bay-12-9566 and marimastat

The cancer cells secrete proteolytic enzymes, which are important in the tumor spreading. The cells must cross basement membrane and extracellular matrix barriers in order to spread. The matrix metalloproteinases are a family of endopeptidases, which enzymatic activity depends on the presence of zinc ion in the catalytic domain. Matrix metalloproteinases hydrolyze extracellular matrix components such as collagen, laminin, fibronectin, proteoglycans and contribute to the spreading of tumor cells by eliminating the surrounding extracellular matrix and basement membrane barriers. This review describes matrix metalloproteinases family classification and structure, their role under physiological conditions and induced proteolysis during pathological processes. There is a balance between proteolytic extracellular matrix degradation and proteolysis inhibition, but under pathological state (e. g. tumor development) the proteolysis becomes uncontrolled. We review tissue inhibitors of matrix metalloproteinases and synthetic matrix metalloproteinase inhibitors, their perspective in cancer treatment; as well as different matrix metalloproteinases expression in patients with tumors and its prognostic significance during cancer progression.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Clinical Trials as Topic; Diphosphonates; Disease Progression; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Organic Chemicals; Phenylalanine; Phenylbutyrates; Prognosis; Protease Inhibitors; Thiophenes; Time Factors; Tissue Inhibitor of Metalloproteinases

In view of the data available from randomized trials, gemcitabine has been established as a new standard for the treatment of pancreatic cancer. It was shown to improve clinical benefit response, time to progression, and survival when compared with agents such as 5-fluorouracil or metalloproteinase inhibitors. In one trial, the combination of cisplatin and gemcitabine significantly improved tumor response and time to progression as compared with gemcitabine alone, while a significant impact on survival yet needs to be shown. No significant, clinically meaningful survival benefit was observed when gemcitabine was combined with bolus or infusional 5-fluorouracil, capecitabine, metalloproteinase inhibitors, or the FTI tipifarnib. Numerous ongoing randomized trials are presently investigating gemcitabine-based combination regimens involving such agents as cisplatin, oxaliplatin, irinotecan, docetaxel, 5-fluorouracil, capecitabine, or pemetrexed.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Camptothecin; Capecitabine; Cisplatin; Deoxycytidine; Docetaxel; Fluorouracil; Gemcitabine; Glutamates; Guanine; Humans; Hydroxamic Acids; Irinotecan; Organic Chemicals; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Pemetrexed; Phenylbutyrates; Quinolones; Randomized Controlled Trials as Topic; Taxoids

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

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

Excessive or poorly regulated matrix metalloproteinase (MMP) activity has been implicated as a pathogenic factor in a range of diseases where the extracellular matrix is degraded or remodelled. Synthetic, potent, low molecular weight MMP inhibitors (MMPIs) have been developed and, over the past five years, these agents have begun clinical testing in patients with cancer, rheumatoid arthritis, osteoarthritis and acute macular degeneration. The past year has seen a number of disappointments with the halting of clinical trials of Ro 32-3555 in patients with rheumatoid arthritis and of BAY 12-9566 in patients with cancer. There have, however, been some successes with perhaps the clearest indication of efficacy being seen in the results of a Phase III trial of marimastat in patients with advanced gastric cancer. Clinical trials are continuing with marimastat and other MMPIs, including prinomastat, solimastat, BMS 275291, metastat and neovastat. Results from these trials are expected in the next two years and it is likely that clinical trials with MMPIs will begin in patients with other diseases where MMPs are believed to be involved, such as restenosis, cerebral haemorrhage and multiple sclerosis. Future research is likely to focus on the identification of specific MMP targets in different diseases, both in order to improve efficacy and to reduce the musculoskeletal side effect profile that has characterised several of the first generation oral MMPIs.

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Breast Neoplasms; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Enzyme Inhibitors; Humans; Hydroxamic Acids; Lung Neoplasms; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Phenylbutyrates

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