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)

An isochromosome 11q in a patient with M5a type acute monoblastic leukemia is reported. The leukemic cells had a few azurophilic and alpha-naphthyl butyrate esterase-positive granules in the cytoplasm. Electron microscopy showed indented nuclei, abundant perinuclear fibrous bundles, and small lysosomes which were characteristic of monocytoid cells. A strong inhibitory activity against urokinase was detected in the cell lysates as compared with other leukemic cells. Cytogenetic analysis of the leukemic cells showed the karyotype 47, XY, +i(11q), which has not been observed hitherto in acute monocytic leukemia.
Cancer Genet Cytogenet 1990 Aug 01
PMID:Isochromosome 11q in acute monoblastic leukemia (M5a). 237 89

Expression of plasminogen activator (PA) enzyme activity is believed to be one of the mechanisms by which malignant cells cause pericellular proteolysis of stromal structures during implantation and tissue invasion. In this study, four cell lines derived from human gliomas were studied to ascertain which PA enzymes and PA inhibitors determine the level of secreted PA activity. A plasminogen-dependent esterolytic assay was used, and two lines (U251 and U373) were found to secrete high levels of PA activity, while PA activity was undetectable in the conditioned media from the remaining two lines (U138 and LM). The PA produced by U251 and U373 resolved as single bands comigrating with high molecular weight urokinase (Mr 54,000) on casein-plasminogen zymography. Northern blot analysis demonstrated high levels of mRNA for urokinase-type PA (uPA) in U251 and U373, as well as a considerably lower level of uPA message in LM. U251 and U373 also contained mRNA for tissue-type PA (tPA), although secreted tPA activity was not demonstrated by zymography. The U138 line contained essentially undetectable levels of mRNA for either uPA or tPA. U138 was also unique in secreting PA inhibitor activity and contained high levels of mRNA for PA inhibitor 2, which was not seen in any other line. All cell lines contained PA inhibitor 1 mRNA, with substantially more expression in the U138 and LM lines than in U251 and U373. None of the lines secreted measureable anti-plasmin activity. We conclude that there is considerable heterogeneity among human glioma cells in expression of PA enzymes and PA inhibitors. The coordinated regulation of these proteins likely determines secreted PA activity and the resultant role of plasminogen activation in tumor implantation and invasion.
Cancer Res 1990 Aug 15
PMID:Expression of heterogeneous profiles of plasminogen activators and plasminogen activator inhibitors by human glioma lines. 237 61

This laboratory recently reported that laminin degradation by cultured colon cancer was plasminogen dependent and reflected the presence of urokinase bound to cell surface receptors. (Schlecte, W.; Murano, G.; Boyd D. Cancer Res., 49:6064-6069; 1989). The present study was undertaken to determine the sensitivity of urokinase receptor directed proteolysis to the type I plasminogen activator inhibitor (PAI-1). Colon cancer cell types, that were highly effective in degrading laminin in vitro, elaborated into their conditioned medium an inhibitor which was indistinguishable from PAI-1 on the basis of its performance in reverse zymography, western blotting, and immunoprecipitation assays. A fraction of this PAI-1 was active, as evidenced by complex formation with the active site of radioactive urokinase. Laminin degradation by the colon cancer cells, however, did not appear to be affected by the endogenous inhibitor, since an antibody to the inhibitor, which blocked urokinase-PAI-1 interactions, had little effect on laminin turnover. Further, addition of exogenous PAI-1, activated by guanidine hydrochloride pretreatment, to the colon cancer cells did not perturb laminin degradation. Because laminin degradation by colonic cells was a function of receptor bound urokinase, presumably immobilized plasminogen activator escaped the neutralizing effect of the inhibitor. These data suggest either a shielding effect of the receptor on the plasminogen activator or a physical separation of activator and inhibitor. Either way, for cultured colon cancer at least, laminin degradation directed by urokinase receptor bound plasminogen activator appeared unaffected by the presence of this inhibitor.
Cancer Commun 1990
PMID:Insensitivity of laminin degradation directed by receptor bound urokinase to PAI-1 in cultured colon cancer. 239 Apr 19

This prospectively randomized clinical trial was carried out in four Dutch hospitals to reduce the development of metachronous liver metastases and to get a better survival in patients with colorectal malignancies after surgically radical en bloc resection of the primary tumor and the regional lymph nodes. Three hundred seventeen patients were randomized to participate in three trial arms. One group of patients was treated by surgery alone (control group); in the other patients a catheter was placed in the dilated umbilical vein and advanced until the tip was lying in the left branch of the portal vein. Fifty percent of these patients got immediate postoperative portal infusion with 1 g 5-fluorouracil (5-FU) and 5000 U heparin daily for 7 days; the others received portal vein infusion with urokinase 10.000 U/hour for 24 hours only. Three hundred four patients were eligible. Overall hospital mortality was 3.6% (11 patients) and was not influenced by adjuvant treatment. After a median follow-up of 44 months 66 patients have died with relapse and 21 as a result of other causes. The chance of developing liver metastases and other distant metastases after portal infusion with 5-FU/heparin was one third of the chance in the control group (P less than 0.001). Only an insignificant reduction of the average death rate in the 5-FU/heparin group was found. In the urokinase group no significant effect in reducing metastases or in survival was noted. Before recommending cytotoxic portal infusion as an adjuvant treatment in patients with colorectal cancer, detailed analysis of other ongoing portal infusion studies has to be awaited and careful calculations have to be made regarding how many patients really can be saved by this treatment.
Cancer 1990 Feb 01
PMID:Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin versus urokinase versus control. Results of a prospective randomized clinical trial (colorectal adenocarcinoma trial I). 240 56

The presence and localization of the plasmin system components urokinase (UPA), tissue type plasminogen activator (TPA), plasminogen (PG), a neoantigen expressed by the plasmin-alpha 2-antiplasmin complex, and plasmin inhibitors alpha 2-antiplasmin (AP) and alpha 2-macroglobulin (MG) have been tested by immunofluorescence on sections of 11 benign and 40 malignant lesions of the breast in an attempt to apply a morphological approach to the problem of tumor invasion in vivo. In benign lesions, TPA was seen in secretions of mammary glands and MG was seen in edematous zones. In one involuting lactating adenoma, UPA, TPA, PG, PAP, and AP were associated with glandular cells. UPA was detected in 11 carcinomas, TPA in 22, PG in 31, PAP in 12, AP in 23, and MG in all 40. All these components were essentially present in invasive territories, with a cellular labeling for UPA and TPA and a fluorescent staining frequently at the periphery of tumoral foci for PG and PAP. AP was more closely associated with cancer cells than MG, which was present in the stroma. Intraductal proliferations were rarely positive and there was no correlation between the localization of PG and the distribution of a basement membrane glycoprotein laminin. These data argue strongly for the involvement of the plasmin system in the infiltrating process of the stroma. This system seems to play a limited role in the breakdown of basement membrane in breast carcinomas in vivo.
Cancer Res 1986 Nov
PMID:Detection of the plasmin system in human mammary pathology using immunofluorescence. 242 83

Components of the plasmin system were comparatively studied in lymph node metastases and corresponding primary tumors by immunofluorescence. Primary tumors, all adenocarcinomas, originated from large bowel (N = 12) or breast (N = 10). We used antisera against plasminogen (Pg), plasminogen activators (PA) such as urokinase (UK) and tissue type PA (t-PA), plasmin inhibitors such as alpha 2 anti-plasmin (alpha 2AP) and alpha 2 macroglobulin (alpha 2M), plasmin-alpha 2 anti-plasmin complex (PAPC). Positivity with anti-PAPC serum was considered as proving that plasmin was formed by Pg activation. The following results were obtained. Breast adenocarcinomas were more strongly stained than colorectal adenocarcinomas using antisera against Pg, PAPC and PA, while their reactivity was much weaker with antisera against both plasmin inhibitors. Lymph node metastases from colorectal adenocarcinomas were more strongly stained than primary tumors using antisera against PAPC and PA. Reactivity with anti-Pg was similar, while that with antisera against plasmin inhibitors was much weaker. Metastasis from breast adenocarcinomas, on the average, showed the same type of staining as primary tumors. However, there was a slight decrease in reactivity with anti-Pg and PAPC in metastases. Tumor cells invading lymphoid areas in metastatic lymph nodes were often strongly labeled using antisera against Pg and UK. Staining was less strong or less frequent using antisera against PAPC and t-PA. These results favor the role of plasmin in the degradation of basement membrane and connective tissue components, thus implicating it in the invasiveness of tumor cells, at least in most primary tumors and metastases.
Int J Cancer 1987 Feb 15
PMID:The plasmin system in human adenocarcinomas and their metastases. A comparative immunofluorescence study. 243 33

To assess the postulated correlation between plasminogen activators (PAs) and malignancy, we determined the mRNA content for urokinase-type (u-PA) and tissue-type (t-PA) enzymes in a prospective series of 29 primary lung and 27 primary breast carcinomas. Dot blots of total RNAs were hybridized with appropriate cRNA probes under conditions that allow quantitative measurement of the mRNA level for each PA. Most tumors (43 of 56) had a u-PA mRNA content higher than the mean + 1 SD of nonmalignant tissue counterparts. A large, 4- to 20-fold, increase in u-PA mRNA content was demonstrated in 14 of 29 lung carcinomas and in 10 of 27 breast carcinomas. A statistically significant correlation (Fisher's test, P = 0.007) was found between elevated u-PA mRNA content in lung carcinomas and the presence of regional lymph node metastases. These results are consistent with a role for u-PA in tumor invasiveness and metastatic propensity and may have important prognostic and therapeutic implications.
Cancer Res 1987 Aug 01
PMID:Increase of urokinase-type plasminogen activator gene expression in human lung and breast carcinomas. 244 May 56

We have developed a highly sensitive sandwich enzyme immunoassay for determination of urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) antigen levels in extracts of human tissues. We determined antigen levels of PAs in extracts of 31 primary cancers and 15 normal mucosal tissues of the urinary bladder using this method. U-PA antigen levels in extracts of bladder cancers were significantly higher than those in normal tissues (p less than 0.005). U-PA antigen levels significantly increased as histological grading of malignancy advanced. There was no correlation between t-PA antigen level and malignancy. These results indicate that an increase of u-PA antigen level may be a parameter of malignant transformation and may play an important role in invasiveness of cancer.
Cancer Res 1989 Feb 15
PMID:Comparative study of plasminogen activators in cancers and normal mucosae of human urinary bladder. 249 5

We have analyzed the plasminogen activator (PA) systems of two metastatic breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231, as a function of 17 beta-estradiol stimulation when the cells were cultured on purified components of extracellular matrix. Laminin enhanced PA levels in both cell lines, but this enhancement seemed to occur via different mechanisms, including dissociation of inhibitor complexes. The major effect was the marked increase in cell-associated urokinase-type PA (u-PA); the increase was independent of estrogen in hormone-insensitive MDA-MB-231 cells grown on laminin-coated surfaces. In estrogen-sensitive MCF-7 cells, 17 beta-estradiol stimulated u-PA secretion in a similar fashion on plastic, laminin, fibronectin, or collagen but acted in synergy with laminin in the production and release of tissue-type PA.
J Natl Cancer Inst 1989 Feb 15
PMID:Modulation of plasminogen activator systems by matrix components in two breast cancer cell lines: MCF-7 and MDA-MB-231. 249 46

Using specific assays, we studied fibrinolytic activity in plasma and colonic mucosa biopsies of 28 patients with inflammatory bowel disease (IBD) (12 with Crohn's disease, 16 with ulcerative colitis) and 28 control patients without inflammatory bowel disease or colon malignancy. Blood coagulation was studied using standard techniques. In plasma of IBD patients significantly decreased tissue type plasminogen activator activity (t-PA) (p less than 0.02), increased plasminogen activator inhibition (PAI) (p less than 0.01) and fibrinogen (p less than 0.001), and prolonged thrombin time (p less than 0.001) and prothrombintime (p less than 0.001) were found. In colon mucosa the percentage of t-PA to urokinase type plasminogen activator (u-PA) was 80:20% in the control group and 71:29% in the IBD group in non-inflamed mucosa. In inflamed mucosa the plasminogen activator percentage was 55:45%, significantly different (p less than 0.01) from the control group. There was also a significant absolute increase in u-PA activity and decrease of t-PA activity in the inflamed mucosa compared to the control group (p less than 0.001 and p less than 0.01, respectively). Patients with inflammatory bowel disease therefore have significant changes in components of the fibrinolytic and coagulation system both systemically and locally in colon mucosa. These changes might contribute to an increased risk for thromboembolic complications and possibly to the pathogenesis of the colitis and to the local complications such as bleeding.
 ...
PMID:Disturbed fibrinolysis in patients with inflammatory bowel disease. A study in blood plasma, colon mucosa, and faeces. 280


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