Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HER-2/neu status and t-PA, u-PA, and PAI-1 cytosol content were evaluated in 88 primary breast cancer patients to determine the relationships between these parameters. HER-2/neu was amplified in 24% (20/84) of tumor samples and overexpressed in 28% (14/50). In the overall series, median t-PA, u-PA and PAI-1 contents, measured by the enzyme-linked immmunoassay (ELISA), resulted in 1.7, 1.1 and 1.0 ng/mg cytosol protein (cyt prot), respectively. HER-2/neu overexpressed cases showed higher u-PA levels than those normally expressed whereas t-PA and PAI-1 levels did not vary in HER-2/neu altered and non altered cases. The t-PA levels did not differ in cases with or without HER-2/neu alterations, when separately considering the node-negative and node-positive cases. A significant relationship between t-PA levels and HER-2/neu alterations was observed only in the ER(+) tumors: t-PA levels were lower in amplified and overexpressed cases (1.4 versus 2.5 ng/mg cyt prot in amplified and single copy gene, respectively; 1.6 versus 2.3 ng/mg cyt prot in overexpressed and normally expressed cases, respectively). Therefore, t-PA and HER-2/neu could provide additional prognostic information for ER-negative patients.
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PMID:Her-2/neu and fibrinolytic factors in human breast-cancer. 2155

The aim of this study is to investigate the anti-cancer effect of the bispecific diphtheria toxin (DT) based immunotoxin DTATEGF, which targets both the epidermal growth factor (EGF) receptor (EGFR) and the urokinase-type plasminogen activator (uPA) receptor (uPAR) in vitro and in vivo when delivered by convection-enhanced delivery (CED) via an osmotic minipump in a human metastatic non-small cell lung cancer (NSCLC) brain tumor mouse xenograft model. The effects of the bispecific immunotoxin DTATEGF, and monospecific DTAT, DTEGF and control DT at various concentrations were tested for their ability to inhibit the proliferation of human metastatic NSCLC PC9-BrM3 cells in vitro by MTT assay. A xenograft model of human metastatic NSCLC intracranial model was established in nude mice using the human NSCLC PC9-BrM3 cell line genetically marked with a firefly luciferase reporter gene. One microgram of DTATEGF in the treatment group or control DT in the control group was delivered intracranially by CED via an osmotic minipump. The bioluminescent imaging (BLI) was performed at day 7, 14, 1 month, 2 months, and 3 months. Kaplan-Meier survival curves for the two groups were generated. The brain tissue samples were stained by hematoxylin and eosin for histopathological assessment. In vitro, DTATEGF could selectively kill PC9-BrM3 cells and showed an IC(50) less than 0.001 nM, representing a more than 100- to 1000-fold increase in activity as compared to monospecific DTAT and DTEGF. In vivo, mice with tumors were treated intracranially with drug via CED where the results showed the treatment was successful in providing a survival benefit with the median survival of mice treated with DTATEGF being significantly prolonged relative to controls (87 vs. 63 days, P = 0.006). The results of these experiments indicate that DTATEGF kills the NSCLC PC9-BrM3 cell line in vitro, and when it is delivered via CED intracranially, it is highly efficacious against metastatic NSCLC brain tumors. DTATEGF is a safe and effective drug where further preclinical and clinical development is warranted for the management of metastatic brain tumors.
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PMID:Intracerebral infusion of the bispecific targeted toxin DTATEGF in a mouse xenograft model of a human metastatic non-small cell lung cancer. 2269 10

Receptor-targeted optical imaging of cancer is emerging as an attractive strategy for early cancer diagnosis and surgical guidance. The success of such strategy depends largely upon the development of receptor-targeted fluorescent probes with high specificity and binding affinity to the target receptors. Recently, a host of such probes have been reported to target cancer-specific receptors, such as somatostatin receptors (SSTRs), integrin receptors, cholecystokinin-2 (CCK(2)) receptor, gastrin-releasing peptide (GRP) receptor, endothelin A (ET(A)) receptor, translocator protein (TSPO) receptor, epidermal growth factor (EGF) receptor, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF) receptor, folate receptor (FR), transferrin receptor (TFR), low-density lipoprotein (LDL) receptors, type I insulin-like growth factor receptor (IGF1R), vasoactive intestinal peptide (VIP) receptors, urokinase plasminogen activator (uPA) and estrogen receptor (ER). This review will describe the recent advances in synthetic targeting optical imaging probes and demonstrate their in vivo imaging potentials. Moreover, current status of near infrared (NIR) fluorescent dyes, targeting moieties and coupling reactions, as well as strategies for designing targeted probes, will also be discussed.
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PMID:Recent advances in receptor-targeted fluorescent probes for in vivo cancer imaging. 2287 63

Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.
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PMID:Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A. 2846 15


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