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Ophthalmic Research 2001In a search for a pharmacologic adjuvant in the management of posttraumatic proliferative vitreoretinopathy (PVR), we investigated the effect of intravitreal injection... (Comparative Study)
Comparative Study
In a search for a pharmacologic adjuvant in the management of posttraumatic proliferative vitreoretinopathy (PVR), we investigated the effect of intravitreal injection of prinomastat (AG3340) on an experimental model. Posterior penetrating eye trauma was created in one eye each of 24 New Zealand white rabbits. One week after the surgery, all rabbits were randomized (1:1) to receive 0.5 mg prinomastat or the vehicle of the drug intravitreally every week for 6 weeks. The degree of PVR for each hemiretina was scored, and the two scores were summed to obtain a total eye score. The mean total eye score was 3.58 in the treatment group and 5.75 in the control group (p = 0.0307). The numbers of eyes with tractional retinal detachment in the prinomastat-treated (n = 12) and control (n = 12) groups were 3 and 9, respectively (p = 0.0391). These results suggest that intravitreally administered prinomastat has an inhibitory effect on posttraumatic PVR.
Topics: Animals; Antineoplastic Agents; Eye Injuries, Penetrating; Female; Injections; Male; Metalloendopeptidases; Organic Chemicals; Rabbits; Retina; Vitreoretinopathy, Proliferative; Vitreous Body
PubMed: 11114600
DOI: 10.1159/000055636 -
Best Practice & Research. Clinical... Mar 2009Recent advances in the understanding of the pathogenesis of cancer have led to the introduction of a variety of biological agents with novel mechanisms of action into... (Review)
Review
Recent advances in the understanding of the pathogenesis of cancer have led to the introduction of a variety of biological agents with novel mechanisms of action into clinical trials and even into clinical practice. In particular, tumour-associated neoangiogenesis has become a major target for this new class of antineoplastic agents. Five anti-angiogenic agents (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use, and many others have entered clinical trials. Many new biological agents with anti-angiogenic properties appear to be associated with an increased risk for thrombosis and, paradoxically, bleeding. Although the mechanisms underlying the increased thromboembolic risk remain ill defined, the main hypothesis is that perturbation of tumour-associated endothelial cells can switch the endothelium from a naturally anticoagulant surface to a prothrombotic surface, thus mediating the activation of systemic coagulation in cancer patients, who are already more susceptible to thromboembolism due to their underlying disease. The toxicity profile differs between the anti-angiogenic agents. Thalidomide, lenalidomide, semaxibin (SU5416) and prinomastat have produced more venous thromboembolic complications, whereas bevacizumab, sunitinib, sorafenib and ZD6126 have been associated with a higher risk of arterial thromboembolism and, in particular, myocardial ischaemia. The observation of these vascular toxicities suggests the need to establish, in randomized clinical trials, the usefulness of thrombosis prophylaxis when anti-angiogenic agents are used in cancer patients, especially when associated with chemotherapy. In addition, careful reporting of haemostatic complications during treatment with new anti-angiogenic drugs is warranted.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Endothelial Cells; Humans; Neoplasms; Neovascularization, Pathologic; Risk Factors; Thrombosis
PubMed: 19285278
DOI: 10.1016/j.beha.2009.01.001 -
Breast Cancer Research and Treatment 1998Matrix metalloproteinases (MMPs) are a family of enzymes responsible for the breakdown of proteins of connective tissue. Through this action they play an important role... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of enzymes responsible for the breakdown of proteins of connective tissue. Through this action they play an important role in growth, development and tissue repair. Recent studies also suggest that MMPs are utilised in cancer, facilitating both local tumour invasion and metastasis. Levels of certain MMPs such as stromelysin-3 and gelatinase are elevated in tumour-associated stroma compared to non-involved tissue. A series of synthetic low molecular weight MMP inhibitors have been produced. Early inhibitors were based on the peptide structure of collagen, although more recently non-peptide inhibitors have also been developed. The inhibitors are selective for the MMP family and are active at low nanomolar concentrations. Experiments in models of breast cancer have shown that MMP inhibitors can significantly reduce the growth rate of both primary and secondary tumours, and can block the process of metastasis. Several MMP inhibitors have now started clinical trials in patients with advanced malignancy. Although not the optimum setting for a tumouristatic agent, early results suggest this approach may be effective in slowing tumour growth. Trials in the adjuvant setting will provide the most important test of these inhibitors and should determine their potential to complement existing cytoreductive treatments and prolong survival.
Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Design; Female; Humans; Metalloendopeptidases; Organic Chemicals; Protease Inhibitors
PubMed: 10066077
DOI: 10.1023/a:1006119319695 -
European Journal of Medicinal Chemistry Mar 2021Matrix metalloproteinases (MMPs) are involved in several pathological and physiological functions. Gelatinases (MMP-2 and -9) have significant attention as therapeutic... (Review)
Review
Matrix metalloproteinases (MMPs) are involved in several pathological and physiological functions. Gelatinases (MMP-2 and -9) have significant attention as therapeutic targets against cancer. Gelatinase inhibitors have demonstrated their effectiveness in several diseases including cancer. However, it is quite a challenging task to develop inhibitors as a therapeutic agent. This review summarizes the patent dedicated to the medicinal chemistry of gelatinase inhibitor reported over last decades. We examine the patent being pursued for gelatinase inhibitor development to highlight the key issues. The main aim is to provide the scientific community with an overview of the patented gelatinase inhibitors to allow further development. During early 2000s, some MMP inhibitors failed to pass the clinical trials. Hence, the lessons learned from early evidence and recent knowledge in that field will rejuvenate the development of selective inhibitors. Various studies and patents have continued in the recent years to expand knowledge. Continuously, our research team has been involved in the design of potent and selective gelatinase inhibitors for the past few years. This study is a part of our efforts. This study may be beneficial in the design and development of better gelatinase inhibitors in the future.
Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Diphosphonates; Drug Design; Humans; Hydroxamic Acids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Models, Molecular; Organic Chemicals; Phenylbutyrates; Structure-Activity Relationship
PubMed: 33279289
DOI: 10.1016/j.ejmech.2020.113044 -
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 -
Journal of Neuropathology and... Sep 2022Facial nerve injury results in degradation of the neuromuscular junction (NMJ) and blocks neurotransmission between the pre- and postsynaptic structures, which are...
Facial nerve injury results in degradation of the neuromuscular junction (NMJ) and blocks neurotransmission between the pre- and postsynaptic structures, which are separated by a synaptic cleft. Matrix metalloproteinases (MMPs), enzymes that degrade and modify the extracellular matrix, play critical roles in regulating NMJ remodeling. We previously demonstrated that MMP1, MMP2, MMP3, MMP7, and MMP9 are overexpressed in facial nerve-innervated orbicularis oris muscle after facial nerve injury in a rat model. In the present study, the MMP inhibitor prinomastat was administered to rats after facial nerve injury. The MMP levels, agrin expression, and muscle-specific kinase (MuSK) phosphorylation were evaluated. Variations in evoked electromyography (EEMG) amplitude were also recorded. Compared with the control group, MMP expression in the orbicularis oris after facial nerve injury was significantly reduced in the prinomastat group. Inhibition of MMP expression maintained agrin expression and MuSK phosphorylation; the NMJ morphology was also protected after the injury. Moreover, prinomastat treatment sustained EEMG amplitude and muscle tension after the injury. These findings indicate that inhibiting MMPs can protect the function and morphology of the NMJ and demonstrate the need for protection of the NMJ at early stages after facial nerve injury.
Topics: Agrin; Animals; Electromyography; Facial Muscles; Facial Nerve Injuries; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Muscle Tonus; Organic Chemicals; Rats
PubMed: 35656867
DOI: 10.1093/jnen/nlac041 -
Journal of the National Cancer Institute Feb 2001The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in... (Review)
Review
The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Drugs, Investigational; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Phenylalanine; Phenylbutyrates; Protease Inhibitors; Pyrazines; Sulfonamides; Tetracycline; Tetracyclines; Thiophenes
PubMed: 11158186
DOI: 10.1093/jnci/93.3.178 -
Lung Cancer (Amsterdam, Netherlands) Aug 2003Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix... (Review)
Review
Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Extracellular Matrix; Humans; Lung Neoplasms; Neovascularization, Pathologic; Treatment Outcome
PubMed: 12867064
DOI: 10.1016/s0169-5002(03)00144-2 -
Mutation Research 2013Matrix metalloproteinase (MMP) comprises a family of zinc-dependent endopeptidases that degrade various components of the extracellular matrix (ECM) and basement... (Review)
Review
Matrix metalloproteinase (MMP) comprises a family of zinc-dependent endopeptidases that degrade various components of the extracellular matrix (ECM) and basement membrane. MMPs are involved in solid and hematological malignancy through modification of cell growth, activation of cancer cells and modulation of immune functions. Several polymorphisms of different MMPs such as MMP-1 (-1607 1G/2G), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A) & MMP-9 (-1562 C/T) and their expression levels have been well documented in different types of solid cancer. These polymorphic variations were found to be associated with angiogenesis, cancer progression, invasion and metastasis. There is paucity of data available in the field of hematological malignancies. Hence the field of matrix biology of hematological malignancies is an area of active exploration. A number of MMP inhibitors (MMPIs) have been developed for the cancer treatment. The most extensively studied classes of MMP inhibitors include Batimastat, Marismastat, Salimatat, Prinomastat and Tanomastat. However, their efficacy and action have not been confirmed and more data is required. The application of one or more selective targeted MMPIs in combination with conventional anti-leukemic treatment may represent a positive approach in combat against hematopoietic malignancies. Balance of MMPs and TIMPs is altered in different malignancies and biochemical pathways. These alternations will add another dimension in the matrix biology of both solid tumor and leukemia. MMP and TIMP singly and in combination are increasingly being recognized as an important player in basic cellular biology. Exploration and exploitation of MMP and TIMP balance in various malignant and nonmalignant lesions is going to be one of the most interesting facets of future use of this system for human health care.
Topics: Animals; Antineoplastic Agents; Hematologic Neoplasms; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms
PubMed: 23370482
DOI: 10.1016/j.mrrev.2013.01.002 -
Clinical and Experimental Pharmacology... May 2013Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of... (Review)
Review
Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biomedical Research; Drug Discovery; Drug Industry; Drugs, Investigational; Humans; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neovascularization, Pathologic; Signal Transduction
PubMed: 23534409
DOI: 10.1111/1440-1681.12083