Dietmar W. Siemann, University of Florida Shands Cancer Center, USA.

"A Multi-Author 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)

• Preface xiiiList of Contributors xv1 Tumor Vasculature: A Target for Anticancer Therapies 1Dietmar W. Siemann1.1 Introduction 11.2 Tumor vasculature 11.3 Impact of tumor microenvironments on cancer management 21.4 Vascular-targeting therapies 31.5 Combinations with conventional anticancer therapies 41.6 Combinations of antiangiogenic and vascular-disrupting agents 51.7 Conclusions 5Acknowledgments 6References 62 Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors 9Peter Vaupel2.1 Introduction 92.2 Basic principles of blood vessel formation in tumors 102.3 Tumor lymphangiogenesis 132.4 Tumor vascularity and blood flow 132.5 Volume and composition of the tumor interstitial space 172.6 Fluid pressure and convective currents in the interstitial space of tumors 182.7 Evidence, characterization and pathogenesis of tumor hypoxia 182.8 Tumor pH 232.9 The ‘crucial Ps’ characterizing the hostile metabolic microenvironment of solid tumors 25Acknowledgment 27References 273 The Role of Microvasculature in Metastasis Formation 31Oliver Stoeltzing and Lee M. Ellis3.1 Introduction 313.2 Regulators of angiogenesis in solid tumors 343.3 Angiogenesis and metastasis formation 473.4 Summary 53References 534 Development of Agents that Selectively Disrupt Tumor Vasculature: a Historical Perspective 63David J. Chaplin and Sally A. Hill4.1 Introduction 634.2 Early history 654.3 Formulation of the VDA concept 674.4 Effects of vascular occlusion on tumor cell survival 684.5 Rational development of VDA therapeutics 684.6 Development of small-molecule VDAs 704.7 Combretastatin A4 phosphate 734.8 The viable rim 764.9 Conclusions 76References 775 Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models 81Mumtaz V. Rojiani and Amyn M. Rojiani5.1 Introduction 825.2 Animal models 825.3 Morphologic and morphometric analysis 845.4 Effects of treatment 85Acknowledgments 92References 926 Molecular Recognition of the Colchicine Binding Site as a Design Paradigm for the Discovery and Development of Vascular Disrupting Agents 95Kevin G. Pinney6.1 Introductory comments 956.2 Colchicine binding site on tubulin 966.3 Brief overview of tubulin biology 976.4 Small-molecule inhibitors of tubulin assembly 1006.5 Design paradigm for small-molecule vascular disrupting agents 1056.6 Concluding remarks 113Acknowledgments 114References 1147 Combined Modality Approaches Using Vasculaturedisrupting Agents 123Wenyin Shi, Michael R. Horsman and Dietmar W. Siemann7.1 Tumor vasculature 1237.2 Vascular-disrupting strategies 1247.3 VDAs and chemotherapy 1257.4 VDAs and radiation therapy 1287.5 VDAs and antiangiogenic agents 1317.6 Summary 131Acknowledgments 132References 1328 Vasculature-targeting Therapies and Hyperthermia 137Michael R. Horsman and Rumi Murata8.1 Introduction 1378.2 Enhancing hyperthermia 1408.3 Enhancing thermoradiotherapy 1488.4 Conclusions and clinical relevance 151Acknowledgments 152References 1529 Flavones and Xanthenones as Vascular-disrupting Agents 159Bronwyn G. Siim and Bruce C. Baguley9.1 Development of FAA and DMXAA 1599.2 Antivascular activity of FAA and DMXAA 1619.3 Cytokine induction by FAA and DMXAA 1629.4 Molecular target 1639.5 Preclinical studies: DMXAA as a single agent 1649.6 Preclinical studies: combination treatments 1659.7 Species differences 1699.8 Clinical studies 171References 17210 Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer 179Adam W. Beck, Rolf Brekken and Philip E. Thorpe10.1 Vascular targeting 17910.2 Pancreatic cancer: the clinical need 18010.3 Phosphatidylserine 18110.4 Proof of concept studies 18310.5 Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model 18510.6 Mechanism of action 18810.7 Conclusion 191References 19111 Cadherin Antagonists as Vasculature-targeting Agents 195Orest Blaschuk and Tracey M. Rowlands11.1 Pericytes as regulators of blood vessel stability 19511.2 Cadherins 19611.3 Cadherins and the vasculature 19711.4 Tumor vasculature 19911.5 Manipulation of the tumor vasculature with cadherin antagonists 20011.6 Summary and future directions 201Acknowledgment 201References 20112 Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells 205Carolyn A. Staton and Claire Lewis12.1 Introduction 20512.2 Discovery of alphastatin 20712.3 Development of alphastatin 21012.4 Conclusions 218References 21813 Cationic Lipid Complexes to Target Tumor Endothelium 221Uwe Michaelis and Michael Teifel13.1 Introduction 22113.2 Tumor vascular targeting by cationic liposomes 22213.3 Potential targets for cationic lipid complexes on tumor endothelial cells 22513.4 Cationic liposomes as drug carriers 22713.5 Side-effects of intravenously administered cationic lipid complexes 23013.6 Preclinical data 23213.7 Clinical data 23813.8 Conclusion 239Acknowledgments 240References 24014 Development of Vasculature-targeting Cancer Gene Therapy 247Graeme J. Dougherty, Peter D. Davis andShona T. Dougherty14.1 Introduction 24714.2 Advantages of tumor vasculature as a target in cancer gene therapy 24814.3 Genes of value in vascular-targeted cancer gene therapy 24914.4 Targeting gene therapy to tumor vasculature 24914.5 Concluding remarks 256Acknowledgment 256References 25715 Vasculature-disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors 261G-One Ahn and J. Martin Brown15.1 Hypoxia and necrosis as a selective target for cancer therapy 26115.2 Use of Clostridia as hypoxia/necrotic selective cancer therapy 26215.3 Advantage of CDEPT over ADEPT and GDEPT 26515.4 Combination of CDEPT with vascular-disrupting agents 26715.5 Clinical significance 272References 27316 Imaging the Effects of Vasculature-targeting Agents 277Susan M. Galbraith16.1 Introduction 27716.2 Methods for imaging tissue blood flow rate 27816.3 Central volume theorem 27916.4 Kety model 28016.5 Fraction of cardiac output or ‘first-pass’ methods 28616.6 Color Doppler ultrasonography 28616.7 Imaging hypoxia 28716.8 Imaging glucose metabolism 28816.9 Preclinical experience of imaging vascular-disrupting agents 29016.10 Clinical experience of imaging vascular-disrupting agents 29316.11 Conclusions 296References 29817 Clinical Progress in Tumor Vasculature-disrupting Therapies 305Andrew M. Gaya and Gordon J. S. Rustin17.1 Introduction 30517.2 Potential clinical advantages of vascular-disrupting agents 30617.3 Biological (ligand-directed) VDAs 30617.4 Small-molecule VDAs 30717.5 Potential surrogate markers of CA4P activity 31417.6 Combination therapy with VDAs 31717.7 VDAs in non-malignant diseases 31817.8 Conclusions 319References 31918 Use of Vasculature-disrupting Agents in Non-Oncology Indications 323Joseph C. Randall and Scott L. Young18.1 Background 32318.2 Age-related macular degeneration (AMD) 32518.3 Myopic macular degeneration 32718.4 Retinopathy of prematurity 33018.5 Proliferative diabetic retinopathy 33118.6 Pediatric hemangiomas 33218.7 Arthritis 33318.8 Psoriasis 33418.9 Conclusions 336References 336Index 341

Dietmar W. Siemann, University of Florida Shands Cancer Center, USA.

"A Multi-Author 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)

• Preface xiiiList of Contributors xv1 Tumor Vasculature: A Target for Anticancer Therapies 1Dietmar W. Siemann1.1 Introduction 11.2 Tumor vasculature 11.3 Impact of tumor microenvironments on cancer management 21.4 Vascular-targeting therapies 31.5 Combinations with conventional anticancer therapies 41.6 Combinations of antiangiogenic and vascular-disrupting agents 51.7 Conclusions 5Acknowledgments 6References 62 Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors 9Peter Vaupel2.1 Introduction 92.2 Basic principles of blood vessel formation in tumors 102.3 Tumor lymphangiogenesis 132.4 Tumor vascularity and blood flow 132.5 Volume and composition of the tumor interstitial space 172.6 Fluid pressure and convective currents in the interstitial space of tumors 182.7 Evidence, characterization and pathogenesis of tumor hypoxia 182.8 Tumor pH 232.9 The ‘crucial Ps’ characterizing the hostile metabolic microenvironment of solid tumors 25Acknowledgment 27References 273 The Role of Microvasculature in Metastasis Formation 31Oliver Stoeltzing and Lee M. Ellis3.1 Introduction 313.2 Regulators of angiogenesis in solid tumors 343.3 Angiogenesis and metastasis formation 473.4 Summary 53References 534 Development of Agents that Selectively Disrupt Tumor Vasculature: a Historical Perspective 63David J. Chaplin and Sally A. Hill4.1 Introduction 634.2 Early history 654.3 Formulation of the VDA concept 674.4 Effects of vascular occlusion on tumor cell survival 684.5 Rational development of VDA therapeutics 684.6 Development of small-molecule VDAs 704.7 Combretastatin A4 phosphate 734.8 The viable rim 764.9 Conclusions 76References 775 Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models 81Mumtaz V. Rojiani and Amyn M. Rojiani5.1 Introduction 825.2 Animal models 825.3 Morphologic and morphometric analysis 845.4 Effects of treatment 85Acknowledgments 92References 926 Molecular Recognition of the Colchicine Binding Site as a Design Paradigm for the Discovery and Development of Vascular Disrupting Agents 95Kevin G. Pinney6.1 Introductory comments 956.2 Colchicine binding site on tubulin 966.3 Brief overview of tubulin biology 976.4 Small-molecule inhibitors of tubulin assembly 1006.5 Design paradigm for small-molecule vascular disrupting agents 1056.6 Concluding remarks 113Acknowledgments 114References 1147 Combined Modality Approaches Using Vasculaturedisrupting Agents 123Wenyin Shi, Michael R. Horsman and Dietmar W. Siemann7.1 Tumor vasculature 1237.2 Vascular-disrupting strategies 1247.3 VDAs and chemotherapy 1257.4 VDAs and radiation therapy 1287.5 VDAs and antiangiogenic agents 1317.6 Summary 131Acknowledgments 132References 1328 Vasculature-targeting Therapies and Hyperthermia 137Michael R. Horsman and Rumi Murata8.1 Introduction 1378.2 Enhancing hyperthermia 1408.3 Enhancing thermoradiotherapy 1488.4 Conclusions and clinical relevance 151Acknowledgments 152References 1529 Flavones and Xanthenones as Vascular-disrupting Agents 159Bronwyn G. Siim and Bruce C. Baguley9.1 Development of FAA and DMXAA 1599.2 Antivascular activity of FAA and DMXAA 1619.3 Cytokine induction by FAA and DMXAA 1629.4 Molecular target 1639.5 Preclinical studies: DMXAA as a single agent 1649.6 Preclinical studies: combination treatments 1659.7 Species differences 1699.8 Clinical studies 171References 17210 Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer 179Adam W. Beck, Rolf Brekken and Philip E. Thorpe10.1 Vascular targeting 17910.2 Pancreatic cancer: the clinical need 18010.3 Phosphatidylserine 18110.4 Proof of concept studies 18310.5 Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model 18510.6 Mechanism of action 18810.7 Conclusion 191References 19111 Cadherin Antagonists as Vasculature-targeting Agents 195Orest Blaschuk and Tracey M. Rowlands11.1 Pericytes as regulators of blood vessel stability 19511.2 Cadherins 19611.3 Cadherins and the vasculature 19711.4 Tumor vasculature 19911.5 Manipulation of the tumor vasculature with cadherin antagonists 20011.6 Summary and future directions 201Acknowledgment 201References 20112 Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells 205Carolyn A. Staton and Claire Lewis12.1 Introduction 20512.2 Discovery of alphastatin 20712.3 Development of alphastatin 21012.4 Conclusions 218References 21813 Cationic Lipid Complexes to Target Tumor Endothelium 221Uwe Michaelis and Michael Teifel13.1 Introduction 22113.2 Tumor vascular targeting by cationic liposomes 22213.3 Potential targets for cationic lipid complexes on tumor endothelial cells 22513.4 Cationic liposomes as drug carriers 22713.5 Side-effects of intravenously administered cationic lipid complexes 23013.6 Preclinical data 23213.7 Clinical data 23813.8 Conclusion 239Acknowledgments 240References 24014 Development of Vasculature-targeting Cancer Gene Therapy 247Graeme J. Dougherty, Peter D. Davis andShona T. Dougherty14.1 Introduction 24714.2 Advantages of tumor vasculature as a target in cancer gene therapy 24814.3 Genes of value in vascular-targeted cancer gene therapy 24914.4 Targeting gene therapy to tumor vasculature 24914.5 Concluding remarks 256Acknowledgment 256References 25715 Vasculature-disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors 261G-One Ahn and J. Martin Brown15.1 Hypoxia and necrosis as a selective target for cancer therapy 26115.2 Use of Clostridia as hypoxia/necrotic selective cancer therapy 26215.3 Advantage of CDEPT over ADEPT and GDEPT 26515.4 Combination of CDEPT with vascular-disrupting agents 26715.5 Clinical significance 272References 27316 Imaging the Effects of Vasculature-targeting Agents 277Susan M. Galbraith16.1 Introduction 27716.2 Methods for imaging tissue blood flow rate 27816.3 Central volume theorem 27916.4 Kety model 28016.5 Fraction of cardiac output or ‘first-pass’ methods 28616.6 Color Doppler ultrasonography 28616.7 Imaging hypoxia 28716.8 Imaging glucose metabolism 28816.9 Preclinical experience of imaging vascular-disrupting agents 29016.10 Clinical experience of imaging vascular-disrupting agents 29316.11 Conclusions 296References 29817 Clinical Progress in Tumor Vasculature-disrupting Therapies 305Andrew M. Gaya and Gordon J. S. Rustin17.1 Introduction 30517.2 Potential clinical advantages of vascular-disrupting agents 30617.3 Biological (ligand-directed) VDAs 30617.4 Small-molecule VDAs 30717.5 Potential surrogate markers of CA4P activity 31417.6 Combination therapy with VDAs 31717.7 VDAs in non-malignant diseases 31817.8 Conclusions 319References 31918 Use of Vasculature-disrupting Agents in Non-Oncology Indications 323Joseph C. Randall and Scott L. Young18.1 Background 32318.2 Age-related macular degeneration (AMD) 32518.3 Myopic macular degeneration 32718.4 Retinopathy of prematurity 33018.5 Proliferative diabetic retinopathy 33118.6 Pediatric hemangiomas 33218.7 Arthritis 33318.8 Psoriasis 33418.9 Conclusions 336References 336Index 341

Dietmar W. Siemann, University of Florida Shands Cancer Center, USA.

"A Multi-Author 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)

• Preface xiiiList of Contributors xv1 Tumor Vasculature: A Target for Anticancer Therapies 1Dietmar W. Siemann1.1 Introduction 11.2 Tumor vasculature 11.3 Impact of tumor microenvironments on cancer management 21.4 Vascular-targeting therapies 31.5 Combinations with conventional anticancer therapies 41.6 Combinations of antiangiogenic and vascular-disrupting agents 51.7 Conclusions 5Acknowledgments 6References 62 Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors 9Peter Vaupel2.1 Introduction 92.2 Basic principles of blood vessel formation in tumors 102.3 Tumor lymphangiogenesis 132.4 Tumor vascularity and blood flow 132.5 Volume and composition of the tumor interstitial space 172.6 Fluid pressure and convective currents in the interstitial space of tumors 182.7 Evidence, characterization and pathogenesis of tumor hypoxia 182.8 Tumor pH 232.9 The ‘crucial Ps’ characterizing the hostile metabolic microenvironment of solid tumors 25Acknowledgment 27References 273 The Role of Microvasculature in Metastasis Formation 31Oliver Stoeltzing and Lee M. Ellis3.1 Introduction 313.2 Regulators of angiogenesis in solid tumors 343.3 Angiogenesis and metastasis formation 473.4 Summary 53References 534 Development of Agents that Selectively Disrupt Tumor Vasculature: a Historical Perspective 63David J. Chaplin and Sally A. Hill4.1 Introduction 634.2 Early history 654.3 Formulation of the VDA concept 674.4 Effects of vascular occlusion on tumor cell survival 684.5 Rational development of VDA therapeutics 684.6 Development of small-molecule VDAs 704.7 Combretastatin A4 phosphate 734.8 The viable rim 764.9 Conclusions 76References 775 Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models 81Mumtaz V. Rojiani and Amyn M. Rojiani5.1 Introduction 825.2 Animal models 825.3 Morphologic and morphometric analysis 845.4 Effects of treatment 85Acknowledgments 92References 926 Molecular Recognition of the Colchicine Binding Site as a Design Paradigm for the Discovery and Development of Vascular Disrupting Agents 95Kevin G. Pinney6.1 Introductory comments 956.2 Colchicine binding site on tubulin 966.3 Brief overview of tubulin biology 976.4 Small-molecule inhibitors of tubulin assembly 1006.5 Design paradigm for small-molecule vascular disrupting agents 1056.6 Concluding remarks 113Acknowledgments 114References 1147 Combined Modality Approaches Using Vasculaturedisrupting Agents 123Wenyin Shi, Michael R. Horsman and Dietmar W. Siemann7.1 Tumor vasculature 1237.2 Vascular-disrupting strategies 1247.3 VDAs and chemotherapy 1257.4 VDAs and radiation therapy 1287.5 VDAs and antiangiogenic agents 1317.6 Summary 131Acknowledgments 132References 1328 Vasculature-targeting Therapies and Hyperthermia 137Michael R. Horsman and Rumi Murata8.1 Introduction 1378.2 Enhancing hyperthermia 1408.3 Enhancing thermoradiotherapy 1488.4 Conclusions and clinical relevance 151Acknowledgments 152References 1529 Flavones and Xanthenones as Vascular-disrupting Agents 159Bronwyn G. Siim and Bruce C. Baguley9.1 Development of FAA and DMXAA 1599.2 Antivascular activity of FAA and DMXAA 1619.3 Cytokine induction by FAA and DMXAA 1629.4 Molecular target 1639.5 Preclinical studies: DMXAA as a single agent 1649.6 Preclinical studies: combination treatments 1659.7 Species differences 1699.8 Clinical studies 171References 17210 Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer 179Adam W. Beck, Rolf Brekken and Philip E. Thorpe10.1 Vascular targeting 17910.2 Pancreatic cancer: the clinical need 18010.3 Phosphatidylserine 18110.4 Proof of concept studies 18310.5 Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model 18510.6 Mechanism of action 18810.7 Conclusion 191References 19111 Cadherin Antagonists as Vasculature-targeting Agents 195Orest Blaschuk and Tracey M. Rowlands11.1 Pericytes as regulators of blood vessel stability 19511.2 Cadherins 19611.3 Cadherins and the vasculature 19711.4 Tumor vasculature 19911.5 Manipulation of the tumor vasculature with cadherin antagonists 20011.6 Summary and future directions 201Acknowledgment 201References 20112 Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells 205Carolyn A. Staton and Claire Lewis12.1 Introduction 20512.2 Discovery of alphastatin 20712.3 Development of alphastatin 21012.4 Conclusions 218References 21813 Cationic Lipid Complexes to Target Tumor Endothelium 221Uwe Michaelis and Michael Teifel13.1 Introduction 22113.2 Tumor vascular targeting by cationic liposomes 22213.3 Potential targets for cationic lipid complexes on tumor endothelial cells 22513.4 Cationic liposomes as drug carriers 22713.5 Side-effects of intravenously administered cationic lipid complexes 23013.6 Preclinical data 23213.7 Clinical data 23813.8 Conclusion 239Acknowledgments 240References 24014 Development of Vasculature-targeting Cancer Gene Therapy 247Graeme J. Dougherty, Peter D. Davis andShona T. Dougherty14.1 Introduction 24714.2 Advantages of tumor vasculature as a target in cancer gene therapy 24814.3 Genes of value in vascular-targeted cancer gene therapy 24914.4 Targeting gene therapy to tumor vasculature 24914.5 Concluding remarks 256Acknowledgment 256References 25715 Vasculature-disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors 261G-One Ahn and J. Martin Brown15.1 Hypoxia and necrosis as a selective target for cancer therapy 26115.2 Use of Clostridia as hypoxia/necrotic selective cancer therapy 26215.3 Advantage of CDEPT over ADEPT and GDEPT 26515.4 Combination of CDEPT with vascular-disrupting agents 26715.5 Clinical significance 272References 27316 Imaging the Effects of Vasculature-targeting Agents 277Susan M. Galbraith16.1 Introduction 27716.2 Methods for imaging tissue blood flow rate 27816.3 Central volume theorem 27916.4 Kety model 28016.5 Fraction of cardiac output or ‘first-pass’ methods 28616.6 Color Doppler ultrasonography 28616.7 Imaging hypoxia 28716.8 Imaging glucose metabolism 28816.9 Preclinical experience of imaging vascular-disrupting agents 29016.10 Clinical experience of imaging vascular-disrupting agents 29316.11 Conclusions 296References 29817 Clinical Progress in Tumor Vasculature-disrupting Therapies 305Andrew M. Gaya and Gordon J. S. Rustin17.1 Introduction 30517.2 Potential clinical advantages of vascular-disrupting agents 30617.3 Biological (ligand-directed) VDAs 30617.4 Small-molecule VDAs 30717.5 Potential surrogate markers of CA4P activity 31417.6 Combination therapy with VDAs 31717.7 VDAs in non-malignant diseases 31817.8 Conclusions 319References 31918 Use of Vasculature-disrupting Agents in Non-Oncology Indications 323Joseph C. Randall and Scott L. Young18.1 Background 32318.2 Age-related macular degeneration (AMD) 32518.3 Myopic macular degeneration 32718.4 Retinopathy of prematurity 33018.5 Proliferative diabetic retinopathy 33118.6 Pediatric hemangiomas 33218.7 Arthritis 33318.8 Psoriasis 33418.9 Conclusions 336References 336Index 341