Vascular Targeted Therapies in Oncology includes target development, preclinical assessment, use in combination with conventional treatment regimens and the current clinical status of these therapies.

Features:

• Rreviews 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
• Emphasizes target development, preclinical assessment, use in combination with conventional treatment regimens and the current clinical status of these therapies

Contents

Introduction

• Tumor vasculature.
• Impact of tumor microenvironments on cancer management.
• Vascular-targeting therapies.
• Combinations with conventional anticancer therapies.
• Combinations of antiangiogenic and vascular-disrupting agents

Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors

• Basic principles of blood vessel formation in tumors.
• Tumor lymphangiogenesis.
• Tumor vascularity and blood flow.
• Volume and composition of the tumor interstitial space.
• Fluid pressure and convective currents in the interstitial space of tumors.
• Evidence, characterization and pathogenesis of tumor hypoxia.
• Tumor pH.
• The ‘crucial Ps’ characterizing the hostile metabolic microenvironment of solid tumors

The Role of Microvasculature in Metastasis Formation

• Regulators of angiogenesis in solid tumors.
• Angiogenesis and metastasis formation

Development of Vascular Targeting Strategies

• Early history.
• Formulation of the VDA concept.
• Effects of vascular occlusion on tumor cell survival.
• Rational development of VDA therapeutics.
• Development of small-molecule VDAs.
• Combretastatin A4 phosphate.
• The viable rim.

Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models

• Animal models.
• Morphologic and morphometric analysis.
• Effects of treatment

The Discovery and Development of Vascular-Disrupting Agents

• Introductory comments.
• Colchicine-binding site on tubulin.
• Brief overview of tubulin biology.
• Small-molecule inhibitors of tubulin assembly.
• Design paradigm for small-molecule vascular-targeting agents

Combined Modality Approaches Using Vascular-Disrupting Agents

• Tumor vasculature.
• Vascular-disrupting strategies.
• VDAs and chemotherapy.
• VDAs and radiation therapy.
• VDAs and antiangiogenic agents

Vascular-Targeting Therapies and Hyperthermia

• Enhancing hyperthermia.
• Enhancing thermoradiotherapy.
• Conclusions and clinical relevance

Flavones and Xanthenones as Vascular-Disrupting Agents

• Development of FAA and DMXAA.
• Antivascular activity of FAA and DMXAA.
• Cytokine induction by FAA and DMXAA.
• Molecular target.
• Preclinical studies: DMXAA as a single agent.
• Preclinical studies: combination treatments

Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer

• Vascular targeting.
• Pancreatic cancer: the clinical need.
• Phosphatidylserine.
• Proof of concept studies.
• Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model.
• Mechanism of action

Cadherin Antagonists as Vascular-Targeting Agents

• Pericytes as regulators of blood vessel stability.
• Cadherins.
• Cadherins and the vasculature.
• Tumor vasculature.
• Manipulation of the tumor vasculature with cadherin antagonists. 11.6 Summary and future directions. Acknowledgements. References.

Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells

• Discovery of alphastatin.
• Development of alphastatin

Cationic Lipid Complexes to Target Tumor Endothelium

• Tumor vascular targeting by cationic liposomes.
• Potential targets for cationic lipid complexes on tumor endothelial cells.
• Cationic liposomes as drug carriers.
• Side-effects of intravenously administered cationic lipid complexes.
• Preclinical data.
• Clinical data

Development of Vascular-Targeted Cancer Gene Therapy

• Advantages of tumor vasculature as a target in cancer gene therapy.
• Genes of value in vascular-targeted cancer gene therapy.
• Targeting gene therapy to tumor vasculature

Vascular-Disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors

• Hypoxia and necrosis as a selective target for cancer therapy.
• Use of Clostridia as hypoxia/necrotic selective cancer therapy.
• Advantage of CDEPT over ADEPT and GDEPT.
• Combination of CDEPT with vascular-disrupting agents.
• Clinical significance

Imaging the Effects of Vascular-Targeting Agents

• Methods for imaging tissue blood flow rate.
• Central volume theorem.
• Kety model.
• Fraction of cardiac output or ‘first-pass’ methods.
• Color Doppler ultrasonography.
• Imaging hypoxia.
• Imaging glucose metabolism.
• Preclinical experience of imaging vascular-disrupting agents.
• Clinical experience of imaging vascular-disrupting agents

Clinical Progress in Tumor Vascular-Disrupting Therapies

• Potential clinical advantages of vascular-disrupting agents.
• Biological (ligand-directed) VDAs.
• Small-molecule VDAs.
• Potential surrogate markers of CA4P activity.
• Combination therapy with VDAs.
• VDAs in non-malignant diseases

Use of Vascular-Disrupting Agents in Non-Oncology Indications

• Age-related macular degeneration (AMD).
• Myopic macular degeneration.
• Retinopathy of prematurity.
• Proliferative diabetic retinopathy.
• Pediatric hemangiomas.
• Arthritis.
• Psoriasis

Index

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