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)

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 mechanism of coagulation activation in renal cell carcinoma was investigated using immunohistochemical techniques applied to fresh frozen sections of resected primary tumors. Tissue factor antigen was detected in the endothelium of vascular channels within the tumors. Fibrinogen and factor V were distributed diffusely in the perivascular tumor connective tissue. Fibrin was readily detected in a linear pattern along the edges of nodules of viable tumor indicating that thrombin had formed from the interaction of coagulation factors demonstrated previously in renal cell carcinoma tissue. Tissue plasminogen activator was detected in the endothelium of blood vessels in the vicinity of the tumor and urokinase in areas of necrosis but neither were associated with viable tumor cells. These results indicate that thrombin is formed locally in renal cell carcinoma tissue that transforms fibrinogen to fibrin. There also appears to be a net deficit in fibrinolysis in situ in this tumor. We postulate that these conditions might contribute to stabilization and progression of renal cell carcinoma and that clinical trials of antithrombotic agents are justified in this tumor type.
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PMID:Fibrinogen-fibrin transformation in situ in renal cell carcinoma. 211 16

Plasminogen activator (PA) activity was identified in the conditioned medium of two human renal carcinoma cell lines, Cur and Caki-1. PA activity of medium, following chromatography on Con A-Sepharose, was divided into effluent and eluate fractions, the latter obtained after elution with methyl mannoside. The ratio of PA activity in effluent:eluate was 90:10 for Caki-1 and 60:40 for Cur. The PA of both effluent fractions and the Caki-1 eluate fraction was of the urokinase (UK) type. Identification rested on molecular weight determination by zymography (major component with Mr 52,000 and a less prominent component of 93,000), lack of binding to fibrin, inhibition by anti-UK antibodies, and lack of inhibitory effect of anti-tissue type PA (TPA) antibodies or the Erythrina trypsin inhibitor, which inhibits TPA but not UK. PA of the Cur eluate fraction gave a more complex pattern in that it bound significantly to fibrin (like TPA), was completely inhibited by both anti-UK and anti-TPA antibodies, but was unaffected by Erythrina trypsin inhibitor. These results raise the possibility of an unusual PA-like enzyme that immunologically cross reacts with anti-UK and anti-TPA. Most of the PA of both cell lines was secreted in a latent form that could be activated by trypsin treatment. The latency appears to result largely from secretion of urokinase proenzyme, which is consistent with the Mr 52,000 of the major PA species and the insensitivity to diisopropyl fluorophosphate inhibition prior to trypsin activation. However, in addition, a UK binding component was found in the conditioned medium, which produced an Mr 93,000 component by reaction with UK.
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PMID:Characterization of plasminogen activator from two human renal carcinoma cell lines. 241 48

Plasminogen activators (PA) have been reported to be associated with fibrinolysis. The amounts of PA in urine, plasma, and tissues of patients with renal cell carcinoma were determined by measuring the amounts of two kinds of antigens, urokinase type (u-PA) antigen and tissue type (t-PA) antigen, by highly sensitive enzyme-immunoassay. The u-PA antigen level in urine showed neither daily variation nor age-relationship. It was, however, significantly higher (164.2 +/- 93.5 x 10(2) U/gCr) in patients with renal cell carcinoma than in healthy subjects (56.8 +/- 22.4 x 10(2) U/gCr) (p less than 0.01). The amount of u-PA antigen in urine tended to be higher in patients with high grade or stage cancer than in those with cancer of low grade or stage, though not statistically significant. The u-PA antigen content in tissues appeared elevated in tumors (8.90 +/- 6.00 x 10(-1) U/g wet tissue) in comparison to normal renal cortex and medulla. However, the difference was not significant, as the cancer samples consisted of various tissue components including necrotic or hemorrhagic tissue in addition to cancer cells. Although the t-PA antigen content in urine was too immeasurably small in 29% cases by the present method, there was no significant difference between patients with renal cell carcinoma and healthy subjects. The plasma level of t-PA antigen tended to be elevated in renal cell carcinoma group (7.87 +/- 5.60 U/ml) compared to the control group (5.7 +/- 2.19 U/ml), but no significant difference was present between them.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The study of plasminogen activator in renal cell carcinoma with special remarks on urokinase type plasminogen activator]. 251 7

Single-chain, urokinase-type plasminogen activator (pro-urokinase), isolated from the conditioned medium of a human renal adenocarcinoma cell line, was administered to six patients with evolving myocardial infarction of less than 5 hours' duration and angiographically confirmed total occlusion of the infarct-related coronary artery. The agent was infused intravenously at a rate of 40 mg over 60 minutes immediately followed in three patients by intracoronary infusion of 20 mg over 30 minutes. In four of the six patients complete reperfusion was obtained during intravenous administration and in one patient after 20 minutes of intracoronary infusion. One patient did not respond. The infusion caused significant changes in the fibrinogen level and generation of fibrinogen breakdown products in only one patient. Single-chain, urokinase-type plasminogen activator can induce clot-selective coronary thrombolysis in patients with acute myocardial infarction.
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PMID:Coronary thrombolysis with human single-chain, urokinase-type plasminogen activator (pro-urokinase) in patients with acute myocardial infarction. 308 Sep 36

This report describes the development and use of functional immunoradiometric assays that distinguish the activity of beta-migrating endothelial-type plasminogen activator inhibitor (PAI-1) from that of placental-type plasminogen activator inhibitor (PAI-2). These assays are based upon the binding of PAI-1 and PAI-2 to immobilized single-chain tissue-type plasminogen activator (tPA) and to immobilized urokinase (UK), respectively. The extent of binding of each PAI is quantified by incubating the PAI-PA complex first with rabbit antiserum specific for the individual PAI and then with 125I-labeled goat antirabbit IgG. In control experiments, the assays were shown to be sensitive, dose-dependent over a wide range, and specific for each PAI. These assays were employed to establish the PAI profile of a variety of human cells. Neither PAI-1 nor PAI-2 could be detected in Bowes melanoma cells or in a renal adenocarcinoma cell line (ACHN), while the histiocytic lymphoma cell (U-937) produced only PAI-2. Five cell lines, including two that were previously shown to contain one or the other PAI (e.g., umbilical vein endothelial cells and a fibrosarcoma cell line, HT-1080) in fact contained both PAIs. The cells containing both PAIs were studied in more detail. In each case, SDS treatment of CM was shown to enhance PAI-1 activity (by converting the latent form of this inhibitor into its active form) and to destroy PAI-2 activity. Various compounds including interleukin 1, dexamethasone, and phorbol myristate acetate were found to selectively influence the cellular production of one PAI without concomitantly affecting the production of the other, suggesting that the synthesis of these inhibitors is not coordinately regulated.
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PMID:Detection of both type 1 and type 2 plasminogen activator inhibitors in human cells. 325 67

In vivo and in vitro experimental models have suggested a major role for the urokinase-type plasminogen activator (uPA) in tumor cell invasion and metastasis. The uPA proteolytic activity of tumor cells has been shown to be largely determined by the extent of the expression and saturation of the uPA receptor. We have analyzed the expression and cellular localization of both uPA and uPA receptor at the protein and mRNA levels in 33 paired samples of renal cell carcinoma (RCC) and non-tumorous kidney tissue. In comparison with adjacent normal non-tumorous kidney tissues RCC tumor cells modestly overexpressed uPA-receptor mRNA and showed significantly decreased uPA mRNA expression. However, the immunoreactive uPA content of tumor cells was comparable to that of the surrounding normal non-tumorous kidney tissue. Assuming constancy of the uPA-receptor affinity for uPA this indicates that a proportion of the RCC-associated uPA may be derived from an exogenous source and subsequently concentrated at the tumor cell surface via uPA receptor expression. The modest increase in uPA receptor expression may lead to a normalization of uPA antigen content in RCC; however, it is not sufficient to substantially increase tumor tissue-uPA content over the level of normal non-tumorous kidney tissue.
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PMID:Modulation of urokinase and urokinase receptor gene expression in human renal cell carcinoma. 760 79

Effects of suramin, a polysulfonated naphthylurea compound, on metastatic ability, proliferation, and production of plasminogen activators and plasminogen activator inhibitors were studied using the highly metastatic human renal cell carcinoma cell line, SN12C-PM6. After renal subscapular implantation of tumor cells in nude mice, suramin significantly inhibited metastasis of tumor cells to the lungs and liver. In vitro growth of tumour cells was inhibited by suramin in a dose-dependent manner, at relatively low doses (ID50 = 105 micrograms/ml). Plasminogen activator inhibitor type 2 (PAI-2) production by tumor cells was enhanced by suramin (100 micrograms/ml), whereas urokinase-type plasminogen activator (uPA) production was suppressed. Thus, the increase in PAI-2 and the decrease in uPA production correlated with the inhibitory effects on tumour growth and metastasis by suramin. Therefore suramin may be beneficial for the treatment of patients with an early stage of renal cancer with potential risk of metastasis.
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PMID:Effects of suramin on metastatic ability, proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6. 788 14

The plasminogen activation system is considered to play an important role in cancer growth and metastasis. Both plasminogen activators (PAs) and their fast-acting inhibitors are produced in tumor cells and their surrounding tissues. In order to clarify the influence of the existence of malignant tumor in urinary tract on the systemic fibrinolytic activity, we designed a study in which we compared the plasma levels of PAs and their inhibitors between before and after radical resection of tumors. Fourteen patients with renal cell carcinoma and 14 patients with transitional cell carcinoma participated in the study. In both groups, plasma levels of tissue-type plasminogen activator and urokinase-type plasminogen activator before the operation were higher than those 15 days after operation. The plasma level of plasminogen activator inhibitor 1 (PAI-1), however, did not change after the operation in the renal cell carcinoma group, and it decreased slightly in the transitional cell carcinoma group although it was not significant. When these values of the groups with or without metastasis were compared to other organs or lymph nodes, the PAI-1 level before operation was significantly higher in the group with metastasis than that without metastasis. In the three groups divided by the degree of atypia, PAI-1 level in the most atypical group was the highest. These results suggest that the fibrinolytic system in the plasma of cancer patients may play an important role in tumor growth and metastasis.
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PMID:Plasminogen activators and plasminogen activator inhibitor 1 in urinary tract cancer. 814 Jun 79

Cultured human mesangial cells (HMC) derived from normal kidneys have been shown to synthesize tissue-type plasminogen activator (t-PA) and excess amounts of PA inhibitor type 1 (PAI-1). Conflicting results have been obtained concerning the production of urokinase-type PA (u-PA) and efforts to show PA inhibitor 2 (PAI-2) met with failure. We evaluated the fibrinolytic profile of cultured HMC lines obtained from 12 patients with renal carcinoma and one cadaveric kidney donor. Subconfluent cells (third passage) were incubated overnight in serum-free medium. t-PA, u-PA, PAI-1 and PAI-2 antigens were assayed by ELISA methods and PA and PAI activities by amidolytic methods both in conditioned medium (CM) and cell extracts (CE). Besides PAI-1, PAI-2 antigen was detected in all but one HMC lines. At variance with the former, which was largely released in the culture medium, PAI-2 was mainly cell-associated. t-PA antigen was found in all but two cell lines while u-PA antigen was detected in relatively high concentrations in 8 cell lines. PA activity, identified as u-PA by functional and immunological criteria, was measured in CM of six of the eight u-PA producing cell lines, whereas PAI activity was undetectable or very low in CM of all cell lines, suggesting that PAI-1 was largely inactive. Functional assays of cell extracts demonstrated the presence of PA activity, again identified as u-PA, only in samples (five lines) containing u-PA antigen in excess over PAI-2. PAI activity was found instead in the extracts in which the inhibitor was higher than the activator (six lines) and was identified as PAI-2, as it inhibited u-PA but not single-chain t-PA and was neutralized by a polyclonal anti-PAI-2 antibody. The heterogeneous fibrinolytic pattern of HMC lines was confirmed by mRNA analysis of three representative lines. Results were similar when HMC lines at passage five were used, except that the u-PA content was significantly reduced both in CM and CE. These findings indicate that the fibrinolytic profile of cultured HMC is more complex than previously reported. The production of large amounts of PAI-2 may represent an additional control mechanism of proteinase activity.
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PMID:Cultured human mesangial cells produce both type 1 and type 2 plasminogen activator inhibitors. 877 30


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