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Der Ophthalmologe : Zeitschrift Der... Apr 2003
Topics: Adult; Angiogenesis Inhibitors; Antineoplastic Agents; Choroidal Neovascularization; Corneal Neovascularization; Diabetic Retinopathy; Endothelial Growth Factors; Eye Diseases; Humans; Infant, Newborn; Intercellular Signaling Peptides and Proteins; Lymphokines; Macular Degeneration; Metalloendopeptidases; Neovascularization, Pathologic; Organic Chemicals; Platelet-Derived Growth Factor; Pregnadienediols; Retinal Neovascularization; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 12723577
DOI: 10.1007/s00101-003-0811-5 -
Annales de Biologie Clinique 2003Matrix metalloproteinases (MMPs) play a key role in the physiology of connective tissue development, morphogenesis and wound healing, but their unregulated activity has... (Comparative Study)
Comparative Study Review
Matrix metalloproteinases (MMPs) play a key role in the physiology of connective tissue development, morphogenesis and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, tumor cell metastasis and atherosclerosis. MMP family consists of at least 20 members; MMPs are produced by the different cell types (vascular smooth muscle cells, monocytes, endothelial cells) involved in the atheromatous plaque formation and participate to extracellular matrix remodelling and cell infiltration or migration. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention to modify vascular pathology, by restoring the MMP/TIMP physiological equilibrium. This review highlights the structures of MMPs and their physiological inhibitors, the Tissue Inhibitors of MMPs (TIMPs), and describes the current developments in pharmacological MMP inhibition.
Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Aortic Diseases; Arteriosclerosis; Case-Control Studies; Clinical Trials as Topic; Coronary Artery Disease; Doxycycline; Humans; Hydroxamic Acids; Hyperlipidemias; Hypolipidemic Agents; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Metalloendopeptidases; Organic Chemicals; Phenylalanine; Polymorphism, Genetic; Prospective Studies; Rats; Risk Factors; Thiophenes; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-3; Tissue Inhibitor of Metalloproteinases
PubMed: 12702469
DOI: No ID Found -
International Journal of Cancer May 2003Membrane type-1 matrix metalloproteinase (MT1-MMP) and alphavbeta3 integrin have been directly implicated in tumor cell dissemination and metastasis. We have...
Membrane type-1 matrix metalloproteinase (MT1-MMP) and alphavbeta3 integrin have been directly implicated in tumor cell dissemination and metastasis. We have demonstrated that in the case of breast carcinoma MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin, the proteinase processes the pro-alphav integrin subunit, thus facilitating alphavbeta3 integrin maturation and cell migration on vitronectin. Our findings show that cell surface MT1-MMP is a short-lived protein with a life span in the range of several hours. In contrast, turnover of alphavbeta3 integrin is much slower. The half-life of alphavbeta3 heterodimer is about 24 hr. This large difference in life span allowed us to distinguish between the effects of MT1-MMP on cell migration brought by matrix proteolysis from those imposed through alphavbeta3 integrin maturation. We then modulated the enzyme's activity by a potent hydroxamate MMP inhibitor, Prinomastat (AG3340), to analyze the divergent effects of MT1-MMP on cell migration. Although Prinomastat immediately blocked MT1-MMP-mediated matrix degradation, the pool of MT1-MMP-modified alphavbeta3 integrin molecules was still capable of mediating cell-matrix interactions. To our considerable surprise, inhibition of MT1-MMP-dependent vitronectin proteolysis by Prinomastat allowed a several-fold increase in migration of MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin. In contrast, long-term Prinomastat inhibition of MT1-MMP-dependent pro-alphav cleavage and thus alphavbeta3 integrin maturation strongly inhibited cell motility. Our studies suggest that MT1-MMP could actually promote cell migration via modification of the cell surface receptors, including alphavbeta3 integrin, rather than facilitate cell migration through direct cleavage of the matrix proteins.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Movement; Enzyme Inhibitors; Humans; Integrin alphaVbeta3; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Organic Chemicals; Tumor Cells, Cultured; Vitronectin
PubMed: 12594807
DOI: 10.1002/ijc.10977 -
American Journal of Physiology. Lung... Mar 2003High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix...
High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.
Topics: Antigens, CD; Antigens, Neoplasm; Antineoplastic Agents; Basigin; Blotting, Western; Cell Line; Culture Media, Conditioned; Endothelium, Vascular; Enzyme Activation; Enzyme Induction; Enzyme Inhibitors; Humans; Lung; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases, Membrane-Associated; Membrane Glycoproteins; Metalloendopeptidases; Organic Chemicals; Periodicity; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Stress, Mechanical; Tissue Inhibitor of Metalloproteinase-2
PubMed: 12456388
DOI: 10.1152/ajplung.00290.2002 -
Academic Radiology Aug 2002
Topics: Animals; Antineoplastic Agents; Cell Line; Diagnostic Imaging; Fluorescence; Fluorescent Dyes; Mammary Neoplasms, Experimental; Matrix Metalloproteinases; Mice; Mice, Nude; Neoplasms, Experimental; Organic Chemicals; Reverse Transcriptase Polymerase Chain Reaction; Spectroscopy, Near-Infrared
PubMed: 12188259
DOI: 10.1016/s1076-6332(03)80214-3 -
Current Eye Research Jan 2002To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, in an animal model of retinal...
PURPOSE
To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, in an animal model of retinal neovascularization.
METHODS
C57BL/6J mice were used to produce oxygen-induced retinal neovascularization. Mice were exposed to room air from birth (P0) to postnatal 7 days (P7) and to hyperoxia (75% oxygen) for the next 5 days. On postnatal day 12 (P12) the animals were returned to the room air and were treated until postnatal day 16 (P16) with intraperitoneal injections of AG 3340. Four groups were assigned: no drug, 1.6 mg/kg/day, 16 mg/kg/day and 48 mg/kg/day. On day 17 (P17) the animals were sacrificed and the eyes prepared for histological sectioning. Preretinal neovascularization was assessed by counting neovascular nuclei of endothelial cells in the preretinal side of the internal limiting membrane (ILM). The use of animals for this study complies with the ARVO guidelines for animal research.
RESULTS
AG3340 administered systemically by intraperitoneal injections inhibited hypoxia-induced retinal neovascularization. The inhibition was dose dependent with highly significant decrease of neovascular nuclei counts among eyes treated with 0, 1.6 mg/kg, 16 mg/kg and 48 mg/kg doses. There appears to be a saturation effect of inhibition at the level of 70% at the two highest doses of 16 mg/kg and 48 mg/kg.
CONCLUSIONS
AG3340 administered systemically significantly inhibits oxygen-induced retinal neovascularization in an animal model and appears to be a promising candidate for the treatment of neovascular retinal diseases.
Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Hypoxia; Injections, Intraperitoneal; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Organic Chemicals; Pregnancy; Retinal Neovascularization
PubMed: 12187492
DOI: 10.1076/ceyr.24.1.33.5429 -
Current Eye Research Feb 2002We studied the effects of intravitreally administered prinomastat on the take rate and growth of uveal melanoma after xenograft implantation in rabbit uveal melanoma...
PURPOSE
We studied the effects of intravitreally administered prinomastat on the take rate and growth of uveal melanoma after xenograft implantation in rabbit uveal melanoma model.
METHODS
Uveal melanoma xenograft was implanted to suprachoroidal space in each eye of 24 pigmented rabbits which were immunosuppressed with cyclosporine. One week after surgery, the eyes were randomized to receive prinomastat or the vehicle of the prinomastat intravitreally every week for 4 weeks. The take rate of the xenograft, tumor height, apoptosis, and necrosis in the eyes which developed tumors from the treatment and control groups were compared.
RESULTS
A tumor mass was identified in 8 of 24 (33%) prinomastat-treated eyes and 20 of 24 (83%) of the vehicle-treated eyes. Echographic measurements revealed a mean tumor height of 2.2 mm in the prinomastat-treated group and 3.8 mm in the control group in those eyes with take of tumor (p < 0.001). Stereomicroscopic measurements showed a mean tumor height of 1.9 mm in the treatment group and 3.9 mm in the control group (p < 0.001). The mean number of apoptotic nuclei detected per mm(2) of the histologic section in the non-necrotic tumor was 8.12 in the prinomastat-treated group and 0.57 in the control group (p < 0.001). Evaluation of the digital images in microscopic sections of the tumors on histologic slides revealed 29.6% necrosis in prinomastat-treated eyes as compared to 10.9% in vehicle-treated eyes (p = 0.003).
CONCLUSIONS
These results suggest that prinomastat treatment significantly reduces the take rate and the growth rate of xenograft in uveal melanoma rabbit model.
Topics: Animals; Antineoplastic Agents; Apoptosis; Enzyme Inhibitors; Fundus Oculi; Humans; Matrix Metalloproteinase Inhibitors; Melanoma, Experimental; Mice; Mice, SCID; Neoplasm Transplantation; Organic Chemicals; Rabbits; Transplantation, Heterologous; Uveal Neoplasms
PubMed: 12187478
DOI: 10.1076/ceyr.24.2.86.8159 -
Revue de Pneumologie Clinique Nov 2001
Comparative Study Review
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Lung Neoplasms; Metalloendopeptidases; Neovascularization, Pathologic; Organic Chemicals; Paclitaxel; Prognosis; Randomized Controlled Trials as Topic; Research; Time Factors
PubMed: 11924244
DOI: No ID Found -
Seminars in Oncology Feb 2002Preclinical studies have provided evidence that matrix metalloproteinases (MMPs), a family of zinc-containing proteolytic enzymes, facilitate tumor invasion, the... (Review)
Review
Preclinical studies have provided evidence that matrix metalloproteinases (MMPs), a family of zinc-containing proteolytic enzymes, facilitate tumor invasion, the establishment of metastases, and the promotion of tumor-related angiogenesis. Matrix metalloproteinase inhibitors (MMPIs) have been shown to inhibit tumor growth and dissemination in preclinical models. Not all lung cancers express the MMPs believed to be most important in promoting the neoplastic process, and there are conflicting reports regarding the prognostic significance of MMPs in lung cancer. However, it is possible that these observations are because of limitations in the procedures for measuring MMPs. Many investigators believe that MMPs are universally involved in tumor progression; this hypothesis was the basis for initiating seven phase III MMPI trials in lung cancer. Four studies were closed at completion of the predefined accrual goal, and three were closed early. There were no significant differences in survival in a non-small cell lung cancer prinomastat study, and in a small cell lung cancer marimastat trial. The results of the remaining five studies have not been reported. At this point it appears that MMPIs will probably not play a major role in the treatment of advanced lung cancer patients.
Topics: Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Clinical Trials as Topic; Disease Progression; Enzyme Inhibitors; Humans; Lung Neoplasms; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Neovascularization, Pathologic; Prognosis; Survival Analysis
PubMed: 11894017
DOI: 10.1053/sonc.2002.31528 -
Journal of Virology Mar 2002The release of neurotoxins by activated brain macrophages or microglia is one mechanism proposed to contribute to the development of neurological disease following...
The release of neurotoxins by activated brain macrophages or microglia is one mechanism proposed to contribute to the development of neurological disease following infection by lentiviruses, including feline immunodeficiency virus (FIV). Since molecular diversity in the lentiviral envelope gene influences the expression of host molecules implicated in neuronal injury, the role of the envelope sequence in FIV neuropathogenesis was investigated by using the neurovirulent FIV strain V1CSF, the nonneurovirulent strain Petaluma, and a chimera (FIVCh) containing the V1CSF envelope gene in a Petaluma background. All three viruses replicated in primary feline macrophages with equal efficiency, but conditioned medium from V1CSF- or FIVCh-infected cells was significantly more neurotoxic than medium from Petaluma-infected cultures (P < 0.001) and could be attenuated in a dose-dependent manner by treatment with either the matrix metalloproteinase (MMP) inhibitor prinomastat (PMT) or function-blocking antibodies to MMP-2. Although FIV sequences were detectable by PCR in brain tissue from neonatal cats infected with each of the viral strains, immunohistochemistry revealed increased astrogliosis and macrophage activation in the brains of V1CSF- and FIVCh-infected cats relative to the other groups, together with elevated markers of neuronal stress that included morphological changes and increased c-fos immunoreactivity. Similarly, MMP-2, but not MMP-9, mRNA and protein expression was increased in brain tissues of V1CSF- and FIVCh-infected cats relative to Petaluma-infected animals (P < 0.01). Infection with V1CSF or FIVCh was also associated with greater CD4(+) cell depletion (P < 0.001) and neurodevelopmental delays (P < 0.005), than in Petaluma-infected animals; these deficits improved following PMT therapy. These findings indicated that diversity in the envelope gene sequence influenced the neurovirulence exhibited by FIV both in vitro and in vivo, possibly through a mechanism involving the differential induction of MMP-2.
Topics: Animals; Animals, Newborn; Brain; Cats; Central Nervous System Viral Diseases; Female; Gene Expression Regulation, Viral; Genes, env; Humans; Immunodeficiency Virus, Feline; Infant, Newborn; Lentivirus Infections; Macrophages; Matrix Metalloproteinases; Mice; Neurons; Pregnancy; Tumor Cells, Cultured; Viral Envelope Proteins; Virulence
PubMed: 11861828
DOI: 10.1128/jvi.76.6.2622-2633.2002