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Contents Preface List of Contributors 1 ? Introduction Dietmar W. Siemann 1.1 Introduction 1.2 Tumor vasculature 1.3 Impact of tumor microenvironments on cancer management 1.4 Vascular-targeting therapies 1.5 Combinations with conventional anticancer therapies 1.6 Combinations of antiangiogenic and vascular-disrupting agents 1.7 Conclusions Acknowledgements References 2 ? Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors Peter Vaupel 2.1 Introduction 2.2 Basic principles of blood vessel formation in tumors 2.3 Tumor lymphangiogenesis 2.4 Tumor vascularity and blood flow 2.5 Volume and composition of the tumor interstitial space 2.6 Fluid pressure and convective currents in the interstitial space of tumors 2.7 Evidence, characterization and pathogenesis of tumor hypoxia 2.8 Tumor pH 2.9 The ?crucial Ps? characterizing the hostile metabolic microenvironment of solid tumors Acknowledgement References 3 ? The Role of Microvasculature in Metastasis Formation Oliver St¿ltzing Lee M. Ellis 3.1 Introduction 3.2 Regulators of angiogenesis in solid tumors 3.3 Angiogenesis and metastasis formation 3.4 Summary References 4 ? Development of Vascular Targeting Strategies David Chaplin Sally A. Hill 4.1 Introduction 4.2 Early history 4.3 Formulation of the VDA concept 4.4 Effects of vascular occlusion on tumor cell survival 4.5 Rational development of VDA therapeutics 4.6 Development of small-molecule VDAs 4.7 Combretastatin A4 phosphate 4.8 The viable rim 4.9 Conclusions References 5 ? Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models Mumtaz V. Rojiani Amyn Rojiani 5.1 Introduction 5.2 Animal models 5.3 Morphologic and morphometric analysis 5.4 Effects of treatment Acknowledgements References 6 ? The Discovery and Development of Vascular-Disrupting Agents Kevin G. Pinney 6.1 Introductory comments 6.2 Colchicine-binding site on tubulin 6.3 Brief overview of tubulin biology 6.4 Small-molecule inhibitors of tubulin assembly 6.5 Design paradigm for small-molecule vascular-targeting agents 6.6 Concluding remarks Acknowledgements References 7 ? Combined Modality Approaches Using Vascular-Disrupting Agents Wenyin Shi Michael R. Horsman Dietmar W. Siemann, PhD 7.1 Tumor vasculature 7.2 Vascular-disrupting strategies 7.3 VDAs and chemotherapy 7.4 VDAs and radiation therapy 7.5 VDAs and antiangiogenic agents 7.6 Summary Acknowledgements References 8 ? Vascular-Targeting Therapies and Hyperthermia Michael R. Horsman Rumi Murata 8.1 Introduction 8.2 Enhancing hyperthermia 8.3 Enhancing thermoradiotherapy 8.4 Conclusions and clinical relevance Acknowledgements References 9 ? Flavones and Xanthenones as Vascular-Disrupting Agents Bronwyn Siim Bruce Baguley 9.1 Development of FAA and DMXAA 9.2 Antivascular activity of FAA and DMXAA 9.3 Cytokine induction by FAA and DMXAA 9.4 Molecular target 9.5 Preclinical studies: DMXAA as a single agent 9.6 Preclinical studies: combination treatments 9.7 Species differences 9.8 Clinical studies References 10 ? Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer Adam W. Beck Rolf Brekken Philip E. Thorpe, PhD 10.1 Vascular targeting 10.2 Pancreatic cancer: the clinical need 10.3 Phosphatidylserine 10.4 Proof of concept studies 10.5 Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model 10.6 Mechanism of action 10.7 Conclusion References 11 ? Cadherin Antagonists as Vascular-Targeting Agents Orest Blaschuk Tracey M. Rowlands 11.1 Pericytes as regulators of blood vessel stability 11.2 Cadherins 11.3 Cadherins and the vasculature 11.4 Tumor vasculature 11.5 Manipulation of the tumor vasculature with cadherin antagonists 11.6 Summary and future directions Acknowledgements References 12 ? Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells Carolyn A. Staton Claire Lewis 12.1 Introduction 12.2 Discovery of alphastatin 12.3 Development of alphastatin 12.4 Conclusions References 13 ? Cationic Lipid Complexes to Target Tumor Endothelium Uwe Michaelis Michael Teifel 13.1 Introduction 13.2 Tumor vascular targeting by cationic liposomes 13.3 Potential targets for cationic lipid complexes on tumor endothelial cells 13.4 Cationic liposomes as drug carriers 13.5 Side-effects of intravenously administered cationic lipid complexes 13.6 Preclinical data 13.7 Clinical data 13.8 Conclusion References 14 ? Development of Vascular-Targeted Cancer Gene Therapy Graeme J. Dougherty Peter D. Davis Shona T. Dougherty 14.1 Introduction 14.2 Advantages of tumor vasculature as a target in cancer gene therapy 14.3 Genes of value in vascular-targeted cancer gene therapy 14.4 Targeting gene therapy to tumor vasculature 14.5 Concluding remarks Acknowledgement References 15 ? Vascular-Disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors G-One Ahn J. Martin Brown 15.1 Hypoxia and necrosis as a selective target for cancer therapy 15.2 Use of Clostridia as hypoxia/necrotic selective cancer therapy 15.3 Advantage of CDEPT over ADEPT and GDEPT 15.4 Combination of CDEPT with vascular-disrupting agents 15.5 Clinical significance References 16 ? Imaging the Effects of Vascular-Targeting Agents Susan M. Galbraith 16.1 Introduction 16.2 Methods for imaging tissue blood flow rate 16.3 Central volume theorem 16.4 Kety model 16.5 Fraction of cardiac output or ?first-pass? methods 16.6 Color Doppler ultrasonography 16.7 Imaging hypoxia 16.8 Imaging glucose metabolism 16.9 Preclinical experience of imaging vascular-disrupting agents 16.10 Clinical experience of imaging vascular-disrupting agents 16.11 Conclusions References 17 ? Clinical Progress in Tumor Vascular-Disrupting Therapies Andy Gaya Gordon Rustin 17.1 Introduction 17.2 Potential clinical advantages of vascular-disrupting agents 17.3 Biological (ligand-directed) VDAs 17.4 Small-molecule VDAs 17.5 Potential surrogate markers of CA4P activity 17.6 Combination therapy with VDAs 17.7 VDAs in non-malignant diseases 17.8 Conclusions References 18 ? Use of Vascular-Disrupting Agents in Non-Oncology Indications Joseph C. Randall Scott Young 18.1 Background 18.2 Age-related macular degeneration (AMD) 18.3 Myopic macular degeneration 18.4 Retinopathy of prematurity 18.5 Proliferative diabetic retinopathy 18.6 Pediatric hemangiomas 18.7 Arthritis 18.8 Psoriasis 18.9 Conclusions References
Library of Congress Subject Headings for this publication:
Cancer -- Chemotherapy.
Blood-vessels -- Effects of drugs on.
Neoplasms -- drug therapy.
Angiogenesis Inhibitors -- therapeutic use.
Blood Vessels -- drug effects.
Drug Delivery Systems.
Endothelial Cells -- drug effects.
Gene Therapy -- methods.