prinomastat and marimastat

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

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

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Metastasis; Organic Chemicals; Phenylalanine; Thiophenes

The purpose of this study was using bioinformatics tools to identify biomarkers and molecular factors involved in the diagnosis of colorectal cancer, which are effective for the diagnosis and treatment of the disease.. We determined differentially expressed genes (DEGs) related to colorectal cancer (CRC) using the data series retrieved from GEO database. Then the weighted gene co-expression network analysis (WGCNA) was conducted to explore co-expression modules related to CRC diagnosis. Next, the relationship between the integrated modules with clinical features such as the stage of CRC was evaluated. Other downstream analyses were performed on selected module genes.. In this study, after performing the WGCNA method, a module named blue module which was more significantly associated with the CRC stage was selected for further evaluation. Afterward, the Protein-protein interaction network through sting software for 154 genes of the blue module was constructed and eight hub genes were identified through the evaluation of constructed network with Cytoscape. Among these eight hub genes, upregulation of MMP9, SERPINH1, COL1A2, COL5A2, COL1A1, SPARC, and COL5A1 in CRC was validated in other microarray and TCGA data. Based on the results of the mRNA-miRNA interaction network, SERPINH1 was found as a target gene of miR-940. Finally, results of the DGIDB database indicated that Andecaliximab, Carboxylated glucosamine, Marimastat, Tozuleristide, S-3304, Incyclinide, Curcumin, Prinomastat, Demethylwedelolactone, and Bevacizumab, could be used as a therapeutic agent for targeting the MMP9. Furthermore, Ocriplasmin and Collagenase clostridium histolyticum could target COL1A1, COL1A2, COL5A1, and COL5A2.. Taken together, the results of the current study indicated that seven hub genes including COL1A2, COL5A1, COL5A2, SERPINH1, MMP9, SPARC, and COL1A1 which were upregulated in CRC could be used as a diagnostic and progression biomarker of CRC. On the other hand, miR-940 which targets SERPINH1 could be used as a potential biomarker of CRC. More ever, Andecaliximab, Carboxylated glucosamine, Marimastat, Tozuleristide, S-3304, Incyclinide, Curcumin, Prinomastat, Demethylwedelolactone, Bevacizumab, Ocriplasmin , and Collagenase clostridium histolyticum were introduced as therapeutic agents for CRC which their therapeutic potential should be evaluated experimentally.

Topics: Bevacizumab; Biomarkers; Colorectal Neoplasms; Curcumin; Gene Regulatory Networks; Humans; Matrix Metalloproteinase 9; Microbial Collagenase; MicroRNAs

Venoms are evolutionary novelties that have real-world implications due to their impact upon human health. However, relative to the abundant studies of elapid and viperid snake venoms, fewer investigations have been undertaken on those of rear-fanged snakes as they are more problematic for obtaining venom. While most rear-fanged venomous snakes are not considered to be of great medical importance, several species are capable of producing fatalities. Most notable among these are snakes from the genus Rhabdophis, the Asian "keelback" snakes. Prior work have described potent procoagulant toxicity suggesting Factor X and prothrombin activation, but did not investigate the ability to activate other clotting factors. Here we show that in addition to activating both Factor X and prothrombin (with prothrombin twice that of FX), the venom of Rhabdophis subminiatus is able to more potently activate Factor VII (ten times that of prothrombin), while also activating FXII and FIX equipotently to prothrombin, and with FXI also activated but at a much lower level. The ability to activate FVII represents a third convergent evolution of this trait. The Australian elapid clade of [Oxyuranus (taipans) + Pseudonaja (brown snakes)] was the first identified to have evolved this trait. and only recently was it shown to be independently present in another lineage (the Central American viperid species Porthidium volcanicum). In addition, the abilities to activate FXI and FXII are also convergent between R. subminiatus and P. volcanicum, but with R. subminiatus being much more potent. By testing across amphibian, avian, and mammalian plasmas we demonstrate that the venom is potently procoagulant across diverse plasma types. However, consistent with dietary preference, R. subminiatus venom was most potent upon amphibian plasma. While a Rhabdophis antivenom is produced in Japan to treat R. tigrinus envenomings, it is scarce even within Japan and is not exported. As this genus is very wide-ranging in Asia, alternate treatment options are in need of development. Hence we tested the ability of candidate, broad-spectrum enzyme inhibitors to neutralize R. subminiatus venom: marimastat was more effective than prinomastat but both marimastat and prinomastat were significantly more effective than DMPS (2,3-Dimercapto-1-propanesulfonic acid). The findings of this study shed light on the evolution of these fascinating rear-fanged snakes as well as explored their systemic effects upon blood coa

Topics: Animals; Antivenins; Australia; Blood Coagulation; Blood Coagulation Factors; Colubridae; Elapidae; Factor VII; Factor X; Humans; Hydroxamic Acids; Mammals; Organic Chemicals; Prothrombin; Snake Venoms; Unithiol

The African viperid snake genera

Topics: Africa South of the Sahara; African People; Animals; Antivenins; Enzyme Inhibitors; Humans; Saudi Arabia; Snake Bites; Viper Venoms; Viperidae

African spitting cobras are unique among cobras for their potent anticoagulant venom activity arising from strong inhibition of Factor Xa. This anticoagulant effect is exerted by venom phospholipase A

Topics: Acetates; Africa; Animals; Antivenins; Enzyme Inhibitors; Hydroxamic Acids; In Vitro Techniques; Indoles; Keto Acids; Naja; Organic Chemicals; Snake Bites; Snake Venoms

Species within the viperid genus Macrovipera are some of the most dangerous snakes in the Eurasian region, injecting copious amounts of potent venom. Despite their medical importance, the pathophysiological actions of their venoms have been neglected. Particularly poorly known are the coagulotoxic effects and thus the underlying mechanisms of lethal coagulopathy. In order to fill this knowledge gap, we ascertained the effects of venom upon human plasma for Macrovipera lebetina cernovi, M. l. lebetina, M. l. obtusa, M. l. turanica, and M. schweizeri using diverse coagulation analysing protocols. All five were extremely potent in their ability to promote clotting but varied in their relative activation of Factor X, being equipotent in this study to the venom of the better studied, and lethal, species Daboia russelii. The Insoserp European viper antivenom was shown to be highly effective against all the Macrovipera venoms, but performed poorly against the D. russelii venom. Reciprocally, while Daboia antivenoms performed well against D. russelii venom, they failed against Macrovipera venom. Thus despite the two genera sharing a venom phenotype (Factor X activation) driven by the same toxin type (P-IIId snake venom metalloproteases), the surface biochemistries of the toxins differed significantly enough to impede antivenom cross- neutralization. The differences in venom biochemistry were reflected in coagulation co-factor dependence. While both genera were absolutely dependent upon calcium for the activation of Factor X, dependence upon phospholipid varied. The Macrovipera venoms had low levels of dependence upon phospholipid while the Daboia venom was three times more dependent upon phospholipid for the activation of Factor X. This suggests that the sites on the molecular surface responsible for phospholipid dependence, are the same differential sites that prevent inter-genera antivenom cross- neutralization. Due to cold-chain requirements, antivenoms may not be stocked in rural settings where the need is at the greatest. Thus we tested the efficacy of enzyme inhibitor Prinomastat as a field-deployable treatment to stabilise patients while being transported to antivenom stocks, and showed that it was extremely effective in blocking the Factor X activating pathophysiological actions. Marimastat however was less effective. These results thus not only shed light on the coagulopathic mechanisms of Macrovipera venoms, but also provide data critical for evidence-b

Topics: Animals; Antivenins; Blood Coagulation; Factor X; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Phospholipids; Species Specificity; Viper Venoms; Viperidae

Envenoming by the West African saw-scaled viper, Echis ocellatus resembles that of most vipers, in that it results in local blistering, necrosis and sometimes life-threatening systemic haemorrhage. While effective against systemic envenoming, current antivenoms have little or no effect against local tissue damage. The major mediators of local venom pathology are the zinc-dependant snake venom metalloproteinases (SVMPs). The high degree of structural and functional homology between SVMPs and their mammalian relatives the matrix metalloproteinases (MMPs) suggests that substrate/inhibitor interactions between these subfamilies are likely to be analogous. In this study, four recently developed MMP inhibitors (MMPIs) (Marimastat, AG-3340, CGS-270 23A and Bay-12 9566) are evaluated in addition to three metal ion chelators (EDTA, TPEN and BAPTA) for their ability to inhibit the haemorrhagic activities of the medically important E. ocellatus venom and one of its haemorrhagic SVMPs, EoVMP2. As expected, the metal ion chelators significantly inhibited the haemorrhagic activities of both whole E. ocellatus venom and EoVMP2, while the synthetic MMPIs show more variation in their efficacies. These variations suggest that individual MMPIs show specificity towards SVMPs and that their application to the neutralization of local haemorrhage may require a synthetic MMPI mixture, ensuring that a close structural component for each SVMP is represented.

Topics: Animals; Biphenyl Compounds; Chelating Agents; Chromatography, Gel; Chromatography, Liquid; Edetic Acid; Egtazic Acid; Ethylenediamines; Evaluation Studies as Topic; Hemorrhage; Hydroxamic Acids; Metalloproteases; Mice; Molecular Structure; Organic Chemicals; Phenylbutyrates; Protein Kinase Inhibitors; Pyrazines; Snake Bites; Statistics, Nonparametric; Sulfonamides; Viper Venoms

Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Humans; Hydroxamic Acids; Matrix Metalloproteinase 1; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals

Topics: Antineoplastic Agents; Azepines; Biphenyl Compounds; Humans; Hydroxamic Acids; Metalloendopeptidases; Organic Chemicals; Phenylalanine; Phenylbutyrates; Protease Inhibitors; Pyrazines; Sulfonamides; Thiophenes

Topics: Angiostatins; Animals; Antineoplastic Agents; Biphenyl Compounds; Clinical Trials, Phase III as Topic; Collagen; Endostatins; Endothelium, Vascular; Humans; Hydroxamic Acids; Metalloendopeptidases; Neovascularization, Pathologic; Organic Chemicals; Peptide Fragments; Phenylbutyrates; Plasminogen