AE-941 (Neovastat): a novel multifunctional antiangiogenic compound.
ABSTRACT AE-941 (Neovastat) is a naturally occurring product extracted from cartilage and has antiangiogenic properties. It has reached Phase III clinical trial evaluation for the treatment of solid tumors (non-small cell lung cancer and renal cell carcinoma) and a pivotal Phase II clinical trial in multiple myeloma is ongoing. AE-941 inhibits several steps of the angiogenesis process, including matrix metalloproteinase activities and VEGF signaling pathways. Moreover, AE-941 induces endothelial cell apoptosis and tissue-type plasminogen activator activity, thus suggesting that it is a multifunctional antiangiogenic drug. Results from Phase I/II clinical trials indicate that AE-941, given orally, is well tolerated. Moreover, the median survival time in patients with renal cell carcinoma and non-small cell lung cancer was significantly longer in patients receiving high doses of AE-941 compared to low doses.
SourceAvailable from: Roosmarijn E Vandenbroucke[Show abstract] [Hide abstract]
ABSTRACT: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initial drug discovery efforts focused on the roles of MMPs in cancer progression, and more than 50 MMP inhibitors have been investigated in clinical trials in various cancers. However, all of these trials failed. Reasons for failure include the lack of inhibitor specificity and insufficient knowledge about the complexity of the disease biology. MMPs are also known to be involved in several inflammatory processes, and there are new therapeutic opportunities for MMP inhibitors to treat such diseases. In this Review, we discuss the recent advances made in understanding the role of MMPs in inflammatory diseases and the therapeutic potential of MMP inhibition in those conditions.dressNature Reviews Drug Discovery 11/2014; DOI:10.1038/nrd4390 · 37.23 Impact Factor
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ABSTRACT: Vascular endothelial growth factor (VEGF) is a crucial growth factor that mediates tumor angiogenesis, and thus many therapeutic agents are being developed to target VEGF or its receptors in the treatment of cancer. Early-phase clinical data indicate that such agents are effective and might lack the nonspecific toxicities of conventional chemotherapies. The anti-VEGF antibody bevacizumab has also shown promising efficacy in Phase III studies. Further research is required, especially into patient selection, the autocrine and paracrine VEGF effector functions in different malignancies, and the long-term safety of these compounds, but it is probable that VEGF and its receptors will soon be important targets in the treatment of cancer.TARGETS 04/2003; 2(2):48-57. DOI:10.1016/S1477-3627(03)02292-X
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ABSTRACT: This study evaluated the anti-angiogenic activities of erianin in vivo and in vitro. Erianin, a natural product from Dendrobium chrysotoxum, caused moderate growth delay in xenografted human hepatoma Bel7402 and melanoma A375 and induced significant vascular shutdown within 4 h of administering 100 mg/kg of the drug. Erianin also displayed potent anti-angiogenic activities in vitro: it abrogated spontaneous or basic fibroblast growth factor-induced neovascularisation in chick embryo; it inhibited proliferation of human umbilical vein endothelial cells (EC50 34.1 ± 12.7 nM), disrupted endothelial tube formation, and abolished migration across collagen and adhesion to fibronectin. Erianin also exerted selective inhibition toward endothelial cells, and quiescent endothelium showed more resistance than in proliferative and tumour conditions. In a cytoskeletal study, erianin depolymerised both F-actin and β-tubulin, more significantly in proliferating endothelial cells than in confluent cells. In conclusion, erianin caused extensive tumour necrosis, growth delay and rapid vascular shutdown in hepatoma and melanoma models; it inhibited angiogenesis in vivo and in vitro and induced endothelial cytoskeletal disorganisation. These findings suggest that erianin has the therapeutic potential to inhibit angiogenesis in vivo and in vitro.European Journal of Cancer 05/2004; DOI:10.1016/S0959-8049(04)00231-X · 4.82 Impact Factor