Inhibition of Matrix Metalloproteinases: Therapeutic Applications

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Presents 112 papers from the conference of the same name held October 1998 in Tampa, Florida. The papers explore ways in which inhibitors of matrix metalloproteinases (MMPs) might be medically useful in arthritis, cancer, periodontal disease, vascular diseases, eye and skin conditions, and osteoporosis. Important themes arising from the papers include the use of inhibitors for just one or two MMPs versus their use as broad-spectrum agents and the necessity for animal and human testing. New areas touched upon include the extension of MMPs into immunology and the role of MMPs in acute coronary rupture and aneurysm expansion. Annotation c. Book News, Inc., Portland, OR (
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Product Details

Table of Contents

Preface xvii
Common Names of Matrix Metalloproteinases xix
Part I. Overview
Engineering of Selective TIMPs 1
Role of Matrix Metalloproteinases and Their Inhibition in Cutaneous Wound Healing and Allergic Contact Hypersensitivity 12
Evaluation of Some Newer Matrix Metalloproteinases 25
Part II. Optimizing the Design of Inhibitors
The Next Generation of MMP Inhibitors: Design and Synthesis 40
Design and Synthetic Considerations of Matrix Metalloproteinase Inhibitors 61
Insights into MMP-TIMP Interactions 73
Aggrecanase: A Target for the Design of Inhibitors of Cartilage Degradation 92
Tissue Inhibitors of Matrix Metalloproteinases in Cancer 108
The Regulation of MMPs and TIMPs in Cartilage Turnover 120
Part IV. Clinical Forum
Scientific Basis of a Matrix Metalloproteinase-8 Specific Chair-side Test for Monitoring Periodontal and Peri-implant Health and Disease 130
MMP-9 Activity in Urine from Patients with Various Tumors, as Measured by a Novel MMP Activity Assay Using Modified Urokinase as a Substrate 141
Fluorogenic MMP Activity Assay for Plasma Including MMPs Complexed to [alpha]2-Macroglobulin 150
Part V. Clinical and Preclinical Studies--Medical
MMP Inhibition in Abdominal Aortic Aneurysms: Rationale for a Prospective Randomized Clinical Trial 159
Effect of Matrix Metalloproteinase Inhibition on Progression of Atherosclerosis and Aneurysm in LDL Receptor-Deficient Mice Overexpressing MMP-3, MMP-12, and MMP-13 and on Restenosis in Rats after Balloon Injury 179
Treatment of Osteoporosis with MMP Inhibitors 191
Clinical Trials of a Stromelysin Inhibitor: Osteoarthritis, Matrix Metalloproteinase Inhibition, Cartilage Loss, Surrogate Markers, and Clinical Implications 201
Part VI. Clinical Studies--Cancer
Experimental Models to Identify Antimetastatic Drugs: Are We There Yet?-- A Position Paper 208
Measurement of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Blood and Tissues: Clinical and Experimental Applications 212
Preclinical and Clinical Studies of MMP Inhibitors in Cancer 228
Broad Antitumor and Antiangiogenic Activities of AG3340, a Potent and Selective MMP Inhibitor Undergoing Advanced Oncology Clinical Trials 236
MMP Inhibition in Prostate Cancer 271
Part VII. Clinical Studies--Dental
A Chemically Modified Nonantimicrobial Tetracycline (CMT-8) Inhibits Gingival Matrix Metalloproteinases, Periodontal Breakdown, and Extra-Oral Bone Loss in Ovariectomized Rats 290
MMP-Mediated Events in Diabetes 311
Clinical Trials of a Matrix Metalloproteinase Inhibitor in Human Periodontal Disease 335
Effects of Chemically Modified Tetracycline, CMT-8, on Bone Loss and Osteoclast Structure and Function in Osteoporotic States 347
Part VIII. Angiogenesis and Related Phenomena
Specialized Surface Protrusions of Invasive Cells, Invadopodia and Lamellipodia, Have Differential MT1-MMP, MMP-2, and TIMP-2 Localization 361
Activation of ProMMP-9 by a Plasmin/MMP-3 Cascade in a Tumor Cell Model: Regulation by Tissue Inhibitors of Metalloproteinases 372
Matrix Metalloproteinase Inhibition: From The Jurassic To The Third Millennium 388
Part IX. Molecular Markers of CT Degradation
C-Telopeptide Pyridinoline Cross-Links: Sensitive Indicators of Periodontal Tissue Destruction 404
Thirty-six Years in the Clinic without an MMP Inhibitor: What Hath Collagenase Wrought? 413
Part X. New Topics in MMPs
Physical and Biological Regulation of Proteoglycan Turnover around Chondrocytes in Cartilage Explants: Implications for Tissue Degradation and Repair 420
Adamalysins: A Family of Metzincins Including TNF-[alpha] Converting Enzyme (TACE) 442
MMP Inhibition and Downregulation by Bisphosphonates 453
Retinoid-Mediated Suppression of Tumor Invasion and Matrix Metalloproteinase Synthesis 466
Part XI. Poster Papers
Determination of Gelatinase-A (MMP-2) Activity Using a Novel Immunocapture Assay 487
Analytical Aspects Regarding the Measurement of Metalloproteinases 491
Hyper-resistance to Infection in TIMP-1-Deficient Mice Is Neutrophil Dependent but Not Immune Cell Autonomous 494
Shed Membrane Vesicles and Selective Localization of Gelatinases and MMP-9/TIMP-1 Complexes 497
Tissue Inhibitor of Metalloproteinase-1 Is Not an Acute-Phase Protein 500
Regulation of TIMP-1 Expression by Hypoxia in Kidney Fibroblasts 503
Induction of Human Tissue Inhibitor of Metalloproteinase-1 Gene Expression by All-trans Retinoic Acid in Combination with Basic Fibroblast Growth Factor Involves both p42/44 and p38 MAP Kinases 506
Transcriptional Regulation of the Human Tissue Inhibitor of Metalloproteinases-1: Mapping Transcriptional Control in Intron-1 510
Balance between MMP-9 and TIMP-1 Expressed by Human Bronchial Epithelial Cells: Relevance to Asthma 512
Use of Encapsulated Cells Secreting Murine TIMP-2 Ameliorates Collagen-Induced Arthritis in Mice 515
TIMP-1 and TIMP-2 Perform Different Functions in Vivo 519
Tissue Inhibitor of Metalloproteinase-2 Induces Apoptosis in Human T Lymphocytes 522
Analysis of the Interaction of TIMP-2 and MMPs: Engineering the Changes 524
Murine TIMP-2 Gene-Targeted Mutation 528
The Expression of TIMP-3 in Hepatoma Cell Lines 531
In Situ Activity of Gelatinases during Lewis Lung Carcinoma Progression 534
Targeting Matrix Metalloproteinases in Human Prostate Cancer 538
Expression of Matrix Metalloproteinases in Gastric Carcinoma and Possibility of Clinical Application of Matrix Metalloproteinase Inhibitor in Vivo 541
Metalloproteinases and Tissue Inhibitors of Matrix-Metalloproteinases in Plasma of Patients with Prostate Cancer and in Prostate Cancer Tissue 544
MMP Inhibition Reduces Intimal Hyperplasia in a Human Vein Graft Stenosis Model 547
Increased MMP-9 Activity in Acute Carotid Plaques: Therapeutic Avenues to Prevent Stroke 551
Enhanced Expression of Matrix Metalloproteinase-3, -12, and -13 mRNAs in the Aortas of Apolipoprotein E-deficient Mice with Advanced Atherosclerosis 555
Defects in Matrix Metalloproteinase Inhibitory Stoichiometry and Selective MMP Induction in Patients with Nonischemic or Ischemic Dilated Cardiomyopathy 559
Modulation of Matrix Metalloproteinases in Trophoblast Cell Lines 563
Effect of Relaxin on Tissue Inhibitor of Metalloproteinase-1 and -2 in the Porcine Uterus and Cervix 565
Matrix Metalloproteinases Exhibit Different Expression Patterns in Inflammatory Demyelinating Diseases of the Central and Peripheral Nervous System 567
Matrix Metalloproteinases in Sterile Corneal Melts 571
Chemokine-Induced Extravasation of MonoMac 6 Cells: Chemotaxis and MMP Activity 575
Elevated Plasma Gelatinase A (MMP-2) Activity Is Associated with Quiescent Crohn's Disease 578
Regulation of Matrix Metalloproteinases in Human Intestinal Mucosa 581
MMP-13 and MMP-1 Expression in Tissues of Normal Articular Joints 583
Expression and Localization of TIMP-1, TIMP-2, MMP-13, MMP-2, and MMP-9 in Early and Advanced Experimental Lung Silicosis 587
Type II Collagen Peptide Release from Rabbit Articular Cartilage 590
Inhibition of Articular Cartilage Degradation in Culture by a Novel Nonpeptidic Matrix Metalloproteinase Inhibitor 594
Collagen-PVP Decreases Collagen Turnover in Synovial Tissue Cultures from Rheumatoid Arthritis Patients 598
Matrix Metalloproteinase Inhibitors Block Osteoclastic Resorption of Calvarial Bone but Not the Resorption of Long Bone 603
Matrix Metalloproteinase Inhibitor CGS 27023A Protects COMP and Proteoglycan in the Bovine Articular Cartilage but Not the Release of Their Fragments from Cartilage after Prolonged Stimulation in Vitro with IL-1[alpha] 607
Modulation of the Synthesis and Activation of Matrix Metalloproteinases in IL-1-Treated Chondrocytes by Antirheumatic Drugs 612
Effects of 1[alpha],25DihydroxyvitaminD[subscript 3] on Matrix Metalloproteinase Expression by Rheumatoid Synovial Cells and Articular Chondrocytes in Vitro 615
Synovial Cytokine and Growth Factor Regulation of MMPs/TIMPs: Implications for Erosions and Angiogenesis in Early Rheumatoid and Psoriatic Arthritis Patients 619
Development and Application of a Microplate Assay Method for the Mass Screening of MMP Inhibitors 622
Heparin and Fragments Modulate the Expression of Collagen-Degrading Enzymes (Matrix Metalloproteinases 1 and 2) by Human Gingival Fibroblasts 625
Inhibition of Matrix Metalloproteinases by Tea Catechins and Related Polyphenols 629
The Citrus Flavonoid Nobiletin Suppresses the Production and Gene Expression of Matrix Metalloproteinases-9/Gelatinase B in Rabbit Synovial Cells 632
Gelastatins, New Inhibitors of Matrix Metalloproteinases from Westerdykella multispora F50733 635
Human Metalloproteinase-1 (Collagenase-1) Is a Tumor Suppressor Protein p53 Target Gene 638
Interaction between Stromal Cells and Tumor Cells Induces Chemoresistance and Matrix Metalloproteinase Secretion 642
Inhibition of Gelatinase A by Oleic Acid 647
Attenuation of Oxidant-Induced Lung Injury by the Synthetic Matrix Metalloproteinase Inhibitor BB-3103 650
Influence of Putative Antiinvasive Agents on Matrix Metalloproteinase Secretion by Human Neoplastic Glia in Vitro 654
Effect of a Matrix Metalloproteinase Inhibitor (BB-1101) on Nerve Regeneration 658
Selective Inhibition of Collagenase-1, Gelatinase A, and Gelatinase B by Chemotherapeutic Agents 662
Meloxicam and Indomethacin Activity on Human Matrix Metalloproteinases in Synovial Fluid 665
Non-antimicrobial and Antimicrobial Tetracyclines Inhibit IL-6 Expression in Murine Osteoblasts 667
CMT-8/Clodronate Combination Therapy Synergistically Inhibits Alveolar Bone Loss in LPS-Induced Periodontitis 671
MMP Inhibition by Chemically Modified Tetracycline-3 (CMT-3) in Equine Pulmonary Epithelial Lining Fluid 675
CMT-3, a Chemically Modified Tetracycline, Inhibits Bony Metastases and Delays the Development of Paraplegia in a Rat Model of Prostate Cancer 678
Collagenase-2 and -3 are Inhibited by Doxycycline in the Chronically Inflamed Lung in Bronchiectasis 683
The Effect of MMP Inhibitor Metastat on Fissure Caries Progression in Rats 686
Tetracycline Derivative CMT-3 Inhibits Cytokine Production, Degranulation, and Proliferation in Cultured Mouse and Human Mast Cells 689
TNF-[alpha]-Converting Enzyme Activity in Colonic Biopsy Specimens from Patients with Inflammatory Bowel Disease Revealed by mRNA and in Vitro Assay 692
MMPs are IGFBP-Degrading Proteinases: Implications for Cell Proliferation and Tissue Growth 696
Phosphonate Inhibitors of Adamalysin II and Matrix Metalloproteinases 700
Roles of MT1-MMP in the Regulation of Cell Surface Proteolysis 703
Transient Increase of Intracellular cAMP by Heat Shock Initiates the Suppression of MT1-MMP Production in Tumor Cells 707
The 9-kDa N-Terminal Propeptide Domain of MT1-MMP Is Required for the Activation of Progelatinase A 710
Cell Type-Specific Involvement of Furin in Membrane Type 1-Matrix Metalloproteinase-Mediated Progelatinase A Activation 713
High Fructose-Fed Rats: A Model of Glomerulosclerosis Involving the Renin-Angiotensin System and Renal Gelatinases 716
Wound Healing in Aged Normal and Ovariectomized Rats: Effects of Chemically Modified Doxycycline (CMT-8) on MMP Expression and Collagen Synthesis 720
Therapeutic Options in Small Abdominal Aneurysms: The Role of in Vitro Studies 724
Inhibition of the Metalloproteinase Domain of Mouse TACE 728
The Effects of Sustained Elevated Levels of Circulating Tissue Inhibitor of Metalloproteinases-1 on the Development of Breast Cancer in Mice 732
Macrophage-Specific Expression of Human Collagenase (MMP-1) in Transgenic Mice 736
TIMP-4 Is Regulated by Vascular Injury in Rats 740
In Vivo Adenoviral Gene Transfer of TIMP-1 after Vascular Injury Reduces Neointimal Formation 742
Paradoxical Stimulation of Matrix Metalloproteinase-9 Expression in HT1080 Cells by a Broad-Spectrum Hydroxamate-Based Matrix Metalloproteinase Inhibitor 744
Identification of the TIMP-2 Binding Site on the Gelatinase A Hemopexin C-Domain by Site-Directed Mutagenesis and the Yeast Two-Hybrid System 747
Index of Contributors 755
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