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

The role of platelets in cancer metastasis was studied by investigating the effects of the antiplatelet agents ticlopidine, diltiazem, dipyridamole and trapidil on artificial and spontaneous pulmonary metastases in mice. These agents were tested at their optimal inhibitory doses on adenosine diphosphate-induced platelet aggregation; namely, 100 mg/kg for ticlopidine, 2 mg/kg for diltiazem, 180 mg/kg for trapidil and 60 mg/kg for dipyridamole. At these doses, trapidil caused moderate inhibition of thrombin-induced platelet aggregation in mice, but the other agents had only slight effects. Artificial pulmonary metastasis was produced by inoculation of Lewis lung carcinoma (LLC) or B16 melanoma (B16) cells into C57BL/6 mice. For induction of spontaneous pulmonary metastases, these tumor cells were implanted subcutaneously into the footpads of mice. The resulting primary tumors of LLC and B16 were removed 9-10 and 17 days later, respectively. Artificial pulmonary metastases were inhibited significantly by all the antiplatelet agents tested. Spontaneous pulmonary metastases were markedly reduced only when these agents were given after removal of the primary tumor. The role of platelets is discussed with respect to thrombus formation in the lodgement of tumor cells and the participation of platelet-derived growth factor in the growth of metastatic foci.
 ...
PMID:Effects of antiplatelet agents on pulmonary metastases. 672 29

We performed coagulation studies in 16 patients with advanced neuroblastoma. Four of these patients had major hemorrhagic or thromboembolic complications. Abnormal coagulation screening tests were seen in all patients with active metastatic disease. We also measured plasma fibrinopeptide A, a sensitive measure of intravascular thrombin generation. Increased concentrations of fibrinopeptide A were found in each patient studied with active metastatic disease. Coagulopathy is a frequent finding in metastatic neuroblastoma and may cause severe morbidity. Laboratory studies suggesting either hyper- or hypocoagulability are frequent findings.
 ...
PMID:Coagulopathy of disseminated neuroblastoma. 687 12

Microangiopathic hemolytic anemia and thrombocytopenia secondary to disseminated intravascular coagulation is a well-described complication of widely metastatic carcinoma. The authors report four cases of gastric carcinoma, one case of colon cancer, and one case of adenocarcinoma of unknown primary in which the patient developed a syndrome analogous to thrombotic thrombocytopenic purpura, consisting of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure without definite evidence of disseminated intravascular coagulation. In contrast to previous reports, postmortem examination in three of the cases revealed no recurrence or only microscopic foci of residual tumor. In the remaining three, there was clinical and pathologic evidence of grossly disseminated carcinoma. Also in contrast to previous cases, all patients evidenced azotemia and proteinuria at the onset of the syndrome and ultimately uremia was a contributing cause of death. Coagulation profiles showed prolonged thrombin times and elevated fibrin degradation products in four instances and did not distinguish the patients with grossly metastatic disease from those with no tumor or only microscopic residua. Circulating immune complexes containing carcinoembryonic antigen were found in the patient with metastatic colon carcinoma. The syndrome was clinically identical whether or not grossly metastatic tumor was present, and it should not be attributed to advanced disease without definite clinical or pathologic evidence of a recurrence.
 ...
PMID:Microangiopathic hemolytic anemia, thrombocytopenia, and renal failure in patients treated for adenocarcinoma. 728 73

Platelets are required for certain experimental metastases. Several lines of animal tumor cells aggregate platelets in vitro and in vivo. Previous studies with one of these lines, an SV40-transformed 3T3 mouse fibroblast (SV3T3) have revealed that the platelet-aggregating material is an extractable membrane-associated sialolipoprotein which requires divalent cation, complement, and a heat-stable plasma component for activity. Little information is available on the interaction of human tumors with platelets. We now report on the ability of two human adenocarcinomas of the colon (LoVo and HCT-8) and an anaplastic mouse tumor (Hut-20) to aggregate platelets by a different mechanism, the generation of thrombin. These spontaneous cell lines aggregate human or rabbit platelet-rich plasma after a 1- to 2-min lag period. This is often followed by a visible clot. Unlike SV3T3 cells, aggregation by LoVo, HCT-8, and Hut-20 cells is not inhibited by neuraminidase, trypsin, or cobra venom factor. These three cell lines markedly shorten the recalcification time of citrated plasma, whereas SV3T3 cells do not. Phospholipase A2 treatment inhibits the shortening of the recalcification time for the three tumors; this parallels its inhibitory effect on platelet aggregation. LoVo, HCT-8, and Hut-20 cells generate thrombin via the "tissue factor" coagulation pathway (using coagulation factor-deficient substrates). Dansylarginine-N-(3-ethyl-1,5-pentanediyl)amide, a highly specific, potent antithrombin antagonist, inhibits LoVo-, HCT-8-, and Hut-20-induced platelet aggregation at 4 to 15 microM, whereas its effect on SV3T3 cells is negligible. If platelets are required for certain human tumor metastases, dansylarginine-N-(3-ethyl-1, 5-pentanediyl)amide, or other antithrombin agents, may prove to be valuable therapeutic agents.
 ...
PMID:Inhibition of the platelet-aggregating activity of two human adenocarcinomas of the colon and an anaplastic murine tumor with a specific thrombin inhibitor, dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. 730 74

In 40 patients with non-metastasising (n = 31) and metastasising (n = 9) renal cell carcinoma, evidence of Stauffer's syndrome (increase in alkaline serum phosphatase and prolongation of prothrombin time) was found in 18 patients. Prolongation of prothrombin time was not due to depletion of vitamin K-dependent coagulation factors or manifest fibrinolysis, but due to the presence of circulating fibrinogen fibrinmonomer-FDP complexes. Ethanol gelation test was found to be positive in 28/40 subjects and soluble fibrin monomer complexes were increased in 38/40 patients. The resulting disturbance of fibrinogen-fibrin conversion was reflected by an increase in thrombin coagulase time and reptilase time. These findings suggests a state of latent compensated intravascular coagulation (presumably triggered within the vascular tumor). For diagnostic purposes the most sensitive indicator is thrombin coagulase time. Thrombin coagulase time normalised after tumor resection and was positive in patients with recurrent metastases. The increase in alkaline serum phosphatase was due to an increase in the hepatic isoenzyme. Such an increase was much more common than the elevation of total alkaline serum phosphatase. Regan's isoenzyme was only found in 1 subject. In parallel, gamma-GT was elevated in 24 patients. The study shows that Stauffer's syndrome occurs more frequently than commonly assumed when thrombin coagulase time, gamma-GT and the hepatic isoenzyme of alkaline serum phosphatase are determined in patients with renal cell carcinoma. DIC and low grade fibrinolysis may account for the coagulation abnormalities of the syndrome.
 ...
PMID:Stauffer's syndrome in renal cell carcinoma evidence for intravascular coagulation. 736 22

In 124 patients with various types of malignancy, fpA and delta fpA were measured. In 35 of these patients the effect of heparin injection on fpA and delta fpA was studied. All patients were ambulant without clinical signs of venous thromboembolism or DIC and had not received cytostatic, anticoagulant, or radiotherapy recently. In about 75% of these patients, fpA was elevated, whereas in the blood of one third of the patients, both elevated fpA levels and accelerated delta fpA were detected. Eight of the 45 patients with accelerated delta fpA (and elevated fpA) presented laboratory signs of low-grade DIC. In the patients taken at random for heparin administration, delta fpA normalized upon heparin injection, whereas in the majority of patients, irrespective of the fpA-generation rate, fpA levels were not affected by "adequate" heparinization. These results indicate that (1) about 30% of the (selected) patients admitted to our cancer clinic present with evidence of intravascular thrombin activity and (2) in 70% of these patients fpA is generated, at least in part, at a site not accessible to heparin. In addition 95% of patients with active metastatic disease showed an elevated fpA, whereas 90% of cancer patients in remission and 80% of patients without metastasis had a normal fpA, indicating that fpA can potentially be used to estimate the spread and the activity of the malignant process.
 ...
PMID:Significance of plasma fibrinopeptide A (fpA) in patients with malignancy. 739 57

Coagulation and fibrinolysis activation have been investigated in fifty-eight women with recently detected gynaecological tumours. Twenty-six were benign and 32 malignant: of the last group nine patients had metastases. A control group consisted of 31 age-matched healthy women. Prothrombin fragment 1 + 2, thrombin-antithrombin III and D-dimer were measured. The median values of all analytes were significantly higher in the malignant tumour group, but not in the benign tumour group, as compared to the control group. The group of patients with a gynaecological tumour and metastases differed from the non-metastasized tumour group in prothrombin fragment 1 + 2, thrombin-antithrombin III and D-dimer. In the non-metastasized malignant tumour group solely prothrombin fragment 1 + 2 was significantly higher than in the benign tumour group. Coagulation and fibrinolysis predominating as can be derived from the elevated D-dimer/thrombin-antithrombin III and D-dimer/prothrombin fragment 1 + 2 ratios. The studied constituents do not enable a differentiation between the benign and malignant processes. However, as the differences of these values in both malignant tumour groups were significant, this might be used to trace the existence of metastases in gynaecological tumours. Investigation of these analytes in several specific types of gynaecological tumours might be clinically relevant.
 ...
PMID:Haemostasis activation markers in plasma of patients with benign and malignant gynaecological tumours: a pilot study. 762 94

The relationship between malignancy and thrombosis and hemostasis has long been recognized but is poorly understood. The interaction of tumor cells and the proteins and cells of coagulation is symbiotic and complex. Selected cancers have been known to respond to antithrombotic and anticoagulant therapies such as warfarin, heparin and most recently, hirudin. The identification of the functional 'tethered ligand' thrombin receptor on platelets, other cells and recently tumor cells has provided additional opportunities to examine and control the course of tumor proliferation. Thrombin, at concentrations which precede fibrin formation, is a potent inducer of tumor cell expression of various integrin receptors and tumor cell adhesion to the matrix and other activated cells. New strategies based on specifically controlling the action of thrombin may be beneficial in arresting the proliferation of these cells.
Invasion Metastasis
PMID:The role of thrombin in tumor cell metastasis. 765 23

DN-9693, c-AMP: phosphodiesterase inhibits platelet aggregation induced by metastasizing tumor cells and blood-borne metastases of these tumors. Effects of this drug on pulmonary metastases was studied in wKA rats, which were sc implanted with 4-dimethylaminoazobenzene (DAB) induced KDH-8 tumor cells. KDH-8 cells (10(5)) were sc inoculated on day 0 and excised on day 20. DN-9693 was ip injected at a dose of 150 micrograms twice a day for 7 days pre operatively (-7 - 0) or perioperatively (-3 - +3) or postoperatively (0 - +7). The rats were sacrificed on day 20 after surgery, and lung weight and the number of surface pulmonary nodules were measured. Both were significantly decreased in the group of perioperative and postoperative administration of DN-9693. The survival of these rats were furthermore prolonged when Cyclophosphamide (40 mg/kg) was sc injected 3 days after surgical resection. KDH-8 tumor cells (10(4)) were iv inoculated on day 0, and DN-9693 was ip injected at a dose of 150 micrograms twice a day for 7 days on day 0 approximately 7. Rats were sacrificed on day 20, and same studies as above were done. In this artificial pulmonary metastases, the decrease of the number of lung nodules was observed in WKA rat treated with DN-9693. Platelet aggregation induced by KDH-8 tumor cells was inhibited by ADP inhibitor (apyrase, CP/CPK) and thrombin inhibitor (heparin, MD-805); KDH-8 tumor cells induced platelet aggregation by two different mechanisms: ADP-mediated aggregation and thrombin-mediated aggregation. This platelet aggregation by KDH-8 tumor cells was inhibited by DN-9693 with dose-dependency. DN-9693 had no direct anti-tumor effects either in vivo or in vitro. The results indicates that this drug prevents pulmonary metastases by inhibiting platelet aggregation.
 ...
PMID:[Effects of platelet aggregating inhibitor on pulmonary metastases of tumor cells after surgical resection]. 822 73

In this study, we examined the effect of triflavin, an Arg-Gly-Asp (RGD)-containing snake venom peptide, on human cervical carcinoma (HeLa) cell- and B16-F10 mouse melanoma cell-induced platelet aggregation (TCIPA) in heparinized platelet-rich plasma. TCIPA appears to play an important role in the development of certain experimental tumor metastases. Two ADP-scavenging agents, apyrase (10 U/ml) and creatine phosphate (CP) (5 mM)/creatine phosphokinase (CPK) (5 U/ml) completely inhibited B16-F10 TCIPA, but hirudin (5 U/ml) had no effect. In contrast, apyrase and CP/CPK did not inhibit HeLa TCIPA while hirudin completely inhibited it. Furthermore, HeLa cells initially induced platelet aggregation and then blood coagulation at a later stage. In addition, HeLa cells shortened, in a concentration-dependent manner, the recalcification time of normal as well as factor VIII- and IX-deficient human plasma, but did not affect the recalcification time of factor VII-deficient plasma. This suggests that HeLa TCIPA occurs via activation of the extrinsic pathway, probably owing to tumor cell expression of tissue factor-like activity. HeLa cell-induced thrombin generation was confirmed by detection of amidolytic activity towards a chromogenic substrate, S-2238 (H-D-Phe-Pip-Arg-p-NA). Triflavin and GRGDS inhibited, in a dose-dependent manner, TCIPA caused by either cell line. On a molar basis, triflavin was 10,000-30,000 times more potent than GRGDS in this regard. Moreover, monoclonal antibodies raised against glycoprotein (GP) IIb/IIIa complex (i.e., 7E3 and AP2) and against GP Ib (i.e., AP1) completely inhibited HeLa TCIPA. 7E3 and AP2 inhibited B16-F10 TCIPA by up to 80% whereas AP1 showed only 30% inhibition of B16-F10 TCIPA. In conclusion, the inhibitory effect of triflavin on HeLa and B16-F10 TCIPA may be mediated principally by the binding of triflavin to the fibrinogen receptor associated with GP IIb/IIIa complex on the platelet surface. However, GP Ib is also involved in HeLa TCIPA as thrombin formation is the key factor in triggering platelet aggregation caused by HeLa cells.
 ...
PMID:Triflavin, an Arg-Gly-Asp-containing peptide, inhibits tumor cell-induced platelet aggregation. 822 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>