Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin can be formed in the tumor cell microenvironment following activation of the clotting cascade by procoagulants of cancer or host cells. We have tested here the effects of thrombin, either "endogenous" or "exogenous" (see below), on arachidonate mobilization from membrane phospholipids of mouse mammary tumor virus-induced (MMTV) carcinoma cells. These tumor cells exhibit in vitro a tissue type procoagulant activity (130 thromboplastin units/10(4) cells) and are therefore able to induce thrombin formation in a plasmatic milieu. To verify the effect of thrombin formation by tumor cell procoagulant ("endogenous thrombin"), either human or mouse platelet-free plasma (20% in DMEM) was added to the cell layer (prelabelled for 5 hr with a trace amount (0.013 microM) of 3H-arachidonate) and the system was recalcified (15 mM CaCl2). Thin-layer radiochromatography of the culture medium showed a significant release of 3H-labelled arachidonate products PGE2, PGF2 alpha and 6-ketoPGF1 alpha after 1 hr of incubation. To verify the effect of thrombin formation from host sources ("exogenous thrombin"), either bovine or purified human alpha-thrombin (0.1-10 U/ml) was added to the cells for different periods (from 5 min to 20 hr). Exogenous thrombin stimulated arachidonate release and metabolism in a dose-related manner. With short labelling periods (0.013 microM 3H-arachidonate for 30 min-1 hr) thrombin stimulated the release of unmetabolized 3H-arachidonate, but not of 3H-arachidonate metabolites. These processes were inhibited by a specific inhibitor of thrombin enzymatic activity (alpha-NAPAP, 140 microM) and by a cyclo-oxygenase inhibitor (ASA 4mM). Tumor-associated procoagulants may thus contribute not only to fibrin deposition but also to generation of multipotent mediators such as arachidonate metabolites.
Int J Cancer 1987 Mar 15
PMID:Thrombin stimulates arachidonate metabolism in murine tumor cells. 310 91

The human myelomonocytic cell line RC2a expressed procoagulant activity following stimulation with human lymphokine (LK) prepared by stimulating peripheral blood mononuclear cells with either mitogens (Concanavalin A, phytohaemagglutinin or antigen (tuberculin). Induction was rapid, with optimal activity observed between 6 and 8 h, was decreased in cultures containing serum and was not inhibited by actinomycin D or cycloheximide. The LK activity was not inhibited by an anti-interferon gamma (IFN gamma) antibody. IFN gamma and phorbol myristate acetate (PMA) had no activity but acted in synergy to induce procoagulant expression; interferon alpha plus PMA were without effect. In contrast to the LK-induced response, procoagulant induced by IFN gamma/PMA was not detected for up to 8 h and steadily rose over 24-48 h culture and was dependent on new protein and RNA synthesis. Bacterial lipopolysaccharide, a potent inducer of thromboplastin on normal human monocytes, failed, either alone or in combination with LK, IFN gamma, PMA or IFN gamma plus PMA, to activate procoagulant expression on RC2a cells. Both LK and IFN gamma/PMA-induced procoagulant had properties of thromboplastin expressed both intracellularly and on intact, viable cells. This study shows that RC2a cells are responsive to factors produced as the result of an activated cell-mediated immune response which may therefore contribute to the coagulopathies common to this form of malignancy.
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PMID:Procoagulant induction by human lymphokine and interferon gamma/PMA on a myelomonocytic cell line, RC2a. 314 14

No previous studies on the possible contribution of cancer-cell procoagulants to metastasis have fulfilled all the criteria for attaining biologically relevant and readily interpretable data (Grimstad et al., 1986), viz: (1) Spontaneous metastasis from primary tumors should be assessed in syngeneic animals; (2) cloned cell lines should be used to correlate cell properties, because heterogeneity within the cell lines employed is a source of serious error; (3) enough clones, derived from the same original tumor, should be used to identify only nonrandom correlations. Observing these criteria, we examined the procoagulant activities of 19 murine fibrosarcoma cell clones and 4 uncloned cell lines with high to moderate or low potential for lung metastases formation. The procoagulant activity found was exclusively of the thromboplastin (tissue factor, factor III) type. It occurred in all cell homogenates, but the quantities did not correlate with metastatic potential. In contrast, all highly to moderately metastatic cell clones and lines from 2 different fibrosarcomas shed thromboplastin activity into the culture medium, whereas no weakly metastatic cells did. Histological examination further supported these indications that release of thromboplastin from cancer cells can promote metastasis by initiating blood clotting and thereby facilitating arrest of the cancer cells in target organ vessels. Examination of a third fibrosarcoma showed that release of thromboplastin activity is not necessary for metastasis in all tumors.
Int J Cancer 1988 Mar 15
PMID:Thromboplastin release, but not content, correlates with spontaneous metastasis of cancer cells. 334 8

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.
Cancer Res 1988 Oct 01
PMID:Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer. 341 10

The ability of malignant tissue from 50 patients with colorectal carcinoma to activate blood coagulation factor X directly was compared with samples of adjacent, macroscopically normal colonic mucosa from the same patients, and tissue from four patients with non-malignant bowel disease. The resected tissue was homogenized and incubated with purified factor X and calcium ions. The subsequent generation of activated factor X was measured spectrophotometrically with a chromogenic substrate. Results were expressed as absorbance units, and as the ratio of tumour and normal activities. Factor X-activating activity (FXAA) was present in all normal and malignant tissues tested. FXAA was significantly greater (P less than 0.001) in the tumour homogenates than in the uninvolved tissue. The tumour:normal ratio was significantly (greater than 1.2) elevated in 38 patients (76 per cent). FXAA was not correlated with the degree of differentiation of the tumour, the Dukes' classification of the disease or the exact site of the tumour. There was no difference between the FXAA content of non-involved tissue from the colorectal cancer group and colonic mucosa from patients with non-malignant bowel disease. It is concluded that colorectal carcinomas contain significantly more FXAA than adjacent, non-malignant colonic mucosa from the same subject, but there is no direct evidence for a relationship between procoagulant levels and the extent of malignancy in these patients.
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PMID:Factor X-activating activity in patients with colorectal carcinoma. 342 59

We have analyzed the CM of 20 human tumor cell lines for the presence of PA, PA-I and PC. Most of the cell lines expressed PA activity as measured by a radioiodinated fibrin plate assay. The urinary type and tissue-type PA activities were specifically quantified by means of purified inhibitory antibodies. U-PA and/or t-PA antigen, as measured by radioimmunoassays, were detected in all but 4 of the CM and were generally 10 times more concentrated than PA activity, indicating the presence of specific PA-Is. Analysis of CM by electrophoresis followed by fibrin-agarose zymography demonstrated the presence not only of free but also of inhibitor-complexed PA. Affinity purification demonstrated that 8/20 cell lines expressed detectable PA-I activity. The PA-I1 and PA-I2 inhibitors were most frequently observed, while PN was recovered only from CM of the HT1080 fibrosarcoma cell line. PC activity, as measured by the plasma recalcification time method, was found in 9/20 CM. It was of the thromboplastin tissue factor type since most of its activity was lost when assayed with a Factor VII-deficient plasma.
Int J Cancer 1986 Nov 15
PMID:Plasminogen activators, plasminogen activator inhibitors and procoagulant analyzed in twenty human tumor cell lines. 349 Apr 46

Among 617 hospitalized patients who started long-term anticoagulant therapy, major bleeding developed before discharge in 28 (5 percent) and minor bleeding in another 38 (6 percent), with daily incidence rates of 0.4 and 0.5 percent, respectively. The most common site of bleeding was gastrointestinal, and one patient died from bleeding. Four independent risk factors for major in-hospital bleeding were identified and weighted using multivariate discriminant analysis in a randomly chosen group of 411 patients: co-morbid conditions other than the indication for anticoagulant therapy (specific signs of heart, liver, or kidney dysfunction, cancer, and severe anemia); the use of heparin to begin therapy in patients age 60 years or older; the intensity of therapy (measured by the maximal prothrombin time or partial thromboplastin time); and liver dysfunction that worsened during treatment. These findings were validated in an independent testing group of 206 patients; the risk factors identified 151 patients at low (1 percent) risk of major bleeding, 33 at moderate (6 percent) risk, and 22 at high (23 percent) risk. The accuracy and clinical impact of this prediction rule should be evaluated further in other hospitals.
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PMID:Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy. 349 97

It has repeatedly been proposed that fibrin plays a role in tumor growth and metastasis. Among tumor cell products or activities which may promote clot formation, cancer procoagulant (CP), a direct activator of coagulation factor X, has been suggested to be selectively associated with the malignant phenotype. We report here the enzymatic and immunological identification of this cysteine proteinase procoagulant in extracts and cells from human melanoma. CP activity was independent of both the intrinsic and extrinsic pathways of blood coagulation, using factor IX and factor VII deficient plasmas, and was inhibited by the cysteine proteinase inhibitors iodoacetamide and HgCl2. CP activity was detectable in extracts and cell suspensions from all 32 patients studied and was higher in extracts from metastases (14.8 +/- 3.9 units/mg protein) than from the primary tumors (3.7 +/- 1.0 units/mg protein). CP activity was not affected by an anti-apoprotein III antibody or by concanavalin A, a known inhibitor of thromboplastin. In contrast, no CP activity or antigen was detected in extracts from six benign melanocytic lesions. The procoagulant activity was dependent on factor VII and was inhibited by anti-apoprotein III antibody and by concanavalin A, properties that suggest that the procoagulant was tissue thromboplastin. These data indicate that CP can be expressed by human tumor cells and that, among melanotic lesions, its presence is associated with the malignant phenotype and its activity is particularly high in metastatic cells.
Cancer Res 1986 Dec
PMID:Cancer procoagulant in human tumor cells: evidence from melanoma patients. 353 81

Mouse Lewis lung (LL) carcinoma cells possess a factor X activator (procoagulant) that is inhibited in vivo by warfarin treatment or diet-induced vitamin K deficiency. This inhibition suggests that vitamin-K-dependent proteins are involved in LL cell activation of factor X. A LL primary tumor clone (LL13) was isolated which contained a warfarin-sensitive vitamin-K cycle of metabolism and expressed factor X procoagulant activity. LL13 cells exposed to media containing warfarin or deficient in vitamin K grew as well as cells in normal media, and activated factor X to similar extents. In contrast, administration of warfarin to mice bearing LL13 cells inhibited factor X procoagulant activity as well as the vitamin K cycle of metabolism in the primary tumors. In relation to LL13 cells grown in media containing fetal bovine serum, those incubated for 20 hr in media containing mouse serum or the sera from LL13-bearing mice exhibited 9- to 10-times higher levels of factor X procoagulant activity. However, LL13 cells exposed to media containing the sera of warfarin-treated LL-13-bearing mice or to barium-sulfate-adsorbed normal mouse serum activated factor X much less efficiently. Collectively, these data suggest that inhibition of vitamin K function in LL cells does not affect the extent of factor X activation and thus the intrinsic factor X procoagulant is not a vitamin-K-dependent protein. They further suggest that both a warfarin-sensitive (vitamin-K-dependent) protein present in normal mouse serum and a LL13 cell component participate in factor X procoagulant activity.
Int J Cancer 1987 May 15
PMID:Evidence for a warfarin-sensitive serum factor that participates in factor X activation by Lewis lung tumor cells. 357 May 55

Heparin was measured, with respect to standard curves prepared with normal pooled plasma, by five methods (APTT, thrombin time, one and two stage coagulation, anti-factor Xa and chromogenic anti-factor Xa) after addition at three concentrations to plasmaprepared from normal young volunteers, hospitalized patients with malignancy and geriatric patients. By the APTT and TT, differences in sensitivity were observed at 0.4iu heparin/ml corresponding to an apparent difference in heparin level of 10 and 14 fold between high and low responding individuals. Such large differences were not apparent by anti-factor Xa assay. A circadian difference in sensitivity was also observed in the patient group such that in samples taken at night, heparin levels were 30-50% higher on average when measured in the APTT and TT. Again, such large differences were not apparent by anti-factor Xa methods. In light of recent findings about the usefulness of anti-factor Xa methods for efficient monitoring of heparin, it is suggested that this conclusion may arise from the tendency for anti-factor Xa methods to determine actual concentrations of heparin.
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PMID:Measurement of heparin in plasma: influence of inter-subject and circadian variability in heparin sensitivity according to method. 360 35


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