Critical appraisal of the use of matrix metalloproteinase. Roles of matrix metalloproteinases in cancer progression. Magnetic resonance center cerm, university of florence, and consorzio interuniversitario risonanze magnetiche di metallo proteine cirmmp, via l. Mmps belong to a family of zincdependent neutral endopeptidases.
Kruger a, soeltl r, sopov i, kopitz c, arlt m, magdolen v, harbeck n, gansbacher b, schmitt mhydroxamatetype matrix metalloproteinase inhibitor batimastat promotes liver metastasis. Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. The matrix metalloproteinase inhibitor batimastat was administered to a human colorectal cancer ascites model, which was initiated by injection of c170hm2 cells into the peritoneal cavity of scid mice and resulted in solid tumour deposits and ascites formation. Batimastat, a synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts. Matrix metalloproteinases and tissue inhibitor of metalloproteinases in inflammation and fibrosis of skeletal muscles. In our study, the hormoneindependent mda435lcc6 human breast cancer cell line was used to seed solid tumors s. Using nps surface conjugated with an elastin antibody, which recognizes only degraded elastin, and loaded with a matrix metalloproteinase inhibitor batimastat, we show that batimastat could be delivered to the site of the aneurysm in a calcium chloride injury model of aaa in rats.
Batimastat bb94 is a synthetic hydroxamate mmp inhibitor whose efficacy has been explored with various protocols in several cancer animal models, notably in. Mechanism and inhibition of matrix metalloproteinases. This dose of bb94 was administered on the basis of experiments, which were carried out by the manufacturer17 and other investigators,18that determined the maximal effective dose for inhibition of mmp activity in rats. Inhibition of matrix metalloproteinases attenuates brain. Batimastat is a broad spectrum inhibitor of matrix metalloproteinases mmp, with ic 50 values of 15 nm for all mmps tested, including mmp1, 2, 3, 7, 9, and 14. Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. The above pathway was applied to study the interaction of inhibitor batimastat with mmps, which resulted in a high correlation between the predic ted binding free energies and experiment, suggesting. Batimastat, a potent matrix mealloproteinase inhibitor. A large body of experimental and clinical evidence has implicated mmps in tumor invasion, neoangiogenesis and metastasis, and therefore they represent ideal pharmacological targets for cancer therapy. Therapeutic effect of the matrix metalloproteinase. Matrix metalloproteinase inhibitor bb94 batimastat. To study the role of matrix metalloproteinase in vascular tumors, we tested the antineoplastic activity of a synthetic inhibitor of matrix metalloproteinases, batimastat, on an experimental model of hemangioma, formed by murine endothelioma cells transformed by polyoma middlet oncogene eend.
In this study, two human ovarian carcinoma hoc xenografts hoc22 and hoc8 were used to investigate the effect of batimastat on the antineoplastic activity of cisplatin. Doxycycline is an mmp inhibitor used for treatment of periodontal disease. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the mmpactive site. The cell line expressed both the 72 and 92 kda forms of gelatinase by zymography. Systemic treatments of mmp inhibitors have shown effectiveness in animal models, but it did not translate to clinical success either because of low doses used or systemic. The ic 50 with the structurally similar collagenase htd is 6 nm, which is comparable with values for mmp1 3 nm, mmp8 10 nm, and mmp3 20 nm. The zinc cation is coordinated by three imidazole side chains from histidine residues, and a water molecule is the fourth ligand. Batimastat, a potent matrix metalloproteinase inhibitor, exhibits pnas. Overexpression of this family of zincdependent endopeptidases has been correlated to various diseases including cancer, in. Development of matrix metalloproteinase inhibitors in cancer therapy. Batimastat bb94 is a synthetic mmp inhibitor that has been shown to inhibit tumor growth and metastasis in mice. Abstract matrix metalloproteinases mmps have outgrown the field of extracellularmatrix. Furthermore, inhibition of mmps using batimastat reduced the activation of mitogenactivated protein kinases and activator protein1 in myofibers of mdx mice. Pdf matrix metalloproteinase enzymes have been implicated in degenerative processes like tumor cell invasion, metastasis, and arthritis.
In 2002, development of batimastat for all indications, including cardiac failure and cerebral infarction, was discontinued. Matrix metalloproteinase inhibitors in cancer therapy molecular. A synthetic hydroxamate, batimastat also known as bb94, inhibits mmps by binding the zinc ion in the active site of the mmp. Batimastat also known as bb94 is a synthetic matrix metalloproteinase inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models. Batimastat bb94 inhibits matrix metalloproteinases of. Matrix metalloproteinase inhibitors as therapy for. Matrix metalloproteinase inhibitor batimastat alleviates pathology and improves skeletal muscle function in dystrophindeficient mdx mice. Effect of matrix metalloproteinase inhibitor batimastat on. Batimastat bb94, a synthetic hydroxamate peptidomimetic matrix metalloproteinase inhibitor, was tested for its ability to inhibit proteolytic and toxic effects induced by bap1, a 24kda hemorrhagic metalloproteinase isolated from the venom of bothrops asper, the medically most important snake species in central america and southern mexico batimastat inhibited proteolytic activity on.
Batimastat bb94 is a potent matrix metalloproteinase inhibitor, exhibits an unexpected mode of binding. The matrix metalloproteinase inhibitor batimastat was administered to a human colorectal cancer ascites model, which was initiated by injection of. The matrix metalloproteinase inhibitor batimastat bb94. Effectiveness of batimastat, a synthetic inhibitor of matrix metalloproteinases, in neutralizing local tissue damage induced by bap1, a hemorrhagic metalloproteinase from the venom of the snake bothrops asper. Overexpression of matrix metalloproteinases mmps facilitates tumor cell invasion. Jr matrix metalloproteinases and their inhibitors in connective tissue remodeling. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. These enzymes have the ability to break down connective tissue. The expression of mmps is increased in various pathological conditions like inflammatory conditions, metabolic bone disease, to cancer invasion, metastasis and angiogenesis. Mmp inhibitors like batimastat or marimastat have demonstrated preclinical in vivo activity rothenberg et al. However, homogenates of lamellar tissue from horses with laminitis showed that eqmmp. Mmp inhibitors are thus being assessed for clinical utility as antimetastatic therapeutics.
Ep1083863b1 reduction of hair growth using inhibitors of. Matrix metalloproteinase inhibitor batimastat alleviates. Matrix metalloproteinases mmps are zincdependent endopeptidases that form a family of 24 members in mammals. Matrix metalloproteinases in gastrointestinal cancer gut. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. Get a printable copy pdf file of the complete article 1. Batimastat inhibits gelatinases a and b with ic 50 values of 4 nm and 10 nm, respectively. Approximately 7% of survivors from meningococcal meningitis mm suffer from neurological sequelae due to brain damage in the course of meningitis.
Prevention of abdominal aortic aneurysm progression by. Effectiveness of batimastat, a synthetic inhibitor of. The matrix metalloproteinase inhibitor bb94 limits. Matrix metalloproteinases, enzyme, mechanism, collagenolysis, elastolysis, inhibitor. Metalloprotease inhibitors are cellular inhibitors of the matrix metalloproteinases mmps. Collagen, elastin, gelatin and casein are major components cleaved by mmps. Batimastat, a potent matrix metalloproteinase inhibitor, exhibits an unexpected mode. It inhibits the growth and spread of lung tumors,breast cancer. The matrix metalloproteinases mmps are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. Matrix metalloproteinases mmps, also known as matrixins, belong to a group of zincdependent proteins, which are thought to play a central role in the breakdown of extracellular matrix. Sacconi 6, 50019 sesto fiorentino, magnetic resonance center cerm, university of florence, and. However, it is clear that aberrant mmp expression can contribute to the pathogenesis of.
Understanding the binding of inhibitors of matrix metalloproteinases by molecular docking, quantum. Matrix metalloproteinases mmps have been shown to contribute functionally to tumor metastasis. Matrix metalloproteinases mmps are zincdependent proteolytic endopeptidases. The matrix metalloproteinase inhibitor batimastat inhibits. New intracellular activities of matrix metalloproteinases. Batimastat is hydroxamatetype inhibitor of matrix metalloproteinases mmp. The model is based on intracisternal infection of balbc mice with a serogroup c neisseria meningitidis.
Batimastat bb94 is a synthetic matrix metalloproteinase inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models. The mmps can be inhibited by specific endogenous tissue inhibitor of mmps timps. Matrix metalloproteinases mmps are thought to play a significant role in tumor invasion and metastasis as well as angiogenesis. Matrix metalloproteinase inhibitor batimastat alleviates pathology. Here we assessed the ability of batimastat to inhibit liver metastases of murine. Inhibition of angiogenesis and murine hemangioma growth by. These enzymes play a central role in tissue remodelling associated with growth, development and repair. All inhibitors replace this water molecule and coordinate to zinc in a monodentate or bidentate fashion. Matrix metalloproteinase inhibitor batimastat alleviates pathology and improves skeletal muscle function in dystrophindeficient mdx mice akhilesh kumar, shephali bhatnagar, and ashok kumar from the department of anatomical sciences and neurobiology, university of louisville school of medicine, louisville, kentucky. Matrix metalloproteinases mmps are a family of enzymes that are responsible for the breakdown of connective tissue proteins. The matrix metalloproteinase inhibitor batimastat bb94 retards human breast cancer solid tumor growth but not ascites formation in nude mice. Batimastat also known as bb49, 4nhydroxyamino2risobutyl3sthiopen2ylthiomethylsuccinyllphenylalaninenmethylamide, is a potent and synthetic inhibitor of a broad spectrum of matrix metalloproteinases mmps, including interstitial collagenase ic 50 3 nm, stromelysin ic 50 20 nm, m r 72,000 type iv collagenase ic 50. Matrix metalloproteinase inhibition prevents colon cancer peritoneal. Matrix metalloproteinases mmps have the ability to degrade the components of the extracellular matrix and are therefore a key participant in the homeostasis of tissue remodeling 1.
Matrix metalloproteinases mmpsmediated extracellular matrix destruction is the major cause of development and progression of abdominal aortic aneurysms. Synthetic inhibitor of matrix metalloproteinases batimastat reduces prostate cancer growth in an orthotopic rat model. Matrix metalloproteinase inhibitors in cancer therapy. Batimastat, 72, was the first mmp inhibitor of the hydroxamic acid series which was tested in clinical trials for treatment of cancer. Matrix metalloproteinases mmps, classically viewed as degraders of the extracellular matrix ecm responsible for matrix protein turnover, are more recently recognized as regulators of a range of extracellular bioactive molecules including chemokines, cytokines, and their binders. Ep1083863b1 ep19980925074 ep98925074a ep1083863b1 ep 1083863 b1 ep1083863 b1 ep 1083863b1 ep 19980925074 ep19980925074 ep 19980925074 ep 98925074 a ep98925074 a ep 98925074a ep 1083863 b1 ep1083863 b1 ep 1083863b1 authority ep european patent office prior art keywords inhibitor method hair growth skin fatty acid prior art date 199612 legal status the legal. Is there new hope for therapeutic matrix metalloproteinase. Hydroxamatetype matrix metalloproteinase inhibitor. In these physiological processes mmp activity is tightly regulated. The new synthetic matrix metalloproteinase inhibitor nature. Batimastat, also known as bb94, acts as an inhibitor of metalloproteinase activity by binding the zinc ion in the active site of mmps. Pollllt companion animal clinical sciences, school of veterinary science and animal production and department. Nci dictionary of cancer terms national cancer institute.
M batimastat and marimastat literature in this area tocris offers the following scientific literature in this area to showcase our products. Batimastat inhibits at least 50% of mmp activity at. Mice were infected with meningococci and randomised for treatment with the mmp inhibitor batimastat. Pdf batimastat, a potent matrix mealloproteinase inhibitor, exhibits. Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis. Matrix metalloproteinase inhibitor batimastat alleviates pathology and improves skeletal muscle function in dystrophindeficient mdx mice july 2010 american journal of pathology 1771.