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 concentrations of cathepsin D (Cath D), urokinase (uPA) and two plasminogen activator inhibitors (PAI-1 and PAI-2) were analysed in the cytosols of 130 human mammary tumours (43 benign tumours and 87 primary and unilateral breast carcinomas). uPA, PAI-1 and PAI-2 levels were measured by antigenic immunoassays and Cath D by immunoradiometric assay. The median levels of the four parameters were significantly higher in the malignant tumours than in the benign ones. Cath D and uPA increases were 4-fold and 5-fold respectively. PAI-1 and PAI-2 increases were much more important, 74-fold and 29-fold respectively. In malignant tumours, median levels of Cath D and uPA did not vary according to classical prognostic factors (histologic grade, presence or absence of axillary lymph nodes, steroid receptors, UICC stage, tumour size, age, and menopausal status). However, PAI-1 decreased in ER+ and PR+ tumours and PAI-2 increased in menopausal women's tumours. When Cath D, uPA, PAI-1 and PAI-2 levels in malignant tumours were compared, positive correlations were found for all combinations. The implication of plasminogen activator inhibitors in the phenomenon was surprising and merits further investigation using tools other than global antigen measurements in tumours.
Br J Cancer 1991 Nov
PMID:Relationship between cathepsin D, urokinase, and plasminogen activator inhibitors in malignant vs benign breast tumours. 193 18

We measured antigen levels of two kinds of plasminogen activators, tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator (UK), as well as their primary inhibitor, type-1 plasminogen activator inhibitor (PAI-1) in the tissue extracts of benign and malignant breast tumors. Tumor tissues of 36 fibroadenomas and 39 breast cancers were examined. t-PA levels were not different in both groups. Malignant tumors contained the significantly higher levels of UK than benign tumors (p less than 0.001). Furthermore in breast cancer tissues, UK antigen levels of tumors with axillary lymph node involvements were significantly higher than those of tumors without lymph node involvements (p less than 0.05). PAI-1 antigen levels of breast cancer tissues were dramatically higher than those of fibroadenoma (p less than 0.001). PAI-1 levels of node positive carcinomas showed also values significantly higher than node negative ones (p less than 0.01). When we divided cancer tissues into three groups as node negative tumors, tumors with positive axillary nodes fewer than four and tumors with four or more positive nodes, PAI-1 levels increased corresponding to the progression of lymph node involvements (p less than 0.05). Immunohistochemical studies, using mouse monoclonal antibodies to human UK and PAI-1, showed that those immunoreactivities were diffusely distributed in the cytoplasm of human breast cancer cells. Their staining patterns were very similar to each other.
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PMID:Increase in levels of plasminogen activator and type-1 plasminogen activator inhibitor in human breast cancer: possible roles in tumor progression and metastasis. 194 23

Neoplastic growth and metastatic spread of adenocarcinomas is characterized by a marked increase of urokinase-type plasminogen activator (u-PA) and a decrease of tissue-type plasminogen activator (t-PA). In this study, the authors determined the activity and antigen levels of u-PA and t-PA, and their inhibitors, plasminogen-activator inhibitors types 1 and 2 (PAI-1 and PAI-2), in normal mucosa, adenomatous polyps, and adenocarcinomas of the human colon. The decrease in t-PA activity in the neoplastic tissues, determined enzymatically and zymographically, was significantly correlated with an increase in PAI-1 and PAI-2, in particular in carcinomas. In spite of significantly higher inhibitor levels in the neoplastic tissues, u-PA was found to be increased as well, both in antigen level and in activity. The authors conclude that PAI-1 and PAI-2 are significantly increased in neoplastic tissue of the human colon and contribute considerably to the decrease of t-PA activity in carcinomas. However, the malignancy-associated increase in u-PA seems not to be affected by the plasminogen activator inhibitors. Thus, it appears that there is an imbalance between plasminogen activators and their inhibitors in colonic neoplasia in favor of u-PA, which may contribute to plasmin-mediated growth, invasiveness, and metastasis. This feature was also noticed in adenomatous polyps, supporting the malignant potency of adenomas.
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PMID:Imbalance of plasminogen activators and their inhibitors in human colorectal neoplasia. Implications of urokinase in colorectal carcinogenesis. 195 18

Acute respiratory failure (ARF) in an 11-year-old child with pre-T acute lymphoblastic leukemia (ALL) at the beginning of induction therapy was observed, connected with a pulmonary thrombosis and not with an infective origin. A systematic search for this pathology identified six other children with the same pulmonary complication, five of whom where in the early phase of acute nonlymphoblastic leukemia (ANLL) and one in induction therapy for ALL in marrow relapse. At the beginning of the symptomatology, all children presented severe hypoxia and hypercapnia, with no or minimal chest radiograph abnormalities and no clear hemodynamic involvement. In all patients the arteriography and nuclear imaging studies confirmed the diagnosis. The causes of the thrombi could be connected with neoplastic emboli after cell lysis and/or with the vascular damage resulting from antiblastic therapy. Intravenous urokinase treatment and respiratory assistance had been successfully carried out in six of seven children.
Cancer 1991 Feb 01
PMID:Acute respiratory failure and pulmonary thrombosis in leukemic children. 198 61

Nude mice given inoculations s.c. of a human squamous carcinoma--HEp3 (1.5 x 10(6) cells/mouse)--developed invasive tumors that produced high levels of urokinase-type plasminogen activator (uPA) and metastasized predictably to the lungs and lymph nodes of the host. To investigate the role of uPA in invasion and metastasis, mice given inoculations of tumor cells were treated daily with s.c. injections of specific, anti-human uPA antibodies (rabbit polyclonal, 150 inhibitory units; mouse monoclonal, 3000 inhibitory units/mouse/day). Control mice received either saline or preimmune rabbit immunoglobulins. A total of approximately 50 mice was studied. The tumors were surgically excised 10 to 17 days postinoculation when weighing 1 to 2 g. Antibody administration was discontinued after tumor excision. Two strategies were used: (a) following the removal of tumors the mice were maintained and observed until respiratory distress, indicative of lung metastasis, was evident; or (b) their lungs were examined for evidence of metastasis on the day of tumor removal. While histological sections of s.c. tumors excised from control mice indicated extensive local invasion, evidence of invasion was absent in most tumors excised from mice in which tumor uPA was inhibited by the antibody (P less than 0.025). The inhibition of local invasion did not, however, lead to a reduced incidence of distant metastasis. Since we found that the presence of HEp3 tumors in mice elicits a pronounced granulocytosis, we propose that this response may facilitate the spread of tumor cells by a mechanism independent of endogenous tumor proteases.
Cancer Res 1991 Jan 01
PMID:Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse. 198 89

Three hundred and forty-four patients with operable colorectal adenocarcinoma, Dukes' stage B or C, were entered into a randomized controlled trial of intraoperative and postoperative intravenous urokinase and/or long-term sodium warfarin therapy. The factorial design of the trial allowed evaluation of each therapy separately. Age, sex, Dukes' stage and cancer site were similar in the treatment groups. Using life-table methods, survival and recurrence/metastases free survival were estimated up to 6 years postoperatively. No significant effects of either therapy on these endpoints were found.
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PMID:The first international urokinase/warfarin trial in colorectal cancer. 201 15

The capacity of solid tumours to invade the surrounding tissue and to metastasize, is correlated with the formation and degradation of structural elements in the vicinity of the tumour cells. Substances with both procoagulant activity and fibrinolytic activity are important factors in the formation or degradation of a "fibrin-fibronectin-gel matrix". This gel is subsequently transformed into the extracellular matrix, which, together with cells, will form the tumour stroma. When analyzing tumour stroma degradation products, it is obvious that the protease plasmin catalyses the disintegration of fibrin and fibronectin. Additional compounds of the tumour stroma and of the basal membrane are also, at least in part, broken down by plasmin or other proteases, such as collagenase IV and cathepsin D. The plasminogen activator urokinase (uPA) seems to play a central role as it was shown that elevated content of uPA is correlated with a high risk of early relapse and shorter overall survival, at least in breast cancer. It has been shown, that by means of quantifying uPA, patients with a relative high or low risk can even be selected within the classical risk groups, which so far are defined by the locoregional extension of the tumour and the hormone receptor status only. Evidently, as uPA content in human breast cancer tissue is an independent prognostic factor, one may speculate, that those experimental or in vitro data, which correlated increase in uPA-synthesis with malignancy, may be of direct relevance for human tumour biology. Moreover, due to these recent observations on the prognostic significance of tumour-associated proteases, new aspects for the selection of risk collectives within the node-negative breast cancer patients for adjuvant therapy have to be considered. It may well be possible, that one may affect tumour invasion and metastasis by inhibiting protease action of solid tumours by disturbing the binding of proteases to tumour cell surface receptors. As it is only a quantitative aspect, which separates benign physiological processes from tumour cell pathophysiology, experimental evidence suggests, that less drastic forms of palliative therapy can be proposed.
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PMID:[Clinical and prognostic significance of tumor-associated proteases in gynecologic oncology]. 204 Apr 18

The highly specific plasminogen activator inhibitor of placental type, PAI-2, occurs in the placenta in a low molecular mass form of 46.6 kDa, and in pregnancy plasma in a (possibly glycosylated) high molecular mass form of 60 kDa. Extensive knowledge is available about the functional properties of PAI-2 as a plasminogen activator inhibitor and about its molecular biology and regulation. Of the several placenta proteins (PP) isolated, one of them, PP10, has a molecular mass of 48 kDa and its occurrence in malignancy and in complications during pregnancy has been the topic of a number of studies, though its properties and physiological significance are unknown. The present findings constitute evidence of immunological identity between PP10 and PAI-2. The sections of the amino acid sequence of PP10 analysed here were found to have identical counterparts in the sequence of the low molecular mass form of PA1-2, but in several preparations PP10 was found to occur in an inactive two-chain form due to cleavage of an Arg-Thr bond, the two peptide chains being linked to each other by a disulphide bridge. The cleavage site is identical to that observed in the reaction between PAI-2 and urokinase. The results make it possible to coordinate and correlate the findings of many separate studies and our own observations on PP10 and PAI-2.
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PMID:Identity between the placental protein PP10 and the specific plasminogen activator inhibitor of placental type PAI-2. 204 83

Malignant tumors are generally characterized by extensive local tissue invasion and destruction of ECM which may be due to increased constitutive expression and activity of secreted proteases. Moreover, a large number of diverse protease activities may be constitutively over-expressed in a simultaneous or co-ordinated fashion, thereby significantly increasing cellular invasive potential of the cells. To explore this relationship, we have measured steady-state levels of mRNA coding for urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), transin and tissue-specific inhibitor of metalloproteinases (TIMP); as well as gelatinolytic, caseinolytic and plasminogen activator activities secreted by SPI, a non-metastatic mouse mammary carcinoma cell line and 4 metastatic sublines derived from it. mRNA encoding metalloproteinase transin was increased 15- to 20-fold, while TIMP transcripts were decreased 3-fold in the metastatic sublines compared to parental SPI tumor cells. Metastatic sublines secreted higher levels of gelatinase (i.e., 92 kDa and 64 kDa) as well as proteases with caseinolytic activity (i.e., 115 kDa and 57 kDa) when compared with SPI cells. Moreover, these enzymes were identified as neutral metalloproteinases. Although the amount of uPA mRNA appeared to be the same in SPI and the metastatic sublines, the latter secreted 1.5-3 times more uPA activity into the culture supernatants. Metastatic competence in the SPI tumor model is therefore associated with increased secretion of several metalloproteinase activities and uPA, as well as decreased TIMP expression, consistent with a more invasive phenotype.
Int J Cancer 1991 Jun 19
PMID:Constitutive expression and secretion of proteases in non-metastatic SP1 mammary carcinoma cells and its metastatic sublines. 204

Determination of FDP D-dimer (D-dimer) has been recently developed for the diagnosis of thrombotic diseases with secondary fibrinolysis. We have studied the correlation between D-dimer and FDP-E concentrations in plasma from 282 patients with 630 samples. A linear correlation (r = 0.9269) was observed between the values of FDP-E and D-dimer. However, 13 out of 282 cases revealed an apparent dissociation of D-dimer concentrations from FDP-E values. Among them, 4 of these 13 cases (Group A) have shown to possess higher level of D-dimer when compared with the expected values from FDP-E, while 9 of 13 cases (Group B) revealed lower levels of D-dimer than that expected from FDP-E. All of Group A patients have been diagnosed as disseminated intravascular coagulation (DIC). On the other hand, in Group B patients, 6 of 9 were shown to have a widespread metastasis of cancer and 2 of them were under treatment with urokinase. To study whether Group B patients were under hypercoagulable or hyper-fibrinolytic state, we have examined ratios of AT III/alpha 2 PI and PIC/TAT in these cases. It has been shown that 4 of 9 patients in Group B have higher ratios of both AT III/alpha 2 PI and PIC/TAT if compared with other patients than Group B. This suggests that patients in Group B have been under hyper-fibrinolytic states.
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PMID:[Study on cases of D dimer values were dissociated from FDP-E]. 205 6


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