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 flow 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 Vasculaturedisrupting 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 significance 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 flow rate 278
16.3 Central volume theorem 279
16.4 Kety model 280
16.5 Fraction of cardiac output or 'first-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
