prinomastat and Neoplasms

Rheumatoid Arthritis (RA) is one of the most common autoimmune inflammatory conditions, affecting approximately 1% of the adult population worldwide. TNF-alpha is a pleitropic, pro-inflammatory cytokine which plays a pivotal role in the origin and progression of RA and other immune mediated disorders. The success of anti-TNF-alpha biological agents proved that inhibition of TNF-alpha could result in effective control of RA. Since the discovery of anti-TNF-alpha biologicals, much efforts have gone into developing an orally bioavailable small size TNF-alpha antagonist. One of the ways to block TNF-alpha in biological fluids is to inhibit TNF-alpha converting enzyme (TACE). This target has been validated in preclinical trials using TACE inhibitors. But, even after more than a decade no single TACE inhibitor has passed the Phase II clinical trials. Very recently, it has been shown that TACE inhibitors could also be used for inhibition of pathogenic EGFR signaling in cancer. Hence, TACE inhibitors could perform a dual role, in curing not only RA but also certain cancerous conditions. Developments in the field have prompted us to review the research work on TACE inhibitors, especially their structure activity relationships and molecular modeling studies.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Arthritis, Rheumatoid; Enzyme Inhibitors; Humans; Models, Molecular; Neoplasms; Structure-Activity Relationship

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

Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less alpha-SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.

Topics: Actins; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Axitinib; Basement Membrane; Blood Vessels; Carcinoma, Lewis Lung; Collagen Type IV; Endothelium, Vascular; Imidazoles; Indazoles; Insulinoma; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Neovascularization, Pathologic; Organic Chemicals; Pericytes; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, Platelet-Derived Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular characteristics of human breast cancers implanted in athymic rats. Twice-daily intraperitoneal administration of Prinomastat over 1.5 days induced significant declines in MRI-assayed microvascular permeabilities (p<0.05); but this leak suppression effect had extinguished by the 10(th) day of MMP treatment using the same dose and time schedule. Results demonstrate that Prinomastat produces a rapid but transient decrease in tumor vascular permeability. Contrast-enhanced MRI using macromolecular contrast medium may prove useful as a biomarker for the dynamic MMP biological effect in cancers.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Capillary Permeability; Cell Division; Cell Line, Tumor; Contrast Media; Enzyme Inhibitors; Female; Homozygote; Humans; Magnetic Resonance Imaging; Matrix Metalloproteinase Inhibitors; Microcirculation; Neoplasm Transplantation; Neoplasms; Organic Chemicals; Rats; Rats, Nude; Statistics as Topic; Time Factors

Topics: Animals; Antineoplastic Agents; Diagnostic Imaging; Extracellular Matrix Proteins; Fluorescence; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Organic Chemicals; Serine Endopeptidases

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: Animals; Antineoplastic Agents; Azepines; Drugs, Investigational; Humans; Hydroxamic Acids; Metalloendopeptidases; Mice; Neoplasms; Organic Chemicals; Protease Inhibitors