Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between serum and tumour cell surface proteolytic enzymes and the development of muscle breakdown in cancer cachexia has been studied in a murine model of the condition (MAC16). The surface of the MAC16 tumour cells carried a proteolytic enzyme referred to as guanidinobenzoatase (GB). Serum from mice also contained an enzyme (referred to as MSE) which cleaved the trypsin inhibitor 4-methylumbelliferyl-p-guanidinobenzoate as a true substrate, but there was no relationship with weight loss or the presence or absence of tumour and the level of this serum enzyme. Polyunsaturated fatty acids (PUFAs) were shown to be inhibitors of MSE at microM concentrations and one PUFA, eicosapentaenoic acid (EPA) was found to be a non-competitive inhibitor of both MSE and GB. The effect of EPA was specific since other proteolytic enzymes, trypsin, esterase and tissue plasminogen activator were unaffected by concentrations inhibiting GB and MSE. MSE and GB are two different enzymes which possess some common properties. However, GB is likely to be significant for tumour development since MSE is also found in normal mouse serum.
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PMID:Observations on the inhibition of serum and cell surface enzymes by eicosapentaenoic acid. 128 67

Circulating thrombomodulin is a novel endothelial cell marker, which may reflect the endothelial injury. Plasma levels of thrombomodulin were quantitated by an enzyme-linked immunosorbent assay (ELISA) in patients with hematological malignancies, liver disease, diabetes mellitus, collagen disease, thrombotic disease, and disseminated intravascular coagulation (DIC), and the thrombomodulin values were compared with those of von Willebrand factor antigen (vWf:Ag) and tissue-type plasminogen activator (t-PA) which are released from stimulated or damaged endothelial cells. The mean plasma concentrations of thrombomodulin in these disease states were elevated as compared with healthy subjects. A relatively high mean thrombomodulin level was observed in DIC, liver disease, and collagen disease. Abnormally high thrombomodulin values (greater than normal mean value + 3 SD) were found in 32.3% of patients with hematological malignancies, 57.7% of patients with liver disease, 39.3% of patients with diabetes mellitus, 30.0% of patients with collagen disease, 23.1% of patients with thrombotic disease, and 69.0% of patients with DIC. Plasma concentrations of both vWf:Ag and t-PA were also elevated in these patients. On the whole, the plasma thrombomodulin concentration was positively correlated with vWf:Ag (r = 0.441, P less than 0.001) and t-PA (r = 0.398, P less than 0.001). These findings indicate that the elevation of plasma thrombomodulin is frequently seen in a variety of diseases and circulating thrombomodulin is possibly useful for evaluating the endothelial damage in selected disease states.
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PMID:Circulating thrombomodulin as a novel endothelial cell marker: comparison of its behavior with von Willebrand factor and tissue-type plasminogen activator. 132 30

The human sarcoma cell line HT1080 was found, by in situ hybridization, to consist of cells expressing various levels of urokinase (uPA) and tissue type (tPA) plasminogen activator (PA) suggesting clonal variation of expression of these genes. Colonies originating from single HT1080 cells were, therefore, established and screened for PA activity using a fibrin agarose overlay. Colonies inducing lysis (clone C+ and H+) or no lysis (clones B- and M-) were isolated and tested for mRNA levels of uPA, tPA, uPA receptor (uPAR) and the 3 PA inhibitors (PAI), PAI-1, PAI-2 and protease-nexin I. The different clones revealed considerable variation of expression of the different PA and PAI genes, with lysis-inducing clones expressing mainly the PA genes, whereas non-lysing clones demonstrated higher expression of the PAI genes. Amplification or loss of specific genes was excluded by Southern blotting. The protein levels of cellular and secreted PA and PAI determined by ELISA and Western blots demonstrated a pattern similar to that observed for PA and PAI mRNA concentrations, suggesting clonal differences either on the level of transcription or in RNA processing and/or stability. Due to complex interactions between PA and PAI, neither mRNA nor protein levels of the different genes were predictive for the amount of functional PA activity present in the supernatant or on the cell surface of the different clones. Receptor-bound uPA activity was found to be considerably higher in lysis-inducing than in non-lysing clones and the activity was dependent on neutralization by PAI-1 rather than on the level of uPAR mRNA.
Int J Cancer 1992 Sep 09
PMID:Clonal variation of expression of the genes coding for plasminogen activators, their inhibitors and the urokinase receptor in HT1080 sarcoma cells. 132 52

Plasma levels of tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor 1 (PAI-1) antigen and t-PA/PAI-1 complex were measured in plasmas from 18 healthy subjects and 75 patients with various diseases (28 patients with haematological malignancies, 20 with thrombotic diseases, five with infectious diseases, four with liver diseases, ten with bleeding disorders and eight miscellaneous conditions). In addition, we studied ten patients with bleeding disorders after DDAVP infusion and 18 healthy subjects after venous occlusion. Plasma levels of t-PA antigen, PAI-1 antigen and t-PA/PAI-1 complex were increased in the patients compared with the healthy subjects. t-PA/PAI-1 complex levels correlated well with t-PA antigen levels and molar concentrations of t-PA antigen were similar to those of the t-PA/PAI-1 complex. Venous occlusion induced an increase in both t-PA antigen and PAI-1 antigen and the molar concentration of the t-PA/PAI-1 complex was equivalent to that of t-PA antigen. Following DDAVP infusion, the levels of t-PA antigen and t-PA/PAI-1 complex increased but PAI-1 antigen levels decreased, and the increase of t-PA antigen was greater than that of t-PA/PAI-1 complex. These findings indicate that PAI-1 antigen exceeds t-PA antigen in healthy subjects and in patients with various diseases. We conclude that part of the t-PA/PAI-1 complex is rapidly cleared from the circulation and that free t-PA increases after DDAVP infusion.
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PMID:Behaviour of tissue plasminogen activator, plasminogen activator inhibitor 1 and their complex in various disease states. 142 Aug 14

Seven patients were treated with recombinant human tissue plasminogen activator (tPA) for severe hepatic venocclusive disease (VOD) that developed after bone marrow transplantation for hematologic malignancy. Recombinant human tPA (10 mg/d x 2 days) and heparin (1,000 U bolus followed by continuous intravenous infusion of 150 U/kg/d x 10 days) were begun a median of 9 days (range, 4 to 18 days) posttransplant. The median total serum bilirubin and percent weight gain from baseline were 19.4 mg/dL (range, 14.6 to 34.9 mg/dL) and 9.1% (range, 1% to 18.5%), respectively, at the start of tPA administration. Five patients responded to therapy with prompt reduction in total serum bilirubin within 96 hours of starting tPA. Three patients are alive 178 to 379 days posttransplant without evidence of VOD. No patient had significant hemorrhagic complications with tPA. We conclude that recombinant human tPA can be administered to patients with severe VOD at the dosage described. Whereas preliminary data suggests that recombinant human tPA can alter the natural history of severe VOD, further study is necessary to determine its efficacy.
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PMID:Recombinant human tissue plasminogen activator for the treatment of established severe venocclusive disease of the liver after bone marrow transplantation. 142 68

Hepatic veno-occlusive disease (VOD) is the most common life threatening complication of preparative-regimen-related toxicity for bone marrow transplantation (BMT). The frequency of VOD varies greatly, from 1-2% in centers performing pediatric BMT for thalassemia to over 50% in some centers doing BMT for hematologic malignancy. The term liver toxicity syndrome is a clinicopathologic definition which encompasses the range of histopathology within the hepatic venules and surrounding sinusoids and hepatocytes. These histologic abnormalities are statistically associated with a clinical syndrome of jaundice, ascites, and painful hepatomegaly developing early post-transplant. Newer modalities which may aid accuracy are transvenous liver biopsy along with determination of the gradient between the wedged and free hepatic venous pressures, and measurement of blood coagulatory components, particularly protein C levels. Analyses of clinical risk factors for VOD are confounded by lack of a clear hierarchy of risk when comparing heterogeneous patient populations, the methods of patient selection and choice of controls, and whether analysis is univariate or multivariate. Prospective multivariate analyses indicate that the risk of developing liver toxicity is independently correlated with intensity of conditioning therapy, pre-transplant viral hepatitis, use of antimicrobial therapy with acyclovir, amphotericin, or vancomycin (reflecting fever), and mismatched or unrelated allogeneic marrow grafts. These analyses plus morphologic and biochemical data support the hypothesis that VOD is caused by cytoreductive injury to hepatocytes and endothelium in zone three of the liver acinus, and in turn strongly influenced by factors which induce the release of tumor necrosis factor-alpha (TNF-alpha) leading to enhancement or activation of coagulation with obstruction of hepatic sinusoids and venules. Pharmacokinetic measurements of busulfan as a conditioning agent demonstrate a correlation between high steady-state busulfan levels and liver toxicity and suggest that safer and/or more efficacious plasma busulfan concentrations can be obtained by making individual dose adjustments and by changing the schedule of administration. Conservative therapy of severe VOD, including the use of peritoneal-pleural shunts for relief of ascites, is unsatisfactory. Results from prophylactic studies aimed at preventing VOD by heparin or prostaglandin E1 indicate considerable differences with toxicity and efficacy. Use of the TNF-alpha blocker, pentoxifylline, has also shown promise in lessening VOD. A statistical model which predicts patients likely to have an unfavorable outcome from VOD has been used to select premorbid patients for promising new therapeutic modalities, such as recombinant tissue plasminogen activator.
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PMID:Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation. 142 75

Normal human fibroblast (i.e., GM2936B, GM2907A, and IMR-90) and cancer-prone human fibroblast (i.e., Fanconi's anemia, Bloom's syndrome, and Ataxia telangiectasia) cells demonstrated the induction of intracellular and extracellular levels of tissue-type plasminogen activator (t-PA) at 6 and 12 hr, respectively, following ionizing radiation. Induced t-PA enzymatic activities following ionizing radiation were blocked by actinomycin D treatments. t-PA enzymatic activities were induced over 14-fold in Ataxia telangiectasia cells, over 9-fold in Bloom's syndrome cells, and over 6-fold in Fanconi's anemia cells, as compared to normal human fibroblasts. Similarly, the induction of t-PA mRNA levels in cancer-prone cells were between 5- to 10-fold higher than those observed in normal cells following equitoxic doses of ionizing radiation. Temporal induction of t-PA mRNA levels for normal and cancer-prone human cells were consistent with quantifiable enzymatic activities. The elevated induction of an intracellular protease (i.e., t-PA) in cancer-prone human cells is reminiscent of an "SOS"-like response observed in yeast and bacteria.
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PMID:Enhanced induction of tissue-type plasminogen activator in normal human cells compared to cancer-prone cells following ionizing radiation. 144 36

Recent reports have suggested that tissue-type plasminogen activator activity is regulated by estrogen in 7,12-dimethylbenz[a]anthracene-induced rat mammary carcinoma type I cells but is not necessarily regulated by estrogen in type II mammary carcinoma cells. We have compared the biological features of these two types of mammary carcinoma cells and have found that, although there is no difference in estrogen receptor content between these two cell types, the plasminogen activator activity markedly differs. Tissue-type plasminogen activator activity is significantly higher in type I carcinoma than in type II carcinoma, urokinase-type activity is significantly higher in type II carcinoma than in type I carcinoma. When these two types were compared in terms of rate of tumor growth, type II carcinomas clearly showed more rapid growth than type I carcinomas. Survival studies showed significantly shorter survival of type II tumor-bearing rats compared with type I tumor-bearing rats. Furthermore, type II carcinomas contained a greater proportion of aneuploid cells than type I carcinomas. These results suggest that type II carcinoma cells, in which estrogen is unable to regulate tissue-type plasminogen activator activity, are considered to be of a higher grade of malignancy than type I carcinoma cells.
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PMID:Demonstration of a possible link between high grade malignancy in dimethylbenz[a]anthracene-induced rat mammary carcinoma and increased urokinase plasminogen activator content. 152 Sep 14

Medroxyprogesterone acetate (MPA), which is widely used clinically as an anticancer steroid preparation, is a very useful drug that seldom causes severe side effects such as bone marrow suppression, and can be dispensed at the outpatient clinic for an oral administration at home to the advantage of QOL. Recently however, there have been several reports suggesting its relationship with thrombosis. We measured t-PA, protein C, factor X, AT III, TAT, plasminogen, PIC, fibrinogen, and D-dimer in 11 patients with gynecologic malignancies who are treated with MPA (600 mg/day) and 11 controls. Then we examined the effects of the drug on blood coagulation and fibrinolytic activities. No changes in these parameters clearly suggested thrombogenesis in either group at this measurement or during the observation period (17 months at the maximum). The present study found no remarkable abnormalities in the blood coagulation and fibrinolytic activities. Thus, to avoid the use of MPA to patients at risk is considered to be the most important precaution for prevention of thrombosis.
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PMID:[Effect of high-dose medroxyprogesterone acetate on coagulative and fibrinolytic factors in patients with gynecological cancers]. 153 83

To investigate the possible involvement of topoisomerases in embryonal differentiation, we examined the effect of topoisomerase inhibitors on the in vitro differentiation of mouse embryonal carcinoma F9 cells. We found that camptothecin, teniposide (VM-26), or genistein, specific inhibitors of topoisomerases, induced morphological as well as biochemical changes (production of tissue plasminogen activator, synthesis of laminin, and disappearance of stage-specific embryonic antigen 1) specific to F9 cell differentiation. Since these changes were indistinguishable from those observed in F9 differentiation induced by retinoic acid (plus dibutyryl cyclic AMP), it was suggested that inhibition of cellular topoisomerase activities triggered F9 cell differentiation into parietal endoderm-like cells in the same manner as retinoic acid (plus dibutyryl cyclic AMP). Experiments using differentiation-resistant mutant F9 cell lines, however, indicated that the molecular cascade involved in topoisomerase inhibitor-induced differentiation involves different steps from those functioning in the retinoic acid-induced differentiation cascade.
Cancer Res 1991 Oct 01
PMID:Induction of in vitro differentiation of mouse embryonal carcinoma (F9) cells by inhibitors of topoisomerases. 168 May 48


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