Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The coagulation and fibrinolysis profile was evaluated in 40 patients with newly diagnosed untreated colorectal carcinoma (24 males, 16 females; 29 patients without and 11 patients with metastases). Fibrinogen, von Willebrand factor antigen, FVIII:C, thrombin-antithrombin III complex (TAT III), fibrin monomers (FM), plasminogen activator inhibitor-1 (PAI-1) and D-dimers were tested. None of the patients had clinical or laboratory evidence of serious hemorrhage or thrombosis. The results of global routine coagulation tests (aPTT, PT) were not significantly changed. Significant elevations were found for median fibrinogen, von Willebrand factor antigen, FVIII:C, TAT III and D-dimers, compared with a healthy reference group. These results confirm earlier reports of an enhanced level of both coagulation and fibrinolysis markers in carcinoma patients and might be helpful in trying to understand the impact of several relatively new sensitive coagulation and fibrinolysis parameters in colorectal cancer. Moreover the position of the coagulation/fibrinolysis balance might be an explanation for the elevated incidence of thrombotic events in patients with cancer.
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PMID:Evaluation of the coagulation/fibrinolysis balance in patients with colorectal cancer. 827 20

The efficacy of transarterial immuno-embolization therapy (TIE) was examined in six operable patients with hepatocellular carcinoma (HCC). We administered OK-432, fibrinogen (30 mg/ml) and thrombin (1 U/ml) through a catheter which was inserted into the tumor-feeding artery. In all patients with a high level of tumor markers (AFP and PIVKA-II), the level decreased promptly to less than the pretreatment level after TIE therapy. The therapy has not caused any serious side effects. No disturbance of the coagulation-fibrinolysis system due to TIE was observed in any patient. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells around tumor cell nests, and lytic necrosis as well as coagulation necrosis of the main tumor and the intrahepatic metastases. Our results indicate that TIE may be an effective and promising modality for HCC patients.
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PMID:[Efficacy of transarterial immuno-embolization therapy (TIE) in operable patients with hepatocellular carcinoma]. 839 97

The purpose of this study was to evaluate whether or not, using sensitive analytical methods for the measurement of coagulation and fibrinolysis enzyme activity, there was a hypercoagulable state in patients with melanoma, and whether differences existed between those with or without metastases. Seventy-one patients were studied, 45 with localized tumors (stages Ia and Ib) and 26 with metastases (stages II-IV). Plasma level of activated factor VII, prothrombin fragment 1 + 2, thrombin-antithrombin complex, fibrinopeptide A, plasmin-antiplasmin complex and D-dimer were much higher in the whole group of 71 patients than in 45 controls with benign nevi. However, when melanoma patients with or without metastases were compared, there were smaller differences, with only thrombin-antithrombin complex, plasmin-antiplasmin and D-dimer significantly higher in metastatic melanoma. These results indicate that in patients carrying a tumor endowed with high procoagulant activity in vitro, there is a laboratory picture of hypercoagulability with secondary hyperfibrinolysis in vivo. However, differences between patients with localized and metastatic tumors for markers of hypercoagulability are not striking, in spite of the fact that metastatic cells support greater coagulant activity than primary cells in vitro.
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PMID:Hypercoagulability and hyperfibrinolysis in patients with melanoma. 892 92

In patients affected with different tumours, disorders concerning clotting are frequently observed. The biological processes leading to coagulation are probably involved in the mechanisms of metastasis. We studied plasma levels of thrombin-antithrombin III complexes (TAT) in 90 patients affected with lung tumours subgrouped in small cell and non-small cell (NSC) lung cancer: 17 patients had no evidence of disease after surgery (NE); the remaining 73 patients were divided according to the absence (LOC) or the presence (META) of metastases. All the patients were followed up for several months. In all the lung cancer patient groups, at the beginning of the study we detected TAT levels that were higher than in controls. During the follow-up period, the NSC-NE patients with no recurrence of the disease as well as the NSC-LOC patients responding to the treatment had a decrease in TAT levels (p < 0.01 and p < 0.05, respectively). The NSC-META patients with progression of their disease had, in contrast, an increase in TAT levels (p < 0.01). Our data reveal the presence of 'latent coagulation disorders' as assessed by the presence of high TAT levels in the majority of lung cancer patients. The follow-up study indicates that in the NSC group, a relation exists between coagulation activation and rate of tumour progression and/or response to treatment. In cancer patients the early detection of coagulation disorders could also allow, therefore, the prevention of thromboembolism and/or haemorrhage by administration of appropriate treatment.
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PMID:Plasma thrombin-antithrombin complexes, latent coagulation disorders and metastatic spread in lung cancer: a longitudinal study. 896 Jan 40

Platelet agonists are known to contribute to the regulation of cytoplasmic Ca2+ levels in tumor cells and this property could be relevant in the stimulation of cell proliferation. In the present study we investigated the ability of ADP, collagen and thrombin to increase cytoplasmic Ca2+ levels in different human tumor cell lines (mesothelioma, DND-1A melanoma, HeLa uterine carcinoma) and we analyzed the effect of the calcium channel blocker verapamil on Ca2+ fluxes and on in vitro tumor cell growth. ADP was able to induce a transient increase in the cytoplasmic Ca2+ concentration in tumor cells from all lines; collagen showed this effect in mesothelioma cells and in HeLa cells, and thrombin was effective only in mesothelioma cells. Verapamil inhibited Ca2+ fluxes induced by the effective agonists in a dose-dependent manner. Values of IC50 for inhibition of ADP-induced Ca2+ transients were 63.5 microM in mesothelioma cells, 97.3 microM in DND-1A cells and 93.5 microM in HeLa cells, while those for inhibition of collagen-induced Ca2+ movements were slightly higher (170.2 microM in mesothelioma cells and 112.3 microM in HeLa cells) and the value of IC50 for inhibition of thrombin-induced Ca2+ fluxes (evaluated only in mesothelioma cells) was lower (22.5 microM). The drug dose-dependently also inhibited the in vitro growth of tumor cells; values of IC50 for growth inhibition were 21.8 microM in mesothelioma cells, 9.1 microM in DND-1A cells and 6.4 microM in HeLa cells, suggesting that the antiproliferative activity of verapamil was partly Ca(2+)-independent. These data may be of interest to elucidate the mechanisms of the two-way interactions of tumors with the hemostatic system and may help to identify new pharmacologic strategies for their control.
Invasion Metastasis 1996
PMID:Verapamil inhibits to different extents agonist-induced Ca2+ transients in human tumor cells and in vitro tumor cell growth. 903 Feb 40

In 49 patients with benign prostatic hyperplasia, 24 metastatic prostatic carcinoma patients all under palliative hormonal treatment, 17 untreated prostatic carcinoma patients without metastases and 14 untreated prostatic carcinoma patients with metastases, plasma levels of thrombin-antithrombin III complex, D-dimer and plasmin-alpha2-antiplasmin were determined. The coagulation activation marker thrombin-antithrombin III complex did not show any significant difference between the different patient groups. Of the fibrinolysis markers, D-dimer levels were elevated in both metastatic groups compared to the non-metastatic group and the benign prostatic hyperplasia group. Surprisingly, the levels of the other fibrinolysis marker, plasmin-alpha2-antiplasmin, showed no significant difference. The nature of these findings is discussed and related to other relevant literature. The general conclusion is that fibrinolysis may not play such a prominent role in prostatic carcinoma as described and expected.
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PMID:Coagulation and fibrinolysis activation markers in prostatic carcinoma patients. 905 45

Platelets and coagulation are involved in the pathogenesis of blood-borne metastases. The aim of this study is to obtain more information about the mechanisms involved in the initial adhesion of tumor cells to endothelial cells. In short term experiments with tumor cells, suspended in the medium of cultured endothelial cells, we tested whether addition of both platelets and thrombin cause more tumor cell adhesion to endothelial cells, than when either platelets or thrombin are acting alone. HeLa cells or HT29 cells, prelabeled with radioactive 51Cr, human platelets, and thrombin were added to human endothelial cell cultures. Following 15 min of shaking at 37 degrees C, the percentage of tumor cell adhesion was calculated. The percentages of adhering tumor cells with the presence of both platelets and thrombin were greatly increased compared to controls. Addition of hirudin 2 min before thrombin lowered the adhesion percentage of tumor cells. Hirudin added immediately before and 2 min after thrombin gave only minor effects. When the endothelium was treated with superoxide dismutase, catalase, and mannitol, the adhesion of tumor cells was lowered with catalase and superoxide dismutase. The cause of tumor cell-endothelial cell interaction is probably complex. Our results show that activated platelets enhance the tumor cell adhesion, and that generation of active oxygen species may be important in the initial phase of the interaction.
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PMID:Addition of both platelets and thrombin in combination accelerates tumor cells to adhere to endothelial cells in vitro. 911 26

We evaluated the in vivo anti-metastatic activity of recombinant Ancylostoma caninum Anticoagulant Peptide (rAcAP), a potent (Ki = 265 pM) and specific active site inhibitor of human coagulation factor Xa originally isolated from bloodfeeding hookworms. Subcutaneous injection of SCID mice with rAcAP (0.01-0.2 mg/mouse) prior to tail vein injection of LOX human melanoma cells resulted in a dose dependent reduction in pulmonary metastases. In order to elucidate potential mechanisms of rAcAP's anti-metastatic activity, experiments were carried out to identify specific interactions between factor Xa and LOX. Binding of biotinylated factor Xa to LOX monolayers was both specific and saturable (Kd = 15 nM). Competition experiments using antibodies to previously identified factor Xa binding proteins, including factor V/Va, effector cell protease receptor-1, and tissue factor pathway inhibitor failed to implicate any of these molecules as significant binding sites for Factor Xa. Functional prothrombinase activity was also supported by LOX, with a half maximal rate of thrombin generation detected at a factor Xa concentration of 2.4 nM. Additional competition experiments using an excess of either rAcAP or active site blocked factor Xa (EGR-Xa) revealed that most of the total factor Xa binding to LOX is mediated via interaction with the enzyme's active site, predicting that the vast majority of cell-associated factor Xa does not participate directly in thrombin generation. In addition to establishing two distinct mechanisms of factor Xa binding to melanoma, these data raise the possibility that rAcAP's antimetastatic effect in vivo might involve novel non-coagulant pathways, perhaps via inhibition of active-site mediated interactions between factor Xa and tumor cells.
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PMID:Ancylostoma caninum anticoagulant peptide blocks metastasis in vivo and inhibits factor Xa binding to melanoma cells in vitro. 960 44

The human ovarian cancer cell line OV-MZ-19, established from a patient with cystadenocarcinoma of the ovary, expressing thrombomodulin (TM), a cell surface receptor for the serine protease thrombin, interacts with monoclonal and polyclonal antibodies having different specificity for TM. These antibodies detect TM antigen by means of flow cytofluorometry, laser scanning microscopy, immunocytochemistry, and ELISA. Therefore a highly sensitive ELISA for TM antigen was established using two different monoclonal antibodies to quantify TM in tissue extracts and biological fluids, e.g. peritoneal malignant ascites. Primary malignant ovarian tumors and metastases of the omentum and intestine contain TM antigen as determined by ELISA but in significantly lower concentrations than benign ovarian tumors (p=0.0056). In contrast, malignant ascitic fluid of patients with advanced ovarian cancer (FIGO IIIc) contain significantly elevated concentrations of soluble TM than benign peritoneal exudates (p=0.0003). Immunoaffinity purified ascites-derived TM efficiently activates protein C. Protein C activation of ascites-derived TM as well as TM expressed by the tumor cells is inhibited by the monoclonal antibodies. TM abrogates the procoagulant activity of thrombin, reduces pericellular thrombin via internalization, accelerates the thrombin-mediated inactivation of pro-uPA, and the EGF domains of TM exhibit mitogenic activity towards fibroblasts and tumor cells. Both, thrombin and pro-uPA play important roles in tumor invasion and metastasis. Therefore, downregulation and/or release of TM into ascitic fluid may play an important role in the malignant behavior of tumor cells.
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PMID:Thrombomodulin, a receptor for the serine protease thrombin, is decreased in primary tumors and metastases but increased in ascitic fluids of patients with advanced ovarian cancer FIGO IIIc. 973 90

Thrombin-treated tumor cells induce a metastatic phenotype in experimental pulmonary murine metastasis. Thrombin binds to a unique protease-activated receptor (PAR-1) that requires N-terminal proteolytic cleavage for activation by its tethered end. A 14-mer thrombin receptor activation peptide (TRAP) of the tethered end induces the same cellular changes as thrombin. Four murine tumor cells (Lewis lung, CT26 colon CA, B16F10 melanoma, and CCL163 fibroblasts) contain PAR-1, as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). B16F10 cells did not contain the two other thrombin receptors, PAR-3 and glycoprotein Ib. TRAP-treated B16F10 tumor cells enhance pulmonary metastasis 41- to 48-fold (n = 17). Thrombin-treated B16F10 cells transfected with full-length murine PAR-1 sense cDNA (S6, S7, S14, and S22) enhanced their adhesion to fibronectin 1.5- to 2.4-fold (n = 5, P <.04), whereas thrombin-treated wild-type cells do not. S6 (adhesion index, 1.5-fold) and S14 (index, 2.4-fold) when examined by RT-PCR and Northern analysis showed minimal expression of PAR-1 for S6 over wild-type and considerable expression for S14. Immunohistochemistry showed greater expression of PAR-1 for S14 compared with wild-type or empty-plasmid transfected cells. In vivo experiments with the thrombin-treated S14 transfectant showed a fivefold to sixfold increase in metastases compared with empty-plasmid transfected thrombin-treated naive cells or S6 cells (n = 20, P =.0001 to .02). Antisense had no effect on thrombin-stimulated tumor mass. Thus, PAR-1 ligation and expression enhances and regulates tumor metastasis.
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PMID:Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. 980 63


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