Vascular-Targeted Therapies in Oncology

Vascular-Targeted Therapies in Oncology provides an interesting insight to the current status and future potential of vascular-disrupting approaches in cancer management. Emphasis is placed on target development, preclinical assessment, and the use of such targeted approaches in combination with conventional treatment regimens and the current clinical status of these therapies.

Dietmar W. Siemann is the editor of Vascular-Targeted Therapies in Oncology, published by Wiley.

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.

2.8 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 Stöltzing, 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).

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.

11.4 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.

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Vascular-Targeted Therapies in Oncology

Summary

Author Biography

Table of Contents

Supplemental Materials