Inhibitor Of Proteasome

. . Cohen, S. B; Rubbert, A. Rheumatol, Suppl, iii i. View publication stats View publication stats Metasta tic spread of tumors continues to be a major obsta cle to successful treatment of malignant tumors.Approximately of those patients diagnosed with a solid tumor have a clinically detectable metastasis and for the remaining, metastases are continually being formed throughout the life of the tumor.Even after the tumor is excised, the threat of death is attributable to the metastasis that may occur through the remaining tumor cells.In addition, treating the metastasis often proves futile since metastasis often vary in size, composition, and anatomical location. New treatments blocking the formation of metastasis will provide greater chances of survival for cancer patients.One family of enzymes that has been shown over the years to play a role in tumor progression is the matrix met Dorzolamide hydrochloride alloproteinase family.Tumor cells are believed to util ize the matr ix deg rad ing capabilityof these enzymes to spread to distant sites.Since then, over members have been added to the family.Although the classification system was developed on the basis of substrate specificity, it is now recognized that there is some overlap between some members of the family. For example, MMP has been reported to have the ability to cleave fibrillar collagen similar to the collagenases.This multigene family of metal containing proteases share several common characteristics: they W.Matrilysin, the smallest member of the MMP family is comprised of only the basic core structure.The remaining enzymes all contain a hemopexin domain Cyclosporine connected to the catalytic domain by a hinge region.The hemopexin domain contains the TIMP binding site and may also be involved in receptor binding.The membrane type me tallopro teases are a unique subdivision in that they contain a transmembrane domain at the carboxyl terminal anchoring the molecule to the cell surface.Another subdivision, the gelatinases contain a fibronectinlike domain within the catalytic domain responsible for collagen binding.The subdivisions correspond to a combination of structural and substrate homo logy.Alteration of all three levels of control have been associated with tumor cell progression.In addition to cytokines and growth factors, MMP production can be regulated by environmental factors.For example, extracellular matrix component peptides have been observed to have an effect on MMP production.The laminin peptide, AG has been shown to enhance gelatinase production and increase in vivo BF melanoma cell lung and liver metastasis.Vitronectin, collagen, and elastin have also been shown to induce collagenases and gelatinases expression in either tumor cells or fibroblasts.These peptides represent a potential therapeutic approach for the treatment of metastasis.These data all suggest that the cell environment plays a key role in regulating MMP production.These latent zymogens must be activated in order to degrade matrix components. This interaction blocks access to the active site and cleavage of this site results in enzyme activation.Trypsin has the ability to activate bo th free proenzyme and proenzyme: TIMP comp lexes, the ma jor form of MMP in vivo.In contrast to other members of the family, MMP does not seem to be activated by plasmin or stromelysin.

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