batimastat and Neoplasms

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

The field of angiogenesis research has seen an explosion of knowledge within the last 10 years. More than 3500 angiogenesis-related papers are presently being published per year compared to the less than 200 annual papers published in the early 1990s. Paralleling the progress in the field of basic angiogenesis research, translational research has led to the identification of more than 100 angiomanipulatory compounds. Presently, more than 40 substances are in various phases of clinical trials. The prospect of these exciting developments is presently dampened by the negative outcome of some advanced clinical trials. Thus, following euphoria and disillusion, the field is presently experiencing that translational clinical research requires endurance to eventually accomplish the successful implementation of angiomanipulatory therapies in the clinical setting. The present article provides an overview of the field of angiogenesis research and summarizes ongoing efforts aimed at developing angiomanipulatory therapies.

Topics: Adult; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Apoptosis; Bevacizumab; Cell Communication; Drug Evaluation, Preclinical; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Ephrins; Forecasting; Growth Substances; Humans; Hydroxamic Acids; Intercellular Signaling Peptides and Proteins; Lymphokines; Metalloendopeptidases; Mice; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Phenylalanine; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Research; Signal Transduction; Thalidomide; Thiophenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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: Angiostatins; Antibiotics, Antineoplastic; Antineoplastic Agents; Collagen; Cyclohexanes; Endostatins; Humans; Hydroxamic Acids; Interferons; Interleukin-12; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Phenylalanine; Plasminogen; Sesquiterpenes; Thalidomide; Thiophenes

Aberrant angiogenesis is closely involved in invasion/metastasis as well as enlargement of tumor. One recent highlight is to develop anti angiogenic drugs by targeting tumor angiogenesis. Here we describe how tumor angiogenesis is regulated and also recent topics related to angiogenic drug in clinical trials.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Cyclohexanes; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Hydroxamic Acids; Interferon-alpha; Interleukin-12; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Phenylalanine; Platelet Factor 4; Polysaccharides, Bacterial; Sesquiterpenes; Thalidomide; Thiophenes; Triazines; Triazoles; Tumor Cells, Cultured

The matrix metalloproteinases (MMPs) are a family of at least fifteen secreted and membrane-bound zinc-endopeptidases. Collectively, these enzymes can degrade all of the components of the extracellular matrix, including fibrallar and non-fibrallar collagens, fibronectin, laminin and basement membrane glycoproteins. MMPs are thought to be essential for the diverse invasive processes of angiogenesis and tumor metastasis. Numerous studies have shown that there is a close association between expression of various members of the MMP family by tumors and their proliferative and invasive behavior and metastatic potential. In some of human cancers a positive correlation has also been demonstrated between the intensity of new blood vessel growth (angiogenesis) and the likelihood of developing metastases. Thus, control of MMP activity in these two different contexts has generated considerable interest as a possible therapeutic target. The tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring proteins that specifically inhibit matrix metalloproteinases, thus maintaining balance between matrix destruction and formation. An imbalance between MMPs and the associated TIMPs may play a significant role in the invasive phenotype of malignant tumors. TIMP-1 has been shown to inhibit tumor-induced angiogenesis in experimental systems. These findings raised the possibility of using an agent that affects expression or activity of MMPs as an anti-cancer therapy. TIMPs are probably not suitable for pharmacologic applications due to their short half-life in vivo. Batimastat (BB-94) and marimastat (BB-2516) are synthetic, low-molecular weight MMP inhibitors. They have a collagen-mimicking hydroxamate structure, which facilitates chelation of the zinc ion in the active site of the MMPs. These compounds inhibit MMPs potently and specifically. Batimastat was the first synthetic MMP inhibitor studied in humans with advanced malignancies, but its usefulness has been limited by extremely poor water solubility, which required intraperitoneal administration of the drug as a detergent emulsion. Marimastat belongs to a second generation of MMP inhibitors. In contrast to batimastat, marimastat is orally available. Both of these agents are currently in Phase I/II trials in US, Europe and Canada. Some other new agents, currently in clinical trials, have been shown to inhibit MMP production. Bryostatins, naturally occurring macrocyclic lactones, have both in vitro and in vivo

Topics: Antineoplastic Agents; Cell Division; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Down-Regulation; Drugs, Investigational; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Hydroxamic Acids; Metalloendopeptidases; Molecular Weight; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Phenylalanine; Protease Inhibitors; Protein Kinase C; Proteins; Thiophenes; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-3; Tissue Inhibitor of Metalloproteinases

Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes. Several synthetic matrix metalloproteinase inhibitors (MMPIs) are currently being developed. Preclinical studies are promising as they suggest inhibition of several steps in the metastatic process. Marimastat is the first MMPI to enter comparative phase III trials after early clinical trials established the safety profile. Clinical trials will need to be specifically designed to optimally evaluate the therapeutic potential of this novel class of cytostatic drugs. Safety studies should consider the markedly different toxicity profile and determine the range of biologically active dosage, while efficacy studies should be performed in selected clinical settings with appropriate end-points. We review the present achievements in preclinical and clinical studies with MMPIs, discuss specific considerations for appropriate study design and reflect on the future prospects of this novel class of agents.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Extracellular Matrix; Humans; Hydroxamic Acids; Metalloendopeptidases; Neoplasm Metastasis; Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes

Topics: Adult; Aged; Animals; Antineoplastic Agents; Ascites; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Extracellular Matrix; Female; Humans; Male; Metalloendopeptidases; Mice; Middle Aged; Neoplasms; Phenylalanine; Pleural Effusion, Malignant; Protease Inhibitors; Rats; Thiophenes

This was an open Phase I study of i.p. matrix metalloproteinase inhibitor BB94 in patients with malignant ascites. The objective of the study was to determine the effect of increasing i.p. doses of BB94 with reference to the tolerance, safety, and pharmacokinetics of the compound. Twenty-three patients with malignant ascites had BB94 instilled into the peritoneal cavity after paracentesis. The compound was well tolerated; no serious adverse events were seen, and no specific toxicities were observed. High plasma concentrations were seen an hour after dosing, and BB94 was still present in the plasma at day 28 after treatment at levels in excess of the IC50 identified in preclinical studies. Five of the 23 patients neither reaccumulated ascites nor died up to 112 days after dosing. Seven patients died without reaccumulating ascites. Although the study was not designed to demonstrate clinical efficacy, the results were encouraging and support the further therapeutic evaluation of matrix metalloproteinase inhibitors in the management of malignant ascites.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Ascites; Dose-Response Relationship, Drug; Female; Humans; Male; Metalloendopeptidases; Middle Aged; Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes

Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m2.

Topics: Adult; Aged; Antineoplastic Agents; Collagenases; Drug Administration Schedule; Female; Gelatinases; Humans; Injections, Intraperitoneal; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Middle Aged; Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes

We demonstrate the accommodation of log-scale concentration gradients of inhibitors on a single microfluidic chip with a semidirect dilution capability of reagents for the determination of the half-inhibitory concentration or IC(50). The chip provides a unique tool for hosting a wide-range of concentration gradient for studies that require an equal distribution of measuring points on a logarithmic scale. Using Matrix metalloproteinase IX and three of its inhibitors, marimastat, batimastat, and CP471474, we evaluated the IC(50) of each inhibitor with a single experiment. The present work could be applied to the systematic study of biochemical binding and inhibition processes particularly in the field of mechanistic enzymology and the pharmaceutical industry.

Topics: Dose-Response Relationship, Drug; Enzyme Inhibitors; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Inhibitory Concentration 50; Kinetics; Lab-On-A-Chip Devices; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Microchip Analytical Procedures; Neoplasms; Phenylalanine; Sensitivity and Specificity; Spectrometry, Fluorescence; Thiophenes

Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.

Topics: Animals; Apoptosis; Hepatitis, Animal; Humans; Interferon-gamma; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Phenylalanine; Protease Inhibitors; Recombinant Proteins; Thiophenes; Tumor Necrosis Factor-alpha

Topics: Animals; Antineoplastic Agents; Ascites; Drugs, Investigational; Humans; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Neoplasms; Phenylalanine; Pleural Effusion, Malignant; Protease Inhibitors; Thiophenes

Matrix metalloproteinase inhibitors represent a new therapeutic approach to the treatment of advanced cancer. These inhibitors block the activity of proteolytic enzymes, matrix metalloproteinases, used by tumor cells to break down and remodel tissue matrices during the process of metastatic spread. As such they were regarded initially as inhibitors of metastasis. However, recent studies have shown that these inhibitors can also act to inhibit tumor growth by (i) preventing local invasion and promoting stromal encapsulation and (ii) by inhibiting tumor neovascularization. Matrix metalloproteinase inhibitors therefore have the potential to halt tumor progression and it is possible to envision their use as a low toxicity complement to cytotoxic therapies. Batimastat (BB-94) is the first inhibitor of this class to enter clinical trial in cancer patients. In a phase I/II trial in patients with malignant ascites batimastat was well tolerated and there were preliminary signs of efficacy.

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Female; Humans; Melanoma, Experimental; Metalloendopeptidases; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes