Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations. These data suggested that the compounds might have vascular targeting activity. In this study, we have evaluated the ability of these compounds to disrupt tumor vasculature and to induce tumor necrosis. We investigated the pharmacokinetic and toxicity profiles of all six compounds and examined their ability to induce tumor necrosis. We next examined the antitumor efficacy of a subset of compounds in three different human solid tumor xenografts. In the human lung tumor xenograft (Calu-6), MX-116407 was highly active, producing tumor regressions in all 10 animals. Moreover, MX-116407 significantly enhanced the antitumor activity of cisplatin, resulting in 40% tumor-free animals at time of sacrifice. Our results identify MX-116407 as the lead candidate and strongly support its continued development as a novel anticancer agent for human use.
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PMID:Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents. 1554 76

The vascular endothelial growth factor-A (VEGF-A) signaling pathway, a key stimulant of solid tumor vascularization, is primarily dependent on the activation of the endothelial cell surface receptor VEGF receptor-2 (VEGFR-2). AZD2171 is an oral, highly potent small-molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo. Here, we show pharmacodynamic changes in VEGFR-2 phosphorylation induced by AZD2171. In mouse lung tissue, a single dose of AZD2171 at 6 mg/kg inhibited VEGF-A-stimulated VEGFR-2 phosphorylation by 87% at 2 h with significant inhibition (>or=60%) maintained to 24 h. To examine inhibition of VEGFR-2 phosphorylation in tumor vasculature by immunohistochemistry, a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken. Antibodies to the phosphotyrosine epitopes pY1175/1173 and pY1214/1212 were found suitable for this application. Calu-6 human lung tumor xenografts, from mice receiving AZD2171 or vehicle treatment (p.o., once daily), were examined by immunohistochemistry. A significant reduction in tumor vessel staining of phosphorylated VEGFR-2 (pVEGFR-2) was evident within 28 h of AZD2171 treatment (6 mg/kg). This effect preceded a significant reduction in tumor microvessel density, which was detectable following 52 h of AZD2171 treatment. These data show that AZD2171 is a potent inhibitor of VEGFR-2 activation in vivo and suggest that AZD2171 delivers therapeutic benefit in Calu-6 tumors by targeting vessels dependent on VEGFR-2 signaling for survival. In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation.
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PMID:Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts. 1769 17