vitamin-k-semiquinone-radical and Neoplasm-Metastasis

Venous thromboembolism (VTE) and cancer are strongly associated, and present a major challenge in cancer patient treatment. Cancer patients have a higher risk of developing VTE, although the risk differs widely between tumour types. VTE prophylaxis is routinely given to cancer patients, in the form of vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). Several studies have reported that cancer patients receiving anticoagulants show prolonged survival and this effect was more pronounced in patients with a good prognosis, although the mechanism is poorly understood. Tissue Factor (TF) is the initiator of extrinsic coagulation, but its non-haemostatic signalling via protease-activated receptors (PARs) is a potent driver of tumour angiogenesis. Furthermore, coagulation activation is strongly implicated in tumour cell migration and metastasis. This review discusses the effects of anticoagulants on cancer progression in patients, tumour cell behaviour, angiogenesis, and metastasis in in vitro and in vivo models. Inhibition of TF signalling shows great promise in curbing angiogenesis and in vivo tumour growth, but whether this translates to patients is not yet known. Furthermore, non-haemostatic properties of coagulation factors in cancer progression are discussed, which provide exciting opportunities on limiting oncologic processes without affecting blood coagulation.

Topics: Animals; Anticoagulants; Blood Coagulation; Coumarins; Heparin, Low-Molecular-Weight; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Thromboplastin; Venous Thromboembolism; Vitamin K

The continuing education course "Hemostasis" provided a comprehensive review of hemostasis and selected perturbations of the underlying processes as well as an assessment of hemostasis in animal models and preclinical testing environments. The session began with a review of the current state of understanding of hemostasis and how the waterfall or cascade of activation has transformed to the current cell-based, membrane-associated sequence of highly regulated events. The specific mechanisms of drug-induced thrombocytopenia were then presented, followed by a discussion of the relationships of coagulation and platelets in inflammation and cancer metastasis and platelet activity. Evaluation of hemostasis and platelet function in animals and especially in the environment of the contract research facility concluded the session.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Education, Continuing; Hemostasis; Humans; Inflammation; Models, Animal; Neoplasm Metastasis; Platelet Activation; Platelet Aggregation; Thrombocytopenia; Vitamin K

Cancer is linked with hypercoagulability and risk of thrombosis and this close association was recognized by Armand Trousseau in 1865. The relation between cancer and blood coagulation is reciprocal: cancer induces a hypercoagulable state and predisposes to thrombosis and activation of platelets, blood coagulation and fibrinolysis interfere with tumor cell biology, tumor growth, angiogenesis and metastatic process. In the present article, we analyze the clinical trials which assessed the influence of anticoagulant treatment on the survival of patients with cancer. The available data show that low-molecular-weight heparins (LMWHs) tend to be more effective and safer than vitamin K antagonists (VKA) in improving survival in patients with cancer. The beneficial effect of anticoagulation with either LMWHs or VKA is not universal for all patients with cancer. There are some histological types of cancers which, at early stages, appear to be more sensitive than others to the effect of anticoagulant treatment. The available clinical trials, although limited, are encouraging for the beneficial effect of anticoagulant treatment on the survival of cancer patients. More clinical trials are needed, targeting groups of patients homogenous regarding the type of cancer, the stage of the disease and life expectancy. The forthcoming clinical trials have to address some issues regarding the optimal dose, the timing and the duration of treatment with LMWH in relation to chemotherapy or other anticancer therapies.

Topics: Animals; Anticoagulants; Clinical Trials as Topic; Double-Blind Method; Drug Screening Assays, Antitumor; Fibrinolytic Agents; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Mice; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic; Research Design; Survival Analysis; Thrombophilia; Thrombosis; Vitamin K; Warfarin

Pathology studies of human cancers suggested to early investigators that the hemostatic system may play an important role in cancer metastasis. Subsequent studies in animal models have demonstrated a reduction of tumor metastasis and improved animal survival with systemic anticoagulation. In many of these experiments, vitamin K antagonists (VKAs) were utilized. Although warfarin was effective in reducing metastasis in a majority of these animal models, effects on the growth of the primary tumor and on animal survival have been less consistent. Clinical studies on the effect of warfarin in human malignancy are limited and less than conclusive. Several small, uncontrolled and controlled clinical studies have been reported but do not definitively suggest a benefit in most malignancies. However, none of the studies of VKAs in humans are adequately designed or sufficiently powered to definitively exclude an impact of oral anticoagulants on cancer survival. Because of the difficulties in managing VKA oral anticoagulation in cancer patients and recent studies suggesting a positive effect on cancer survival with low-molecular-weight heparins, it unlikely that further studies on the use of VKAs in cancer patients will be undertaken.

Topics: Animals; Anticoagulants; Disease Progression; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Survival Rate; Vitamin K; Warfarin

There is considerable evidence that the hemostatic system is involved in the growth and spread of malignant disease. There is an increased incidence of thromboembolic disease in patients with cancers and hemostatic abnormalities are extremely common in such patients. Antihemostatic agents have been successfully used to treat a variety of experimental tumors, and several clinical trials in humans have been initiated. Although metastasis is undoubtedly multifactorial, intravascular coagulation activation and peritumor fibrin deposition seem to be important. The mechanisms by which hemostatic activation facilitates the malignant process remain to be completely elucidated. Of central importance may be the presence on malignant cells of tissue factor and urokinase receptor. Recent studies have suggested that these proteins, and others, may be involved at several stages of metastasis, including the key event of neovascularization. Tissue factor, the principal initiator of coagulation, may have additional roles, outside of fibrin formation, that are central to the biology of some solid tumors.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Biomarkers; Blood Coagulation Tests; Cell Adhesion; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Factor Xa; Fibrin; Fibrinolysis; Hemostasis; Heparin; Humans; Monocytes; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Platelet Activation; Platelet Aggregation Inhibitors; Receptors, Thrombin; Thrombophilia; Thrombophlebitis; Thromboplastin; Vitamin K

Topics: Adult; Anti-Bacterial Agents; Fluorouracil; Hemangioma; Hepatic Artery; Humans; Ligation; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms; Male; Necrosis; Neoplasm Metastasis; Serum Albumin; Vitamin K

After 6months, little is known about the optimal anticoagulant strategy for an acute episode of VTE in cancer patients.. The objective was to determine the risk of recurrent VTE and anticoagulant-related bleeding at 6months of follow-up and after 6months, in cancer patients who received tinzaparin during at least 3months for an acute episode of VTE. We conducted a multicenter retrospective cohort study from January 2004 to March 2011.. Two hundred fifty patients were included. Stopping anticoagulation before 6months in patients considered at low risk by physicians (i.e.; patients who had prior cancer surgery) and for another reason than bleeding or death was the only factor associated with a significant increased risk of recurrent VTE (OR 7.2 95%CI, 2.0-25.7; p=0.002). The type of anticoagulation did not influence the risk of recurrent VTE. We found a trend towards an increased risk of recurrent VTE when anticoagulation was stopped because of major bleeding while on anticoagulant therapy and patients with metastatic cancer (OR 2.3, 95%CI, 0.9-5.4; p=0.07; and OR 1.8 95%CI, 1.0-3.3; p=0.07; respectively). No factors were found to increase the risk of major bleeding at 6months and after. The overall mortality was 42.8%.. The risk of recurrent VTE was mainly related to early discontinuation of anticoagulation in patients considered at low risk of recurrence (after surgery). When the anticoagulation was stopped before the sixth month, the risk was eight fold higher. After 6month, the risks of recurrent VTE, major bleeding and death were similar in patients with either VKA or tinzaparin when patients were treated according to the guidelines.

Topics: Anticoagulants; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasm Metastasis; Neoplasms; Recurrence; Retrospective Studies; Risk Factors; Tinzaparin; Treatment Outcome; Venous Thromboembolism; Vitamin K

Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent.

Topics: Administration, Oral; Animals; Male; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Naphthoquinones; Neoplasm Metastasis; Vitamin K

Electrochemical methods have been widely used to monitor physiologically important molecules in biological systems. This report describes the first application of the scanning electrochemical microscope (SECM) to probe the redox activity of individual living cells. The possibilities of measuring the rate and investigating the pathway of transmembrane charge transfer are demonstrated. By this approach, significant differences are detected in the redox responses given by nonmotile, nontransformed human breast epithelial cells, breast cells with a high level of motility (engendered by overexpression of protein kinase Calpha), and highly metastatic breast cancer cells. SECM analysis of the three cell lines reveals reproducible differences with respect to the kinetics of charge transfer by several redox mediators.

Topics: Animals; Breast; Breast Neoplasms; Cattle; Cell Line; Cell Membrane; Cell Movement; Cells, Immobilized; Electrochemistry; Epithelial Cells; Female; Humans; Isoenzymes; Microscopy, Electron, Scanning; Naphthoquinones; Neoplasm Metastasis; Oxidation-Reduction; Protein Kinase C; Protein Kinase C-alpha; Transfection; Tumor Cells, Cultured; Vitamin K

We noted that patients treated with high-dose interleukin (IL)-2 (600,000 IU/kg every 8 h by intravenous bolus) at our institution frequently developed prolongation of their prothrombin time (PT). We therefore performed a prospective study of coagulation function during IL-2 treatment. Since IL-2 treated individuals are known to develop cholestatic liver dysfunction, we hypothesized that the hypoprothrombinemia was due to deficiency of liver-synthesized clotting factors and could be prevented by vitamin K replacement. Alternating patients served as controls or received prophylactic subcutaneous subcutaneous vitamin K. While the nine control patients did not exhibit a significant increase (mean +/- SD) in PT (13.6 +/- 0.6 s pretreatment, 15.0 +/- 2.2 on day 4, and 15.0 +/- 2.5 on day 7, p = 0.77 by repeated measures analysis), three patients developed marked increases in PT (greater than 18 s). Changes in partial thromboplastin time (PTT) over this interval were also not statistically significant. Factor VII levels decreased in all patients from 106 +/- 22 to 59 +/- 16 and 52 +/- 26% on days 4 and 7 (p = 0.0002). Factor VII levels in four patients dropped below the lower limit of normal. Prophylactic treatment of seven patients with vitamin K on days 1-8 of the IL-2 therapy protocol resulted in diminished changes in PT and factor VII compared to control patients (p = 0.02 and 0.003 respectively). No vitamin K-treated patient developed PT or Factor VII levels significantly outside the normal range. Prophylactic vitamin K can prevent hypoprothrombinemia in patients treated with IL-2. This may be of importance in patients with decreased hepatic vitamin K stores, who may be at risk for bleeding complications.

Topics: Blood Coagulation; Humans; Hypoprothrombinemias; Interleukin-2; Kidney Neoplasms; Liver; Melanoma; Neoplasm Metastasis; Parenteral Nutrition; Recombinant Proteins; Vitamin K

A highly metastatic line of Lewis lung tumor cells established in fetal bovine serum (10%) was subcultured into normal rodent (mouse or rat) serum or rodent serum made deficient in functional vitamin K-dependent proteins (barium sulfate adsorption or warfarin treatment of animals). Following injection of cells cultured in normal rodent serum into C57BL/6 mice, Factor X activator activity in the primary tumors increased at a near linear rate per gram tumor and attained 5- to 8-fold higher levels than did cells grown in either of the deficient sera. Secondary lung foci were also visible in all mice of the normal-rodent serum groups within 10 days after injection, and by 21 days extensive tumor growth in the lungs had developed. No secondary lung foci were apparent in any mice of the deficient serum groups throughout 21 days of tumor burden. Cells cultured in nonrodent serum (fetal bovine serum) were less proficient than cells grown in normal mouse serum in developing primary tumor Factor X activator activity and producing secondary tumors. Exposure of cells cultured in barium sulfate-treated mouse serum to normal mouse serum for 3 h and 3 weeks prior to injection partially restored primary tumor Factor X activator and metastatic competence. These data strongly suggest that in Lewis lung tumor cells at least one species selective, plasma/serum vitamin K-dependent protein plays a major role in the regulation of metastatic events and demonstrate that there is a positive correlation between primary tumor Factor X activation activity and metastasis.

Topics: Animals; Blood Proteins; Coagulants; Cysteine Endopeptidases; Factor X; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms, Experimental; Tumor Cells, Cultured; Vitamin K

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.

Topics: Animals; Biotransformation; Blood Coagulation Factors; Cell Line; Culture Media; Factor X; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Vitamin K; Vitamin K Deficiency; Warfarin

Anticoagulants of the coumarin type have long been reported to inhibit metastasis growth in experimental animals; however, the mechanisms of such effects has not been clarified. Systemic anticoagulation per se does not appear to account completely for such metastasis growth depression. More recent information gathered on a cell procoagulant activity, which is vitamin K-dependent, could probably supply a fresh insight into this problem. Indeed, vitamin K deficiency induced either dietarily or pharmacologically by warfarin, does inhibit the activity of a cysteine protease with direct factor-X-activating properties. This protease is only present in warfarin-sensitive tumors. The correlation of this activity with cancer cell invasiveness is supported by experimental data in metastatic variants and, lately, also by the observation of markedly higher cancer procoagulant activity in extracts from metastases than from primary human melanomas.

Topics: Animals; Antineoplastic Agents; Blood Coagulation Factors; Cysteine Endopeptidases; Endopeptidases; Humans; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Protease Inhibitors; Vitamin K; Warfarin

Microsomes isolated from Lewis lung (LL) primary tumors raised in C57BL/6 mice have been shown to (i) contain a 4-hydroxycoumarin (warfarin)-sensitive cycle of vitamin K metabolism which is at least qualitatively similar to that of liver, and (ii) catalyze the incorporation of NaH14 CO3 into endogenous protein in a vitamin-K hydroquinone-dependent reaction to produce gamma-carboxyglutamate. As in liver microsomes, LL microsomal reduction of vitamin K 2,3-epoxide to vitamin K was greatly enhanced by exogenous dithiols such as dithiothreitol, but under identical conditions the former was 10-fold faster. The R(+) and S(-) warfarin enantiomers were highly and equally effective inhibitors of both the liver and tumor vitamin K 2,3-epoxide reductases-the average I50 against the tumor enzyme was 0.25 microM. Partially purified reductases isolated by centrifugation of sodium-cholate-treated liver and LL tumor microsomes over a discontinuous sucrose gradient were also inhibited by the sulfhydryl reagent N-ethylmaleimide following their reduction by dithiothreitol. Like the activity of the epoxide reductase, that of the gamma-carboxylase was much lower in tumor than in liver microsomes and was only detectable in microsomes isolated from tumor-bearing mice previously administered S(-) warfarin. In view of the reported inhibition of LL tumor metastasis by warfarin and diet-induced vitamin-K deficiency, vitamin-K-dependent proteins may play a role in the spread and/or subsequent growth of LL cells.

Topics: Animals; Dithiothreitol; Liver; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Microsomes; Mixed Function Oxygenases; Neoplasm Metastasis; Neoplasm Proteins; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

Topics: Animals; Blood Coagulation Factors; Factor X; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Vitamin K; Vitamin K Deficiency; Warfarin

The decreased capacity of the liver to synthesize proteins is the main cause of decreased blood levels of clotting factors II, V, VII, IX, X and of antithrombin III in patients with liver disease. Therefore, determination of the activity or concentration of these coagulation proteins is a useful test of liver function and guide to prognosis, provided that other mechanisms which may influence the blood level are carefully considered. Clotting factor assays have an only limited value for the differential diagnosis in liver disease.

Topics: Acute Disease; Antithrombins; Blood Coagulation Disorders; Blood Coagulation Tests; Carcinoma, Hepatocellular; Chronic Disease; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Factor XIII; Fibrinogen; Hepatitis; Humans; Jaundice, Chronic Idiopathic; Liver Cirrhosis; Liver Diseases; Liver Function Tests; Liver Neoplasms; Neoplasm Metastasis; Prothrombin; Vitamin K

Topics: Animals; Cell Transformation, Neoplastic; Naphthalenesulfonates; Neoplasm Metastasis; Neoplasms, Experimental; Radiation-Sensitizing Agents; Rats; Sarcoma, Experimental; Vitamin K

Topics: Administration, Oral; Animals; Blood Coagulation; Female; Idoxuridine; Injections, Intravenous; Iodine Isotopes; Leukemia, Experimental; Lung Neoplasms; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; Sarcoma, Experimental; Transplantation, Homologous; Vitamin K; Warfarin

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Angiography; Aspartate Aminotransferases; Carcinoma, Hepatocellular; Catheterization; Female; Floxuridine; Hepatic Artery; Humans; Injections, Intra-Arterial; Injections, Intramuscular; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Radionuclide Imaging; Uric Acid; Vitamin K

Topics: Adenocarcinoma; Adult; Aged; Animals; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Cystadenoma; Female; Humans; Iodine Radioisotopes; Kidney Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Mice; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Peritoneal Neoplasms; Radiation-Sensitizing Agents; Radionuclide Imaging; Rats; Rectal Neoplasms; Sigmoid Neoplasms; Stomach Neoplasms; Vitamin K

Topics: Analgesics; Bile Duct Neoplasms; Cholangiography; Cholelithiasis; Cysts; Dexamethasone; Gallbladder Neoplasms; Humans; Liver Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Penicillins; Postoperative Care; Prednisolone; Preoperative Care; Stomach Neoplasms; Vitamin K

Topics: Adenocarcinoma; Autoradiography; Colonic Neoplasms; Dysgerminoma; Female; Gallbladder Neoplasms; Hodgkin Disease; Humans; Injections, Intra-Arterial; Injections, Intravenous; Melanoma; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Radiotherapy Dosage; Skin Neoplasms; Tritium; Vitamin K