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

The regulation of urokinase plasminogen activator (uPA) expression was investigated in 2 highly metastatic rat mammary adenocarcinoma cell lines, BC1 and MAT 13762. BC1 cells were observed to synthesize, on average, 10 times less uPA enzyme and mRNA than MAT 13762 cells; however this difference was not accounted for by differences in uPA gene copy number/structure or in the rate of uPA gene transcription in the cell lines studied. Moreover, Northern blot analysis of invasive sub-populations derived in vitro from the BC1 cell line revealed levels of uPA expression similar to those of the parent, but a 3-fold elevation in expression of the metalloprotease gene, transin. Further investigation showed that treatment of BC1 cells with either of the protein synthesis inhibitors, cycloheximide or anisomycin, increased the level of both nuclear and cytoplasmic uPA RNA 6- to 18-fold in 4 hr, whilst inducing a maximum 2.6-fold increase in the rate of uPA gene transcription. This increase in uPA gene expression may therefore reflect, in part, an increase in the stability and/or processing of nuclear uPA transcripts. These results suggest that the degree of uPA gene expression does not correlate directly with BC1 tumor-cell invasion in vitro, and that the uPA gene is down-regulated, at least in part, post-transcriptionally in the nucleus of BC1 mammary tumor cells.
Int J Cancer 1992 Apr 01
PMID:Post-transcriptional regulation of urokinase plasminogen activator gene expression occurs in the nucleus of BC1 rat mammary tumor cells. 155 91

We studied infectious and mechanical complications occurring with 55 central venous catheters (CVCs) managed in hospital and at home, in 53 children with hematological malignancies who underwent bone marrow transplantation (BMT). The total catheter life span was 6906 days (median 111), 2359 days (median 40) in hospital and 4547 days (median 78.5) at home. Duration of neutropenia was 1241 days (median 20), mostly in hospital. We observed 21 CVC-related infections from 17/55 CVCs (31%): 0.30 episodes/100 days of CVC use with 0.55/100 days in hospital vs 0.17/100 days at home. Antibiotic treatment resolved 72% of infections without CVC removal, which was required in six instances. There were 14 mechanical complications (0.20 episodes/100 days of CVC use) in 6/55 CVCs (11%), with three removals. Interventions to resolve mechanical problems included catheter declotting by urokinase, repair and replacement. We conclude that CVC is an essential component of care of children with cancer undergoing BMT and that it has a relatively low complication rate. Most complications can be resolved by an appropriate CVC handling and by a multidisciplinary intervention in the critical post-BMT phase.
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PMID:Central venous catheter-related complications after bone marrow transplantation in children with hematological malignancies. 157 9

In the United States, approximately one million patients each year develop a pleural effusion. Pleural effusions have classically been divided into transudative and exudative pleural effusions. A transudative pleural effusion occurs when the systemic factors influencing pleural fluid formation and reabsorption are altered so that pleural fluid accumulates; an exudative pleural effusion occurs when the local factors influencing pleural fluid formation and reabsorption are altered, allowing accumulation of pleural fluid. The leading causes of transudative pleural effusions are left ventricular failure and cirrhosis with ascites. The leading causes of exudative pleural effusions are pneumonia, malignancy, and pulmonary embolization. Transudative pleural effusions can be differentiated from exudative pleural effusions by measurement of the pleural fluid protein and lactic dehydrogenase (LDH) levels. The ratio of the pleural fluid protein to the serum protein is less than 0.5, the ratio of the pleural fluid LDH to the serum LDH is less than 0.6, and the absolute value of the pleural fluid LDH level is less than two thirds of the upper normal limit for serum with transudative pleural effusions while at least one of these criteria is not met with exudative effusions. Most patients who have a pleural effusion with congestive heart failure have left ventricular failure. It is believed that the transudation of the pulmonary interstitial fluid across the visceral pleura overwhelms the capacity of the lymphatics to remove the fluid. Most patients with cirrhosis who have a pleural effusion also have ascites. It is also believed that the pleural effusions form when fluid moves directly from the peritoneal cavity into the pleural cavity through pores in the diaphragm. Approximately 40% of patients with pneumonia will have a pleural effusion. If these patients have a significant amount of pleural fluid, a diagnostic thoracentesis should be performed. Chest tubes should be inserted if the pleural fluid is gross pus, if the Gram stain of the pleural fluid is positive, if the pleural fluid glucose level is below 40 mg/dl, or if the pleural fluid pH level is less than 7.00. If drainage with the chest tubes is unsatisfactory, either streptokinase or urokinase should be injected intrapleurally. If drainage is still unsatisfactory, a decortication should be considered. The three leading malignancies that have an associated pleural effusion are breast carcinoma, lung carcinoma, lymphomas and leukemias. The diagnosis of pleural malignancy is made most commonly with pleural fluid cytology; in recent years immunohistochemical tests have proved invaluable in differentiating benign from malignant pleural effusions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pleural diseases. 157 32

Recent progress in elucidating the complex and heterogeneous interactions between malignancy and coagulation or fibrinolysis reactions in humans has clarified the pathogenesis of disseminated intravascular coagulation that occurs with malignancy and has revealed evidence for two distinct pathways of growth regulation based on production by tumor cells of initiators of thrombin formation versus plasminogen activators. We have proposed a preliminary classification of tumors (see Table 2) based on these interactions. Type I tumors are those in which the tumor cells are associated with an intact coagulation pathway that leads to thrombin formation at the tumor periphery but in which the tumor cells lack u-PA. Examples of tumors in this category include SCCL, malignant melanoma, and renal cell carcinoma. Type II tumors are those in which the tumor cells express u-PA but lack an associated coagulation pathway leading to thrombin formation. Examples of type II tumors include prostate cancer, colon cancer, breast cancer, and N-SCLC. Type III tumors are those that express neither of these pathways, or exhibit some other pattern of interaction. Obviously, this formulation must be regarded as hypothetical. However, this concept fits with the limited data available to date from clinical trials. More importantly, this hypothesis can be tested further by means of intervention aimed at interrupting pathways relevant to specific tumor types. Characterization of additional tumor types by the methods described should permit amplification of this classification of tumors and other patterns of interaction may be defined. Exploration of the coagulation-cancer interaction holds considerable promise for gaining new understanding of both the coagulation mechanism and tumor biology. Most intriguing is the prospect that imaginative approaches to cancer treatment may be devised that are not only relatively nontoxic and low cost, but also effective.
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PMID:Pathways of coagulation/fibrinolysis activation in malignancy. 157 11

The production of metastasis appears to involve a number of different proteases including the urokinase form of plasminogen activator, cathepsin B, cathepsin D and various metalloproteases. Early data implicating these proteases in metastasis were mostly indirect and based on correlation studies in animal models. More recent work, using specific protease inhibitors and antibodies against proteases to block experimental metastasis, have provided more direct evidence that proteases play a role in cancer spread. In addition, transfection of genes encoding certain proteases increases the metastatic phenotype of the recipient cells. In human tumours, a number of different proteases also correlate with metastatic potential. It is concluded that certain proteases may be new prognostic markers in cancer as well as new targets for anti-metastatic therapy.
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PMID:The role of proteolytic enzymes in cancer invasion and metastasis. 158 84

HOC-I ovarian cancer cells express the single-chain form of the urokinase-type plasminogen activator (uPA) and cathepsin B (cath B) on their cell surface. The significance of the expression of cell surface uPA/cath B activity to the invasive potential was examined by preincubating with uPA/cath B-modulating agents in in vitro invasion assay. The anti-uPA monoclonal antibody 394 effectively inhibited invasion in a dose-dependent manner. On the contrary, anti-cath B antibody did not affect the invasive potential of the cells. E-64, a specific inhibitor for cysteine proteases, blocked invasion as effectively as monoclonal antibody 394. The data reveal that the uPA and cysteine proteases contribute significantly to the invasive capacity of the cells. We suggest that the cysteine proteases facilitate the action of uPA, possibly by activating proenzyme uPA produced by cancer cells. Evidence for the role of a cathepsin-uPA activation cascade in HOC-I cell invasion is provided.
Cancer Res 1992 Jul 01
PMID:Inhibition of in vitro ovarian cancer cell invasion by modulation of urokinase-type plasminogen activator and cathepsin B. 161 32

The plasminogen activator (PA) activity in various cell lines is suppressed by glucocorticoids. These phenomena are attributed to either a suppression of PA biosynthesis, to an increase of PA inhibitor or to a combination of both. The regulation of urokinase (UK) production in a human pre-B cell lymphoma line, RC-K8, by dexamethasone (Dex) and phorbol myristate acetate (PMA) was investigated. RC-K8 is a cell line which is consistently producing a high molecular weight UK in the conditioned medium (Kubonishi, I., et al: Jpn. J. Cancer Res. 76, 12-15, 1985). The cells were cultured in RPMI-1640 with Dex or PMA for 1-4 days. UK activity was measured using a chromogenic substrate S-2444 and the antigen by an ELISA kit. PAI-1 and PAI-2 antigens were also measured by ELISA kits and the complex between PA and PAI was examined by SDS-PAGE fibrin-zymography. The UK secretion in RC-K8 cells was inhibited by cycloheximide and actinomycin D. PMA at 0.16-1.6 uM up-regulated the UK activity approximately two-fold, parallel with the antigen, whereas Dex at 1-10 uM decreased the UK expression approximately half. These were verified by SDS-PAGE fibrin-zymography. Neither PAI-1, PAI-2 nor PA/PAI complex was detected in the conditioned medium and in the cell lysate. These data suggest that PMA up-regulates the UK secretion without inducing PAIs and the down-regulation of the UK secretion by Dex results from the inhibition of the expression of UK itself but not from the induction of PAIs.
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PMID:Down-regulation of urokinase secretion from a human lymphoma cell line RC-K8 by dexamethasone without inducing plasminogen activator inhibitors. 163 98

There is increasing evidence that urokinase secreted by tumor cells can be bound to a cell surface receptor retaining its full potential to activate plasminogen and subsequently cleave basement membrane constituents. This study was undertaken to discriminate between soluble and cell surface bound urokinase as a potential mediator of in vitro invasion by cultured colon cancer. Extracellular matrix invasion by a colon cancer cell line GEO, characterized as being a poor secretor of urokinase and having few receptors (less than 10(4) receptors/cell) was not augmented when these cells were made to secrete up to 8 times as much urokinase, in response to an exogenous urokinase gene driven by the Rous sarcoma virus long terminal repeat promoter. The majority of the plasminogen activator (greater than 95%) appeared in the culture medium, this reflecting the low numbers of binding sites displayed by GEO cells. In contrast, the cell line HCT 116 equipped with 10 times as many binding sites, (greater than 10(5)/cell), the majority of which are occupied with endogenous ligand, was an efficient invader of the extracellular matrix. Inhibition of urokinase binding to the cell surface receptors using an antibody to the A chain of the plasminogen activator reduced invasion by 65%. The cell line RKO is equipped with 3 x 10(5) receptors/cell, 15% of which are tagged with endogenous urokinase. Pretreatment of these cells with a concentration range of urokinase known to result in the majority of these binding sites being charged with the plasminogen activator led to a dose dependent increase in extracellular matrix invasion. Together, these data suggest that for cultured colon cancer, at least, invasion is a function of the amount of cell surface receptor bound urokinase.
Cancer Res 1991 Jul 15
PMID:Role of the urokinase receptor in facilitating extracellular matrix invasion by cultured colon cancer. 164 43

The urokinase-type plasminogen activator (uPA) activity in sera of patients suffering from nasopharyngeal carcinoma was examined by a uPA-specific immunocapture assay. The results revealed that the activity levels in the patient sera were significantly higher than that of normal healthy controls. The uPA activity also increased with the staging of the disease and the anti-EBV VCA IgA titre which is a diagnostic test for the disease, although the results were not statistically different. These findings showed that the levels of the enzyme were related to the spread of the disease. In addition, it was demonstrated that the sensitivity of the assay could be increased by using SDS. If the sera were treated with 0.2% sodium dodecyl sulphate (SDS) prior to the assay, higher levels of measureable PA activity were detected.
Cancer Lett 1991 Jul 04
PMID:Measurement of urokinase-type plasminogen activator activity in sera of nasopharyngeal carcinoma patients by an immunocapture assay. 164 95

We have investigated the role of urokinase (UK) and its cell-surface receptor in determining the invasiveness of prostate cancer cells. Three human cell lines, DU-145, PC-3 and LNCaP, that differ in androgen-responsiveness and growth characteristics, were tested. Analysis of the conditioned medium by an enzyme-linked immunosorbent assay showed secretion of UK by DU-145 (63 ng/mL/10(6) cells/48 hr) and PC-3 (682 ng/mL/10(6) cells/48 hr), but absence of secretion by LNCaP cells. Western blot analysis and enzyme activity assay of the conditioned medium confirmed these results. Scatchard analysis of radioligand binding with acid pretreated cells showed the presence of a single population of high affinity UK receptors on DU-145 cells (93,000 sites/cell, Kd = 0.9 nM) and PC-3 cells (25,000 sites/cell, Kd = 1.0 nM) but not on LNCaP cells. DU-145 and PC-3 cells were found to be highly invasive in in vitro invasion assays: 4.5 +/- 0.5% and 6.5 +/- 0.5%, respectively, of total tumor cells (approximately 2 x 10(5)) had penetrated reconstituted basement membrane (Matrigel) in a 72 hr incubation in serum-free growth medium. Under similar conditions, less than 0.25% LNCaP cells invaded Matrigel. The data indicate that androgen unresponsive, aggressive prostate tumor cells of high metastatic potential, DU-145 and PC-3, secrete UK and display cell-surface UK receptors, fully charged with the protease. Conversely, relatively indolent LNCaP cells of low metastatic potential do not secrete UK nor do they possess its binding sites. UK receptor antagonists, UK 12-32 and UK 6-135, which compete with labeled UK for binding to prostatic cells but do not inhibit cellular proliferation or UK secretion, markedly reduced DU-145 and PC-3 cell invasion (80-85% inhibition), thereby suggesting an important role of receptor-bound UK in prostate tumor cell invasion.
Cancer Commun 1991 Aug
PMID:Involvement of urokinase and its receptor in the invasiveness of human prostatic carcinoma cell lines. 165 86


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