Angiogenesis Inhibitors and Stimulators - S. Mousa (Landes, 2000) WW

174 Pages·2000·2.31 MB·English

Shaker A. Mousa

Angiogenesis Inhibitors and Stimulators

Angiogenesis Inhibitors
and Stimulators
Potential Therapeutic Implications

MEDICAL INTELLIGENCE UNIT 20

Shaker A. Mousa, Ph.D., M.B.A.
DuPont Pharmaceuticals Company
Wilmington, Delaware, U.S.A.

Angiogenesis Inhibitors
and Stimulators:
Potential Therapeutic Implications

MEDICAL
INTELLIGENCE
UNIT 20

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ANGIOGENESIS INHIBITORS AND STIMULATORS:
POTENTIAL THERAPEUTIC IMPLICATIONS

Dedication

I would like to specially thank my wife Mawaheb, my sons Ahmed and Adam, my
daughters Shaymaa, Sarah, and Deena, my father and my mother for their love, encourage-
ment and support.

This book is dedicated to my family.

Shaker A. Mousa

CONTENTS

Preface

1. Mechanisms of Angiogenesis: Potential Therapeutic Targets .................1
Shaker A. Mousa
Regulation of Angiogenesis.................................................................... 3
Angiogenic Mediators............................................................................ 3
Role of Kinases ...................................................................................... 4
FIK-1 Antagonists for Inhibition of Angiogenesis .................................. 4
Identifying Inhibitors of Receptor/Ligand Interactions Involved
in Angiogenesis.................................................................................. 4
Natural Anti-Endothelial and Neovascular Targeting Mechanisms
of Platelet Factor-4 (PF4) Angiostatic Activity................................... 5
Role of Cell Adhesion Molecules and Extracellular Matrix .................... 5
Angiogenesis Models ............................................................................. 6
Angiogenesis and Ocular, Cancer, Inflammatory, Wound Healing
and Cardiovascular Diseases .............................................................. 6
Potential Therapeutic Applications of Anti-Angiogenic Agents.............. 9
Conclusion .......................................................................................... 12

2. Angiogenesis and Ischemia: ..................................................................13
Derrick S. Grant and Zofia Zukowska-Grojec
Normal Vascular Distribution and Angiogenesis in the Limbs............. 13
Cardiovascular Risk in Diabetic Patients ............................................. 14

3. The Role of Smooth Muscle Cells and Pericytes in Angiogenesis ......... 25
Jennifer J. Walter and David C. Sane
The Role of SMCs in Controlling Flow to the Capillary Bed .............. 25
Pericytes .............................................................................................. 26
Detection of SMCs and Pericytes in Neovasculature ........................... 27
SMCs as Sources of Angiogenic Growth Factors ................................. 27
The Role of SMCs in the Production and Degradation
of the Extracellular Matrix ............................................................... 29
The Role of SMCs in Plasminogen Activation..................................... 29
Effects of Angiogenesis Inhibitors on SMCs ........................................ 30
Conclusion .......................................................................................... 30

4. Integrin αv in Health and Disease—Role of αvβ3 in Metastasis,
Vascular Remodeling and Angiogenesis................................................ 37
Shaker A. Mousa, Judith A. Varner, David Cheresh
Integrin αvβ3 ...................................................................................... 37
Expression of Integrins αvβ3 and αvβ5 in Angiogenesis ..................... 38
Integrin αvβ3 in Restenosis ................................................................. 40
Integrin αvβ3 and Apoptosis ............................................................... 40
Integrin αvβ3 and Proteinases ............................................................. 41
Conclusion .......................................................................................... 41

5. PECAM-1 and Angiogenesis ................................................................45
Horace M. DeLisser
PECAM-1—A Multi-Functional Vascular Cell Adhesion
and Signaling Molecule ................................................................... 45
The Involvement of PECAM-1 in In Vivo Angiogenesis ..................... 46
The Involvement of PECAM-1 in Endothelial Tube Formation
and Migration ................................................................................. 46
A Proposal for the Mechanisms of PECAM-1’s Involvement
in Angiogenesis................................................................................ 49
Summary............................................................................................. 49

6. Thrombospondin and Angiogenesis .....................................................52
Luisa A. DiPietro
The Molecular Structure of TSP1 ....................................................... 52
TSP1 as a Regulator of In Vitro Angiogenesis ..................................... 53
TSP1 and In Vivo Angiogenesis .......................................................... 55
Interactions of TSP1 with Angiogenic Factors ..................................... 55
Interactions of TSP1 with Proteases .................................................... 55
TSP1 as a Regulator of Physiologic Angiogenesis................................. 56
TSP1 in Pathologic Angiogenesis ........................................................ 56
Therapeutic Uses of TSP1 ................................................................... 57
The Regulation of Angiogenesis by TSP1 ............................................ 57

7. The Role of Vascular Endothelial Growth Factor in Angiogenesis........ 61
Napoleone Ferrara
Biological Activities of VEGF .............................................................. 61
Organization of the VEGF Gene and Characteristics of the VEGF
Proteins ........................................................................................... 62
Regulation of VEGF Gene Expression................................................. 63
The VEGF Receptors .......................................................................... 65
The Flt-1 and Flk-1/KDR Tyrosine Kinases........................................ 65
Role of VEGF and Its Receptors in Physiological Angiogenesis ........... 68
Role of VEGF in Pathologic Angiogenesis ........................................... 69
Therapeutic Applications of VEGF-Induced Angiogenesis .................. 72
Perspectives ......................................................................................... 73

8. Regulation of Angiogenesis by Fibroblast Growth Factors ...................84
Carla Mouta Carreira, Francesca Tarantini, Igor Prudovsky,
Susan Garfinkel and Thomas Maciag
The FGF Gene Family ........................................................................ 84
The FGFR Gene Family...................................................................... 88
Mechanisms of FGF Release ................................................................ 89
Future Directions ................................................................................ 92

9. Role of Angiogenesis in Wound Healing ............................................ 102
Hynda K. Kleinman and Katherine M. Malinda
Wound Healing ................................................................................ 102
Angiogenesis ...................................................................................... 102
Angiogenic Stimulators ..................................................................... 103
Use of Angiogenic Stimulators in Wound Repair .............................. 103
Angiogenic Thymic Peptides: Thymosin a1 and Thyomsin b4 .......... 105
Summary........................................................................................... 107

10. Ocular Neovascularization .................................................................110
Peter A. Campochiaro and Naba Bora
Types of Ocular Neovascularization .................................................. 111
Ischemia (or Hypoxia) Plays a Central Role in the Development
of Retinal Neovascularization ........................................................ 111
VEGF is the Major Stimulatory Factor Involved in Retinal
Neovascularization ........................................................................ 111
Hypoxia Leads to Increased VEGF by Transcriptional Activation
and Stabilization of mRNA ........................................................... 111
Permissive Factors may Increase Endothelial Cell Responsiveness
to VEGF in Ischemic Retina ......................................................... 112
Endogenous Inhibitors that Normally Antagonize Effects
of VEGF may be Decreased in Ischemic Retina............................. 113
Intracellular Signaling Stimulated by VEGF is Complex
and Overlaps with Other Growth Factors...................................... 113
VEGF Signaling Promotes Expression of Genes Involved
in Progression through the Cell Cycle, Proteinases,
Proteinase Inhibitors and Integrins ................................................ 113
Mature New Vessels are Less Dependent on VEGF........................... 113
Strategies for Inhibiting Retinal Neovascularization .......................... 114
The Pathogenesis of Choroidal Neovascularization
is Poorly Understood ..................................................................... 114
Models of Choroidal Neovascularization ........................................... 115
Stimulatory Factors for Choroidal Neovascularization ....................... 115
Strategies for Inhibiting Choroidal Neovascularization ...................... 116
Future Applications and Anticipated Developments .......................... 116

11. Anti-Angiogenesis Strategies: Potential Therapeutic Implications ...... 120
Shaker A. Mousa
Small Molecule Integrin Antagonists ................................................. 120
Broad Anti-Cancer Effects of AG3340, Matrix Metalloproteinase
Inhibitor........................................................................................ 120
Agents Modulating Fibrinolytic, Coagulation and Platelet
Functions ...................................................................................... 121
CM101: An Anti-Pathoangiogenic Agent and Its Receptor ............... 121
Kringle 5, a Naturally Occurring Inhibitor of Tumor Antiogenesis ... 121
Anti-Angiogenesis Strategies Using Monoclonal Antibodies .............. 121

Angiogenesis Inhibitor Squalamine.................................................... 121
Angiostatic Steroid, AL-3789: Potential in Corneal
Neovascularization ........................................................................ 121
Ocular Phamacokinetics of AG3340: Metalloproteases
after Oral Administration .............................................................. 122
TNP-470 (AGM-1470) .................................................................... 122
Potentiation of Cytotoxic by Anti-Angiogenic Agents ....................... 122
Conclusion ........................................................................................ 123

12. Matrix Metalloproteinase Inhibitors in Angiogenesis-Mediated
Disorders with Special Emphasis on Cancer.......................................124
Henrik S Rasmussen
Matrix Metalloproteinases ................................................................. 124
Matrix Metalloproteinase Inhibitors .................................................. 126
Conclusions....................................................................................... 131

13. Pharmaceutical Development of an Antiangiogenic
Drug-Candidate: Challenges and Opportunities ................................134
Marc Rivière, Violetta Dimitriadou, Gerald Batist, Éric Dupont
New Therapeutic Area....................................................................... 134
Challenges ......................................................................................... 135

14. Surrogate Endpoints as a Measure of Efficacy in Clinical Trials
of Angiogenesis Inhibitors ..................................................................143
Przemek Twardowski, Stephen Gately and William Gradishar
Biomarkers in the Circulation ........................................................... 143
Histopathological Markers ................................................................ 146
Clinical Response Rates ..................................................................... 146
Imaging Studies................................................................................. 146
Wound Healing ................................................................................ 146
Specific Angiogenesis Inhibitor Biomarkers ....................................... 147
Conclusion ........................................................................................ 147

15. Lessons from Clinical Trials of Anti-Angiogenic Drugs
in the Treatment of Cancer ................................................................151
Maggie C. Lee, James Tomlinson and Mai Nguyen
Background ....................................................................................... 151
TNP-470 .......................................................................................... 152
Thalidomide...................................................................................... 153
Carboxyamido-Triazole ..................................................................... 153
CM-101 ............................................................................................ 154
Inhibitors of Angiogeneic Factors ...................................................... 155
Cytokines .......................................................................................... 156
Inhibitors of Matrix Interactions ....................................................... 156
Discussion ......................................................................................... 156

Index ..................................................................................................161

Shaker A. Mousa, Ph.D., M.B.A., F.A.C.C., F.A.C.B.
Research Fellow and Professor of Pharmacology
DuPont Pharmaceuticals Company
Wilmington, Delaware, U.S.A.
Chapters 1, 4 and 11

EDITORS

CONTRIBUTORS

Gerald Batist
McGill Centre for Translational
Research in Cancer
Montreal, Quebec, Canada
Chapter 13

Naba Bora
The Departments of Ophthalmology
and Neuroscience
The Johns Hopkins University School
of Medicine
Baltimore, Maryland, U.S.A.
Chapter 10

Peter A. Campochiaro
The Departments of Ophthalmology
and Neuroscience
The Johns Hopkins University School
of Medicine
Baltimore, Maryland, U.S.A.
Chapter 10

Carla Mouta Carreira
Center for Molecular Medicine
Maine Medical Center Research Institute
South Portland, Maine, U.S.A.
Chapter 8

David A. Cheresh
The Scripps Research Institute
LaJolla, California, U.S.A.
Chapter 4

Robert D'Amato
Department of Ophthalmology
Harvard Medical School,
Children's Hospital
Boston, Massachusetts, U.S.A.
Chapter 10

Horace DeLisser
Pulmonary and Critical Care Division
Department of Medicine
University of Pennsylvania
Medical Center
Philadelphia, Pennsylvania, U.S.A.
Chapter 5

Violetta Dimitriadou
Æterna Laboratories, Inc.
Sainte-Foy, Quebec, Canada
Chapter 13

Luisa A. DiPietro
Loyola University
Medical Center
Maywood, Illinois, U.S.A.
Chapter 6

Éric Dupont
Æterna Laboratories, Inc.
Sainte-Foy, Quebec, Canada
Chapter 13

Napoleone Ferrara
Department of Cardiovascular Research
Genentech, Inc.
San Francisco, California, U.S.A.
Chapter 7

William J. Gardishar
Department of Medicine
Northwestern University Medical School
Chicago, Illinois, U.S.A.
Chapter 14

Susan Garfinkel
Center for Molecular Medicine
Maine Medical Center Research Institute
South Portland, Maine, U.S.A.
Chapter 8

Stephen Gately
Department of Medicine
Northwestern University Medical School
Chicago, Illinois, U.S.A.
Chapter 14

Derrick S. Grant
Cardeza Foundation for Hematological
Research
Jefferson University
Philadelphia, Pennsylvania, U.S.A.
Chapter 2

Hynda K. Kleinman
Cell Biology Section
National Institute of Dental Research
Bethesda, Maryland, U.S.A.
Chapter 9

Maggie C. Lee
Division of Oncology
University of California
Los Angeles, California, U.S.A.
Chapter 15

Thomas Maciag
Center for Molecular Medicine
Maine Medical Center Research Institute
South Portland, Maine, U.S.A.
Chapter 8

Katherine M. Malinda
Cell Biology Section
National Institute of Dental Research
Bethesda, Maryland, U.S.A.
Chapter 9

Mai Nguyen
Division of Oncology
University of California
Los Angeles, California, U.S.A.
Chapter 15

Igor Prudovsky
Center for Molecular Medicine
Maine Medical Center Research Institute
South Portland, Maine, U.S.A.
Chapter 8

Henrik S. Rasmussen
British Biotech, Inc.
Annapolis, Maryland, U.S.A.
Chapter 12

Marc Rivière
Æterna Laboratories, Inc.
Sainte-Foy, Quebec, Canada
Chapter 13

James Rusche
Research and Development
Repligen Corporation
Needham, Massachusetts, U.S.A.
Chapter 10

David C. Sane
Section of Cardiology
Wake Forest Univeristy School
of Medicine
Winston-Salem, North Carolina, U.S.A
Chapter 3

Francesca Tarantini
Center for Molecular Medicine
Maine Medical Center Research Institute
South Portland, Maine, U.S.A.
Chapter 8

James Tomlinson
Division of Oncology
University of California
Los Angeles, California, U.S.A.
Chapter 15