vascular-disrupting Agents 159 Bronwyn G. Siim and Bruce C. Baguley 9.1 Development of FAA and DMXAA 159 9.2 Antivascular activity of FAA and DMXAA 161 9.3 Cytokine induction by FAA and DMXAA 162 9.4 Molecular target 163 9.5 Preclinical studies: DMXAA as a single agent 164 9.6 Preclinical studies: combination treatments 165 9.7 Species differences 169 9.8 Clinical studies 171 References 172 10 Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer 179 Adam W. Beck, Rolf Brekken and Philip E. Thorpe 10.1 Vascular targeting 179 10.2 Pancreatic cancer: the clinical need 180 10.3 Phosphatidylserine 181 10.4 Proof of concept studies 183 10.5 Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model 185 10.6 Mechanism of action 188 10.7 Conclusion 191 References 191 11 Cadherin Antagonists as Vasculature-targeting Agents 195 Orest Blaschuk and Tracey M. Rowlands 11.1 Pericytes as regulators of blood vessel stability 195 11.2 Cadherins 196 11.3 Cadherins and the vasculature 197 11.4 Tumor vasculature 199 11.5 Manipulation of the tumor vasculature with cadherin antagonists 200 11.6 Summary and future directions 201 Acknowledgment 201 References 201 12 Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells 205 Carolyn A. Staton and Claire Lewis 12.1 Introduction 205 12.2 Discovery of alphastatin 207 12.3 Development of alphastatin 210 12.4 Conclusions 218 References 218 13 Cationic Lipid Complexes to Target Tumor Endothelium 221 Uwe Michaelis and Michael Teifel 13.1 Introduction 221 13.2 Tumor vascular targeting by cationic liposomes 222 13.3 Potential targets for cationic lipid complexes on tumor endothelial cells 225 13.4 Cationic liposomes as drug carriers 227 13.5 Side-effects of intravenously administered cationic lipid complexes 230 13.6 Preclinical data 232 13.7 Clinical data 238 13.8 Conclusion 239 Acknowledgments 240 References 240 14 Development of Vasculature-targeting Cancer Gene Therapy 247 Graeme J. Dougherty, Peter D. Davis and Shona T. Dougherty 14.1 Introduction 247 14.2 Advantages of tumor vasculature as a target in cancer gene therapy 248 14.3 Genes of value in vascular-targeted cancer gene therapy 249 14.4 Targeting gene therapy to tumor vasculature 249 14.5 Concluding remarks 256 Acknowledgment 256 References 257 15 Vasculature-disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors 261 G-One Ahn and J. Martin Brown 15.1 Hypoxia and necrosis as a selective target for cancer therapy 261 15.2 Use of Clostridia as hypoxia/necrotic selective cancer therapy 262 15.3 Advantage of CDEPT over ADEPT and GDEPT 265 15.4 Combination of CDEPT with vascular-disrupting agents 267 15.5 Clinical signifi cance 272 References 273 16 Imaging the Effects of Vasculature-targeting Agents 277 Susan M. Galbraith 16.1 Introduction 277 16.2 Methods for imaging tissue blood fl ow rate 278 16.3 Central volume theorem 279 16.4 Kety model 280 16.5 Fraction of cardiac output or 'fi rst-pass' methods 286 16.6 Color Doppler ultrasonography 286 16.7 Imaging hypoxia 287 16.8 Imaging glucose metabolism 288 16.9 Preclinical experience of imaging vascular-disrupting agents 290 16.10 Clinical experience of imaging vascular-disrupting agents 293 16.11 Conclusions 296 References 298 17 Clinical Progress in Tumor Vasculature-disrupting Therapies 305 Andrew M. Gaya and Gordon J. S. Rustin 17.1 Introduction 305 17.2 Potential clinical advantages of vascular-disrupting agents 306 17.3 Biological (ligand-directed) VDAs 306 17.4 Small-molecule VDAs 307 17.5 Potential surrogate markers of CA4P activity 314 17.6 Combination therapy with VDAs 317 17.7 VDAs in non-malignant diseases 318 17.8 Conclusions 319 References 319 18 Use of Vasculature-disrupting Agents in Non-Oncology Indications 323 Joseph C. Randall and Scott L. Young 18.1 Background 323 18.2 Age-related macular degeneration (AMD) 325 18.3 Myopic macular degeneration 327 18.4 Retinopathy of prematurity 330 18.5 Proliferative diabetic retinopathy 331 18.6 Pediatric hemangiomas 332 18.7 Arthritis 333 18.8 Psoriasis 334 18.9 Conclusions 336 References 336 Index 341
Rezensionen
"[A] text describing techniques of targeting the abnormal vasculature of tumours by drugs ... This is cutting edge clinical science." ( 2007 BMA Medical Book Competition Programme and Award Winners)
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