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Advances in Internal Medicine 2001
Review
Topics: 2-Methoxyestradiol; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Collagen; Endostatins; Endothelial Growth Factors; Enzyme Inhibitors; Estradiol; Humans; Hydroxamic Acids; Lymphokines; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Peptide Fragments; Protein-Tyrosine Kinases; Thalidomide; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 11795074
DOI: No ID Found -
Lung Cancer (Amsterdam, Netherlands) Dec 2001Numerous inhibitors of angiogenesis are currently under study in lung cancer. Four trials of adjuvant interferon after chemotherapy for small cell lung cancer (SCLC)... (Review)
Review
Numerous inhibitors of angiogenesis are currently under study in lung cancer. Four trials of adjuvant interferon after chemotherapy for small cell lung cancer (SCLC) were negative. Several metalloproteinase inhibitors (MMPIs) are now in study in SCLC and non-small cell lung cancer (NSCLC). Two large randomized trials have closed recently in which Marimastat 10 mg bid was compared to placebo in responding patients with SCLC. Two randomized studies of Prinomastat versus placebo with combination chemotherapy in advanced NSCLC have also completed accrual. The results of these trials are not yet available, but should be reported in mid-2001. A Phase III trial of BMS-275291, a broad-spectrum MMPI in combination with paclitaxel and carboplatin is open for patients with advanced NSCLC. Neovastat, a standardized shark cartilage extract is under study in inoperable Stage III NSCLC. VEG-F gene expression is increased in many tumors including NSCLC, and may act as a paracrine mediator of growth. A randomized Phase II trial of paclitaxel and carboplatin with or without a recombinant humanized anti-VEG-F has been undertaken in NSCLC. Modestly better response and survival were seen with anti-VEG-F and a large Phase III trial is planned. Numerous receptor tyrosine kinases (TK) have been found to be directly or indirectly involved in angiogenesis including Flk-1, Flt-l, Tie-1 and Tie-2. SU5416 is a small molecular TK inhibitor and potent inhibitor of VEG-F-mediated Flk-1 receptor signaling. Another TK inhibitor SU6668 blocks VEG-F, bFGF and PDGF receptor signaling. It is orally available, and it may be evaluated in lung cancer trials in the near future. ZD4190 is an inhibitor of KDR/Flk-1 that may be evaluated in SCLC. Thalidomide has recently been shown in pre-clinical models to be anti-angiogenic. A randomized trial of paclitaxel/carboplatin and radiation with or without thalidomide is open for patients with Stage IIIB NSCLC in the United States. Numerous other anti-angiogenesis agents are in early clinical trials, but have not been evaluated in lung cancer yet.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Drug Therapy, Combination; Endothelial Growth Factors; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Lymphokines; Neovascularization, Pathologic; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 11740999
DOI: 10.1016/s0169-5002(01)00377-4 -
American Journal of Respiratory Cell... Dec 2001Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the...
Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.
Topics: ADAM Proteins; ADAM17 Protein; Acute Disease; Animals; Antigens, CD; Antigens, Neoplasm; Antineoplastic Agents; Barotrauma; Basigin; Capillary Permeability; Culture Media, Conditioned; Drug Evaluation, Preclinical; Enzyme Induction; Enzyme Inhibitors; Fibroblasts; Injections, Intraperitoneal; Lung; Lung Injury; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Membrane Glycoproteins; Metalloendopeptidases; Models, Animal; Organic Chemicals; Positive-Pressure Respiration; Premedication; Pressure; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Stress, Mechanical; Tumor Necrosis Factor-alpha; Ventilators, Mechanical
PubMed: 11726397
DOI: 10.1165/ajrcmb.25.6.4558f -
The Journal of Biological Chemistry Mar 2002Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases,...
Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase.
Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases, MT1-MMP directly processes a single chain precursor of alpha(v) integrin subunit (pro-alpha(v)) into the heavy and light alpha-chains connected by a disulfide bridge. To evaluate functionality of MT1-MMP-processed integrins, we examined breast carcinoma MCF7 cells co-expressing alpha(v)beta(3) integrin with either the wild type or mutant MT1-MMP in a variety of migration and adhesion tests. Specific inhibitors of proprotein convertases and MMP were employed in our cell system to attenuate the individual pathways of pro-alpha(v) maturation. We present evidence that MT1-MMP cleavage of pro-alpha(v) in the cells did not affect RGD-ligand binding of the resulting alpha(v)beta(3) integrin but enhanced outside-in signal transduction through a focal adhesion kinase pathway. Enhanced tyrosine phosphorylation of focal adhesion kinase in cells co-expressing MT1-MMP and alpha(v)beta(3) integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of alpha(v)beta(3) integrin. These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and alpha(v)beta(3) integrin in tumor cells and identify downstream signaling pathways resulting from their interactions. Regulation of integrin maturation and functionality may be an important role of MT1-MMP in tumor cells.
Topics: Antineoplastic Agents; Binding Sites; Blotting, Western; Cell Adhesion; Cell Movement; Disulfides; Dose-Response Relationship, Drug; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Ligands; Matrix Metalloproteinase 1; Oligopeptides; Organic Chemicals; Phosphorylation; Precipitin Tests; Protein Binding; Protein-Tyrosine Kinases; Receptors, Vitronectin; Time Factors; Transfection; Tumor Cells, Cultured; Tyrosine; Vitronectin
PubMed: 11724803
DOI: 10.1074/jbc.M110269200 -
Journal of Ocular Pharmacology and... Jun 2001To determine the ocular pharmacokinetics, physiological and histological effects of prinomastat (a matrix metalloprotease inhibitor), a total of seventy-seven eyes of...
To determine the ocular pharmacokinetics, physiological and histological effects of prinomastat (a matrix metalloprotease inhibitor), a total of seventy-seven eyes of New Zealand White rabbits received intravitreous and subtenon injections of prinomastat or of acidified water vehicle as control, Doses of 0.5 mg in 0.05 mL of prinomastat or acidified water were used for intravitreal injection. For the subtenon injections, doses of 5 mg prinomastat in 0.5 mL of acidified water were administered in the superotemporal quadrant. Intraocular pharmacokinetics were determined by analyzing vitreous samples at different postinjection time points using Liquid Chromatography-Mass Spectroscopy/Mass Spectroscopy (LC-MS/MS). The toxicity was evaluated by biomicroscopy, electroretinography (ERG), pneumatonometry, and histology. No toxicity was found with either administration method. At day 14 after intravitreal injection, levels of prinomastat in the vitreous and choroid were 1.4 ng/mg and 7.8 ng/mg, respectively. The retinal levels of prinomastat were 22 ng/mg at 24 hr and dropped below 1 ng/mg at 48 hr. Prinomastat remained well above minimum effective concentration in the choroid for at least four weeks after a single intravitreal injection, suggesting that local intravitreal injection may have potential in treating choroidal neovascularization.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Chromatography, High Pressure Liquid; Drug Evaluation, Preclinical; Electroretinography; Gas Chromatography-Mass Spectrometry; Intraocular Pressure; Metalloendopeptidases; Organic Chemicals; Rabbits; Retina; Tonometry, Ocular; Vitreous Body
PubMed: 11436949
DOI: 10.1089/108076801750295326 -
Oncogene Dec 2000Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in... (Review)
Review
Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in tumor invasion and metastasis. Based on this evidence, the pharmaceutical industry produced several well tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated. Bayer and Agouron have discontinued their ongoing Phase III drug trials of MMPIs in advanced cancer. In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established. Our understanding of MMP pathophysiology in cancer has expanded considerably in the past 10 years. Current views indicate that: (1) most MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cancer cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; and (3) MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix. MMPs have a dual function in tumor angiogenesis: MMP-2 and MT1-MMP are required in breaking down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In spite of considerable recent progress in identifying multiple roles of MMPs in disease, our understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials focus on: (1) patients with early stage cancer; (2) the use of MMPIs along with chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI therapy; and (4) identification of biomarkers that reflect activation or inhibition of MMPs in vivo.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Models, Biological; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Stromal Cells
PubMed: 11426650
DOI: 10.1038/sj.onc.1204097 -
Nature Medicine Jun 2001A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One...
A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.
Topics: Animals; Antineoplastic Agents; Cell Line; Diagnostic Imaging; Fibrosarcoma; Fluorescence; Fluorescent Dyes; Humans; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Nude; Neoplasms, Experimental; Organic Chemicals; Peptides; Protease Inhibitors; Spectroscopy, Near-Infrared
PubMed: 11385514
DOI: 10.1038/89126 -
Nature Medicine Jun 2001
Topics: Animals; Antineoplastic Agents; Diagnostic Imaging; Extracellular Matrix Proteins; Fluorescence; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Organic Chemicals; Serine Endopeptidases
PubMed: 11385494
DOI: 10.1038/89016 -
Cancer Letters Apr 2001The present study was aimed at evaluating the effect of the matrix metalloproteinase (MMP) inhibitor prinomastat (AG3340) on tumor progression using an orthotopic...
Inhibitory effect of a matrix metalloproteinase inhibitor on growth and spread of human pancreatic ductal adenocarcinoma evaluated in an orthotopic severe combined immunodeficient (SCID) mouse model.
The present study was aimed at evaluating the effect of the matrix metalloproteinase (MMP) inhibitor prinomastat (AG3340) on tumor progression using an orthotopic pancreatic carcinoma model in severe combined immunodeficient mice. In controls, receiving vehicle only, the poorly differentiated ductal adenocarcinoma invaded into adjacent organs and metastasized to different sites in the abdomen and to the lungs. Treatment with prinomastat, intraperitoneally twice daily for 21 days, reduced primary tumor volume significantly to 19.0 (+/-7.7)% of control, with induction of necrosis, differentiation, and fibrotic tissue in the pancreatic tumors. Invasion was not observed in 63% of prinomastat-treated mice, and metastases were reduced markedly. Surprisingly, prinomastat-treated tumors had on average higher microvessel densities as a consequence of an increased angiogenesis in perinecrotic tumor areas. We conclude that prinomastat is highly effective in inhibiting pancreatic carcinoma growth and progression in an orthotopic cancer model. This model appears to be a valuable tool to investigate the potency of novel antimetastatic strategies in pancreatic ductal adenocarcinoma by specifically targeting certain MMPs.
Topics: Adenocarcinoma; Animals; Antigens, CD34; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Differentiation; Female; Fibrosis; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase Inhibitors; Mice; Mice, SCID; Necrosis; Neoplasm Invasiveness; Neoplasm Transplantation; Organic Chemicals; Pancreatic Neoplasms; Tumor Cells, Cultured
PubMed: 11275365
DOI: 10.1016/s0304-3835(01)00420-7 -
Annals of Neurology Feb 2001The release of potentially neurotoxic molecules by HIV-infected brain macrophages is accompanied by neuronal injury and death that results in the development of...
The release of potentially neurotoxic molecules by HIV-infected brain macrophages is accompanied by neuronal injury and death that results in the development of HIV-associated dementia (HAD). Among the potential neurotoxins implicated in the development of HAD is the HIV-1 transactivating protein, Tat. To investigate the mechanism by which Tat causes neurotoxicity, brain-derived Tat sequences from nondemented (Tat-ND) and demented (Tat-HAD) AIDS patients, which differed primarily in the augmenting region of Tat, were expressed in U937 monoblastoid cells and primary human macrophages. Cells expressing Tat-HAD protein exhibited elevated matrix metalloproteinase (MMP)-2 and -7 release and activation, but cells expressing Tat-ND did not exhibit enhanced MMP expression. Conditioned media from Tat-HAD-transfected cells caused significantly greater neuronal death (15.4 +/- 4.3%) than did Tat-ND (4.4 +/- 2.1%) or nontransfected (2.1 +/- 0.8%) cell-derived conditioned media. The neurotoxicity induced by Tat-HAD was inhibited by anti-MMP-2 or -7 antibodies (p < 0.005) but not by antibodies against MMP-9 or Tat. Similarly, scid/nod mice receiving striatal implants of Tat-HAD-transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p < 0.005) than did animals receiving Tat-ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p < 0.005). These findings indicate that Tat causes neuronal death through an indirect mechanism that is Tat sequence dependent and involves the induction of MMPs.
Topics: AIDS Dementia Complex; Amino Acid Sequence; Animals; Cell Death; Gene Products, tat; HIV-1; Humans; Immunohistochemistry; Matrix Metalloproteinase 2; Matrix Metalloproteinase 7; Matrix Metalloproteinase Inhibitors; Mice; Molecular Sequence Data; Neurons; Peptide Fragments; Polymerase Chain Reaction; tat Gene Products, Human Immunodeficiency Virus
PubMed: 11220743
DOI: 10.1002/1531-8249(20010201)49:2<230::aid-ana43>3.0.co;2-o