warfarin and Neoplasm-Metastasis

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

Experimental and clinical studies have shown an anticancer effect of anticoagulant drugs. The aim of this study is to review the mechanisms by which the common types of anticoagulants influence the primary tumor and metastatic processes of solid tumors. The review evaluates the interference of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and warfarin on the growth of primary tumors and on the development of metastases. The first part of the review evaluates the effect on the growth and development of primary tumors. Attention is paid to the interference with proliferation of cancer cells, tumor angiogenesis and to the interference with the immune system. The second part of the review describes the metastatic process and the effect of anticoagulants on the cell motility and cancer cell adhesion. The third part refers to the outcomes of clinical studies with anticoagulant treatment in patients with cancer. The problem of thromboembolic disease in patients with advanced cancer is also mentioned. The anticoagulants are more effective in inhibition of stages of the metastatic cascade than in the influence on primary tumors. They can interfere with tumor angiogenesis, immunity system, cancer cell motility and adhesion. The first clinical trials showed an effect on the development of primary tumors and survival of patients namely with lung cancer.

Topics: Anticoagulants; Antineoplastic Agents; Clinical Trials as Topic; Heparin; Humans; Neoplasm Metastasis; Neoplasms; Warfarin

Metastases formation involves platelets activation and coagulation cascade. Drugs interfering with such mechanisms have shown promising activity in controlling neoplastic spread. Particularly, combined treatment with coumarins and the most recent antiplatelet agents could open interesting therapeutic perspectives.

Topics: Administration, Oral; Drug Therapy, Combination; Humans; Neoplasm Metastasis; Neoplasms; Platelet Aggregation Inhibitors; Warfarin

Clinical and experimental observations have firmly established the concept of a two-way interaction between malignancy and the hemostatic system. On the one hand, certain tumors can activate platelets and the coagulation mechanism in vivo, on the other, a convincing case has been made for the involvement of platelets and fibrin in tumor growth and metastasis. A large number of clinical and experimental studies have been conducted in order to test the efficacy of platelet inhibitors and anticoagulants as adjuvants in the treatment of cancer. Antiplatelet drugs gave variable results, depending on the drug and the tumor system tested. Prostaglandin synthetic pathways by both the host and tumor seem to be an important determinant in the response to platelet function inhibitors. Of the various anticoagulants tested, the coumarin derivatives gave somewhat consistent antitumor effect in certain human and experimental cancer. The antitumor effect of oral anticoagulants does not appear to be a primary drug effect and seems related to their role as vitamin K antagonists. It should be emphasized that although the antitumor potential of antithrombotic agents is a subject of keen interest at the present, their use in treating human cancer is still controversial.

Topics: Anticoagulants; Blood Coagulation Factors; Blood Platelets; Growth Substances; Hemostasis; Heparin; Humans; Neoplasm Metastasis; Neoplasms; Warfarin

Plasminogen activator activity (PAA) has been detected in various tumor cells or in their excretion products. In some cell systems PAA is a symptom of cell transformation, but its amount is questionably correlated with the invasiveness of the tumor cells. Procoagulant and aggregation activities on platelets, have been demonstrated in various tumor cells. There are weakly correlated with the metastatic potential of these cells. In vivo, the treatment of animals by modifiers of the hemostasis, or of the fibrinolysis systems provides contradictory results. Some reduction of metastatic diffusion and increase of life span have been noted with Warfarin. Clinical trials are scarce and their methodology is debatable. When conclusive, a lengthening of the life span has been observed, but not a reduction of the metastatic spread as metastases were still present.

Topics: Animals; Antifibrinolytic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Factors; Blood Vessels; Cell Adhesion; Cell Aggregation; Cell Line; Clinical Trials as Topic; Endothelium; Fibrinolysis; Fibrinolytic Agents; Hemostasis; Heparin; Humans; Indomethacin; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Plasminogen Activators; Warfarin

Cancer cells may promote fibrin formation in the tumor microenvironment through availability of procoagulant activities which are mainly of two types: tissue thromboplastin-like or direct activator of coagulation factor X. The pharmacological modulation of these activities could be potentially important in the control of metastasis growth. However, very limited information is available so far on this issue; it has recently been shown that the direct activator of coagulation factor X is a vitamin K-dependent activity which is depressed by warfarin treatment, not by anticoagulation with heparin or defibrinating enzymes. Whether the inhibition of this peculiar cancer procoagulant is involved in the antimetastatic activity of warfarin is a stimulating hypothesis which needs to be further substantiated.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Blood Coagulation Factors; Cell Membrane; Cysteine Endopeptidases; Endopeptidases; Humans; Leukemia, Myeloid, Acute; Mice; Mucins; Neoplasm Metastasis; Neoplasm Proteins; Thromboplastin; Warfarin

Topics: Animals; Aspirin; Blood Vessels; Capillaries; Endothelium; Fibrin; Heparin; Lung Neoplasms; Microcirculation; Neoplasm Metastasis; Neoplasms; Platelet Aggregation; Warfarin

Topics: Animals; Blood Coagulation; Blood Platelets; Coumarins; Disease Models, Animal; Fibrin; Fibrinolysis; Hemostasis; Humans; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Platelet Aggregation; Warfarin

Anticoagulants have been demonstrated to reduce tumor growth in certain experimental animal systems. Inhibition of clot formation interferes with tumor growth and spread while enhancement of coagulation promotes tumor growth and spread. The fact that the coagulation mechanism is commonly activated in human malignancy together with preliminary reports of therapeutic efficacy of anticoagulants suggests that the coagulation mechanism may be of pathophysiologic significance also in the growth of human tumors. A VA Cooperative Study has been established to test the hypothesis that warfarin anticoagulation will modify the course of malignancy in man. The purpose of this paper is to present the rationale and experimental design for this study with emphasis on management of anticoagulant administration in cancer patients. This paper serves as the basis for forthcoming reports of toxicity and therapeutic efficacy of warfarin in human malignancy.

Topics: Animals; Blood Coagulation; Cell Adhesion; Clinical Trials as Topic; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Research Design; Warfarin

Topics: Animals; Anticoagulants; Female; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Heparin; Humans; Immunosuppression Therapy; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Peptide Hydrolases; Uterine Neoplasms; Warfarin

Of the four major biological mechanisms of cancer spread, hematogenous dissemination is perhaps the most significant, as it usually heralds a fatal outcome for the patient. Recent experimental approaches have shown ways of altering the metastatic process and even totally inhibiting it in some animal models. It appears that these models may be applicable to certain human cancers. To prevent hematogenous metastasis formation the process must be inhibited at any one of four levels: 1) growth of the primary; 2) invasion of vessel walls; 3) release of viable tumor cells; or 4) entrapment and growth in distant organs. Judicious handling of the primary can decrease metastasis by minimizing the shedding of tumor cells. New experimental agents prevent the release of tumor cells from the primary by normalizing the blood vessels of the tumor. Warfarin, heparin, and fibrinolytic agents inhibit the entrapment of circulating tumor cells, presumably by their effect on coagulative mechanisms. A better understanding of the benefits of combined approaches to cancer using chemotherapy, irradiation, and immunotherapy, alone and as adjuncts to surgery, offers new opportunity to study methods of controlling metastatic disease.

Topics: Animals; Antineoplastic Agents; Biopsy; Cell Adhesion; Cell Movement; Detergents; Formaldehyde; Heparin; Humans; Immunotherapy; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Pharmaceutic Aids; Piperazines; Polyethylene Glycols; Propane; Rats; Rats, Inbred Strains; Warfarin

Topics: Animals; Anticoagulants; Antineoplastic Agents; Dicumarol; Drug Synergism; Drug Therapy, Combination; Ear Neoplasms; Endothelium; Factor XIII; Fibrinolysin; Fibrinolytic Agents; Heparin; Humans; In Vitro Techniques; Iodine Radioisotopes; Lung Neoplasms; Lymphatic Metastasis; Mice; Microcirculation; Neoplasm Metastasis; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Adhesiveness; Rabbits; Thrombosis; Warfarin

Topics: Animals; Blood Coagulation; Capillaries; Embolism; Heparin; Humans; Immunotherapy; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Thrombin; Warfarin

Topics: Animals; Benz(a)Anthracenes; Cell Movement; Culture Techniques; Ear; Fibrinolysin; Histological Techniques; Humans; Leukocytes; Lung Neoplasms; Lymphatic Metastasis; Mice; Motion Pictures; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Prothrombin Time; Rabbits; RNA; Thrombosis; Time Factors; Warfarin

Anticoagulants, especially vitamin K antagonists (VKAs) such as warfarin, have been hypothesized to have antitumor properties, and use of VKAs has been associated with a lower prostate cancer (PCa) risk. This study estimated PCa risk among users of warfarin and other anticoagulants.. All anticoagulant use among 78,615 men during 1995-2009 was analyzed. Cox regression, adjusted for age, screening trial arm and use of other medications, with medication use as a time-dependent variable, was used to estimate PCa risk overall, and by tumor grade and stage.. In total, 6537 men were diagnosed with PCa during 1995-2009 (1210 among warfarin users). Compared to non-users, warfarin use was associated with an increased risk of PCa [multivariable-adjusted hazard ratio (HR) = 1.11, 95% confidence interval (CI) 1.01-1.22]. This was limited to short-term, low-dose use, and was not observed in long-term use. A similar overall risk increase was observed for Gleason grade 7-10 PCa. Low-dose, short-term use of warfarin was associated with an increased risk of metastatic PCa. However, the increase in risk vanished with continued use. Compared to other anticoagulants, low-dose use of warfarin was associated with a slightly elevated overall PCa risk (HR = 1.19, 95% CI 1.00-1.43). The increase in risk disappeared in long-term, high-dose use.. This study, which included a larger number of PCa cases with warfarin exposure than previous studies, does not support previous notions of decreased risk of PCa among warfarin users. A similar risk of PCa was found among warfarin users and the general population, and no difference in risk was found between warfarin and other anticoagulants.

Topics: Aged; Anticoagulants; Early Detection of Cancer; Finland; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Prostatic Neoplasms; Risk Factors; Time Factors; Warfarin

Malignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of 'in vivo' clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients' hemostatic parameters were evaluated before entry into the study and after starting chemotherapy +/- prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p <0.001), F1+2 (p <0.001), D-dimer (p <0.0001) and FVIIa (p <0.05), as well as an increase of FVII proteolysis (p <0.05), whereas plasma PC and AT concentrations were not different from controls. After starting chemotherapy, markers of clotting activation were progressively lower in the group receiving warfarin prophylaxis compared to the group on placebo. Differences between the groups became statistically significant (p <0.01) after the 4th course of chemotherapy. Deep vein thrombosis occurred in two patients in the placebo arm. The results of this study indicate that before therapy, an hypercoagulable state is present in stage IV breast cancer, and after starting chemotherapy, abnormalities of hypercoagulation markers persist, however they are reduced by very-low-dose-warfarin. None of the laboratory variables could predict thrombosis in the single patient.

Topics: Adult; Aged; Anticoagulants; Biomarkers, Tumor; Blood Coagulation Disorders; Breast Neoplasms; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Middle Aged; Neoplasm Metastasis; Prospective Studies; Risk Factors; Thromboembolism; Warfarin

Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease. Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications. We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis. Women receiving chemotherapy for metastatic breast cancer were randomly assigned either very-low-dose warfarin (152 patients) or placebo (159). The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio (INR) of 1.3 to 1.9. Study treatment continued until 1 week after the end of chemotherapy. The average daily dose from initiation of titration was 2.6 (SD 1.2) mg for the warfarin group and the mean INR was 1.52. The mean time at risk of thrombosis was 199 (126) days for warfarin-treated patients and 188 (137) days for placebo recipients (p = 0.45). There were 7 thromboembolic events (6 deep-vein thrombosis, 1 pulmonary embolism) in the placebo group and 1 (pulmonary embolism) in the warfarin group, a relative risk reduction of about 85% (p = 0.031). Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient. There was no detectable difference in survival between the treatment groups. Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Double-Blind Method; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Thromboembolism; Thrombophlebitis; Treatment Outcome; Warfarin

VA Cooperative Study #75 was established to test in a controlled, randomized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy. No differences in survival were observed between warfarin-treated and control groups for advanced non-small cell lung, colorectal, head and neck and prostate cancers. However, warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression (P = 0.016) and a significant improvement in survival (P = 0.018) for patients with small cell carcinoma of the lung, including the subgroup of patients with disseminated disease at the time of randomization (P = 0.013). A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non-small cell lung cancer who had minimal disease at randomization. These results suggest that warfarin, as a single anticoagulant agent, may favorably modify the course of some, but not all, types of human malignancy, among which is small cell carcinoma of the lung. Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present.

Topics: Adenocarcinoma; Blood Coagulation; Carcinoma, Small Cell; Clinical Trials as Topic; Colonic Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation; Warfarin

Plasminogen activator activity (PAA) has been detected in various tumor cells or in their excretion products. In some cell systems PAA is a symptom of cell transformation, but its amount is questionably correlated with the invasiveness of the tumor cells. Procoagulant and aggregation activities on platelets, have been demonstrated in various tumor cells. There are weakly correlated with the metastatic potential of these cells. In vivo, the treatment of animals by modifiers of the hemostasis, or of the fibrinolysis systems provides contradictory results. Some reduction of metastatic diffusion and increase of life span have been noted with Warfarin. Clinical trials are scarce and their methodology is debatable. When conclusive, a lengthening of the life span has been observed, but not a reduction of the metastatic spread as metastases were still present.

Topics: Animals; Antifibrinolytic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Factors; Blood Vessels; Cell Adhesion; Cell Aggregation; Cell Line; Clinical Trials as Topic; Endothelium; Fibrinolysis; Fibrinolytic Agents; Hemostasis; Heparin; Humans; Indomethacin; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Plasminogen Activators; Warfarin

The object of this study was to see if the addition of anticoagulants to a regimen of cytotoxic drugs would improve the prognosis in patients with small cell carcinoma of the bronchus. Twenty-four patients were randomly allocated to receive chemotherapy or chemotherapy plus anticoagulants. The median survival in the group receiving the anticoagulants was not improved.

Topics: Antineoplastic Agents; Bronchial Neoplasms; Carcinoma; Clinical Trials as Topic; Drug Therapy, Combination; Female; Heparin; Humans; Male; Neoplasm Metastasis; Prognosis; Random Allocation; Warfarin

Anticoagulants have been demonstrated to reduce tumor growth in certain experimental animal systems. Inhibition of clot formation interferes with tumor growth and spread while enhancement of coagulation promotes tumor growth and spread. The fact that the coagulation mechanism is commonly activated in human malignancy together with preliminary reports of therapeutic efficacy of anticoagulants suggests that the coagulation mechanism may be of pathophysiologic significance also in the growth of human tumors. A VA Cooperative Study has been established to test the hypothesis that warfarin anticoagulation will modify the course of malignancy in man. The purpose of this paper is to present the rationale and experimental design for this study with emphasis on management of anticoagulant administration in cancer patients. This paper serves as the basis for forthcoming reports of toxicity and therapeutic efficacy of warfarin in human malignancy.

Topics: Animals; Blood Coagulation; Cell Adhesion; Clinical Trials as Topic; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Research Design; Warfarin

Topics: Animals; Anticoagulants; Blood Coagulation; Carcinoma 256, Walker; Cecal Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fibrinolysin; Fibrinolytic Agents; Heparin; Humans; Lung Neoplasms; Lymphoma; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Ovarian Neoplasms; Pelvic Neoplasms; Rabbits; Stomach Neoplasms; Swine; Thrombosis; Vena Cava, Superior; Warfarin

Topics: Administration, Oral; Anticoagulants; Antineoplastic Agents; Breast Neoplasms; Busulfan; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia, Myeloid; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Warfarin

We recently defined cancer metastatic chemoprevention as utilizing safe and effective molecules to comprehensively prevent the spark of activation-adhesion-extravasation-proliferation metastatic cascade caused by circulating tumor cells (CTCs). The strategy focuses on preventing the most important starting point of the cascade. We identified an extract from a well-known medical plant Murraya paniculata, which inhibited both embryonic implantation to human endometrium as traditionally-used for abortion and CTC adhesion to human endothelium. Here, we separated and characterized five coumarin-containing components (Z1-Z5) from the botanic extract. Flow cytometry revealed that within 1-100 μg/mL, Z3 and Z5 down-regulated EpCAM expression in human colon HCT116, whereas, Z1 and Z2 did oppositely. Warfarin and Z1-Z5 component mixture (CM) also down-regulated EpCAM expression. The down-regulation of EpCAM by Z3, Z5, CM and warfarin was confirmed by western blotting, and caused inhibition on adhesion of cancer cells to human endothelial cells. Rat coagulation study showed that warfarin prolonged prothrombin time, whereas, Z3 did not. The present studies revealed that, for the first time, warfarin and coumarin-like components Z3, Z5 and CM from Murraya paniculata could directly inhibit EpCAM-mediated cell-cell adhesion.

Topics: Animals; Anticoagulants; Antineoplastic Agents, Phytogenic; Cell Adhesion; Cell Survival; Coumarins; Down-Regulation; Drug Therapy, Combination; Epithelial Cell Adhesion Molecule; Female; HCT116 Cells; Human Umbilical Vein Endothelial Cells; Humans; Murraya; Neoplasm Metastasis; Rats; Warfarin

Anticoagulants have been postulated to possess antitumor activity, although clinical data supporting this claim are conflicting. No definitive data exist on the clinical impact of anticoagulation therapy in patients with prostate cancer. The aim of this study was to investigate the association between therapeutic anticoagulant use and survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel chemotherapy.. We retrospectively reviewed the records of 247 consecutive patients with mCRPC who received first-line docetaxel chemotherapy between 1998 and 2010 at a single institution. Among them, 29 patients (11.7 %) received therapeutic anticoagulation (low-molecular-weight heparin [LMWH] or warfarin) for the treatment of venous thromboembolism. Univariate and multivariable Cox proportional hazards regression models were used to investigate the effect of anticoagulant use on overall survival.. In univariate analysis, anticoagulant use was associated with improved survival (hazard ratio [HR], 0.61; P = .024). Median survival was 20.9 months in the anticoagulation group versus 17.1 months in the control group (P = .024). In multivariable analysis, anticoagulant use remained a significant predictor of survival after adjusting for other baseline prognostic factors (HR, 0.49; P = .023). When each anticoagulant was considered separately in the multivariable model, LMWH remained significantly prognostic for survival (HR, 0.48; P = .035), whereas warfarin use did not.. Anticoagulant use (LMWH in particular) is an independent predictor of improved survival in men with mCRPC receiving docetaxel. These data provide the impetus to further explore the antitumor properties of anticoagulants in patients with prostate cancer and warrant validation in prospective studies.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Docetaxel; Drug Synergism; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids; Treatment Outcome; Venous Thromboembolism; Warfarin

Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality.. Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality.. Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses.. There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Breast Neoplasms; Cohort Studies; Colorectal Neoplasms; Databases, Factual; Female; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Prostatic Neoplasms; Warfarin

Repurposing "old" drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Axl Receptor Tyrosine Kinase; Carcinoma, Pancreatic Ductal; Cell Division; Cell Line, Tumor; Cell Movement; Deoxycytidine; Disease Progression; Drug Synergism; Epithelial-Mesenchymal Transition; Female; Gemcitabine; Gene Knockdown Techniques; Humans; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Pancreatic Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; RNA, Small Interfering; Signal Transduction; Specific Pathogen-Free Organisms; Warfarin; Xenograft Model Antitumor Assays

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

Topics: Adaptor Proteins, Signal Transducing; Animals; Anticoagulants; Axl Receptor Tyrosine Kinase; c-Mer Tyrosine Kinase; Female; Killer Cells, Natural; Male; Mammary Neoplasms, Experimental; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-cbl; Receptor Protein-Tyrosine Kinases; Ubiquitin-Protein Ligases; Ubiquitination; Warfarin

High-risk prostate cancer (PC) has poor outcomes due to therapeutic resistance to conventional treatments, which include prostatectomy, radiation, and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in PC patients. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit when administered with radiotherapy in patients with high-risk PC.. Analysis was performed on 74 high-risk PC patients who were treated with radiotherapy from 2005 to 2008 at UT Southwestern. Of these patients, 43 were on AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were analyzed.. Median follow-up was 56.6 mo for all patients. For patients taking any AC compared with no AC, there was improved FFBF at 5 years of 80% vs. 62% (P = 0.003), and for aspirin the FFBF was 84% vs. 65% (P = 0.008). Aspirin use was also associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7%, P = 0.039). On subset analysis of patients with Gleason score (GS) 9-10 histology, aspirin resulted in improved 5-year OS (88% vs. 37%, P = 0.032), which remained significant on multivariable analysis (P<0.05).. AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with GS 9-10, who are most likely to experience mortality from PC. This hypothesis-generating result suggests AC use may represent an opportunity to augment current therapy.

Topics: Aged; Aged, 80 and over; Anticoagulants; Aspirin; Chemoradiotherapy; Clopidogrel; Drug Screening Assays, Antitumor; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Retrospective Studies; Risk; Ticlopidine; Treatment Outcome; Warfarin

New approaches targeting metastatic neovasculature are needed. Payload capacity, cellular transduction efficiency, and first-pass cellular uptake following systemic vector administration, motivates persistent interest in tumor vascular endothelial cell (EC) adenoviral (Ad) vector targeting. While EC transductional and transcriptional targeting has been accomplished, vector administration approaches of limited clinical utility, lack of tumor-wide EC expression quantification, and failure to address avid liver sequestration, challenged prior work. Here, we intravenously injected an Ad vector containing 3 kb of the human roundabout4 (ROBO4) enhancer/promoter transcriptionally regulating an enhanced green fluorescent protein (EGFP) reporter into immunodeficient mice bearing 786-O renal cell carcinoma subcutaneous (SC) xenografts and kidney orthotopic (KO) tumors. Initial experiments performed in human coxsackie virus and adenovirus receptor (hCAR) transgenic:Rag2 knockout mice revealed multiple ECs with high-level Ad5ROBO4-EGFP expression throughout KO and SC tumors. In contrast, Ad5CMV-EGFP was sporadically expressed in a few tumor vascular ECs and stromal cells. As the hCAR transgene also facilitated Ad5ROBO4 and control Ad5CMV vector EC expression in multiple host organs, follow-on experiments engaged warfarin-mediated liver vector detargeting in hCAR non-transgenic mice. Ad5ROBO4-mediated EC expression was undetectable in most host organs, while the frequencies of vector expressing intratumoral vessels and whole tumor EGFP protein levels remained elevated. In contrast, AdCMV vector expression was only detectable in one or two stromal cells throughout the whole tumor. The Ad5ROBO4 vector, in conjunction with liver detargeting, provides tractable genetic access for in-vivo EC genetic engineering in malignancies.

Topics: Adenoviridae; Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Coxsackie and Adenovirus Receptor-Like Membrane Protein; Endothelial Cells; Genetic Therapy; Genetic Vectors; Humans; Kidney Neoplasms; Liver; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Receptors, Cell Surface; Transcription, Genetic; Transgenes; Warfarin

Long term anticoagulant therapy is recommended for treatment and secondary prevention of venous thromboembolism in cancer patients. We assessed outpatient anticoagulants [warfarin, low molecular weight heparins (LMWHs), fondaparinux and unfractionated heparin (UFH)] use in adult, cancer patients, 20years of age or older, who incurred a venous thromboembolism (primary or secondary in-hospital diagnosis) in Quebec, Canada between 2007 and 2009.. Data were obtained from the Quebec Health Insurance Agency. Patients with an in-hospital cancer diagnosis between April 2007 and June 2009 and an in-hospital venous thromboembolism diagnosis either concurrently or consequently were eligible at the date of discharge (index date). Those patients registered with the provincial drug plan and discharged to the community were included in the study and followed for 6months.. Among 2,070 study patients, 72.4% received anticoagulant therapy at index date, 60% of whom were persistent with therapy and received it for ≥80% of follow-up days. Outpatient anticoagulant use was more likely in those with primary versus secondary diagnosis of venous thromboembolism and less likely in patients with cerebrovascular disease, peptic ulcer disease or previous anticoagulant use. The small number of patients who used either UFH (n=11) or fondaparinux (n=5) at index date were included in the LMWH group. Warfarin use was less likely than LMWH use in corticosteroid users, previous anticoagulant users, patients with metastatic cancer and those with catheter or chemotherapy in the previous three months. Warfarin use was more likely than LMWH use in: older patients, those residing in rural areas, those with lower income and those suffering from ischemic heart disease, atrial fibrillation or chronic kidney disease. Patients with ischemic heart disease were more likely to have used a non-dalteparin LMWH versus dalteparin (currently, the only LMWH approved by health Canada for chronic treatment of VTE), while those residing in rural areas and those with catheter/chemotherapy were less likely to have used them. A primary (versus secondary) discharge diagnosis of venous thromboembolism [Odds Ratio 1.42; 95% confidence interval (1.14, 1.76)], and metastatic cancer 1.27 (1.00, 1.60) were associated with persistence on anticoagulant treatment.. Guideline recommended outpatient use of anticoagulant in cancer patients hospitalized with venous thromboembolism was influenced by cancer status, old age and low income. Risk factors for bleeding prevented outpatient anticoagulant use in some patients.

Topics: Adult; Aged; Anticoagulants; Cohort Studies; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Odds Ratio; Polysaccharides; Retrospective Studies; Time Factors; Venous Thromboembolism; Warfarin

It is well established that the blood coagulation system is activated in cancer. In addition, there is considerable evidence to suggest that clotting activation plays an important role in the biology of malignant tumors, including the process of blood-borne metastasis. For many years our laboratory has used experimental models of lung metastasis to study the events that follow the introduction of procoagulant-bearing tumor cells into circulating blood. This chapter focuses on the basic methods involved in assessing the anti-metastatic effects of anticoagulants and anti-platelet agents using rodent models of experimental metastasis. In addition, it summarizes our experience with these models, which collectively suggests that intravascular coagulation and platelet activation are a necessary prelude to lung tumor formation and that interruption of coagulation pathways or platelet aggregation may be an effective anti-metastatic strategy.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Blood Coagulation; Cell Line, Tumor; Enoxaparin; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Platelet Aggregation Inhibitors; Thromboplastin; Warfarin

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Endothelial Growth Factors; Fluorouracil; Hemorrhage; Humans; Intercellular Signaling Peptides and Proteins; Leucovorin; Lymphokines; Neoplasm Metastasis; Thrombosis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Warfarin

There is strong evidence for an association between the haemostatic system and malignancy. Thus, cancer may adversely affect the host coagulation system while the haemostatic system may play a role in the development of both primary and metastatic tumours. Metastatic growth is not dependent simply on haemodynamic factors, and properties of both the tumour cell and host organ are important determinants of the site of metastatic growth. Previous studies have demonstrated that some organs are preferred sites for metastasis while others are less preferred or resistant. We have measured the procoagulant activity (PCA) of normal rat and human tissues and correlated the results with the previously reported ability of these organs to support metastatic tumour growth. In addition, we determined changes in PCA in rat tissues during oral anticoagulant therapy, and following colonic anastomosis and partial hepatectomy, procedures which are known to affect experimental metastasis. In both rat and human studies, organs which are preferred sites for metastasis had significantly higher PCA than non-preferred organs (P less than 0.001). The PCA of adrenal, lung and colon was significantly reduced by administration of warfarin (P less than 0.001). PCA was significantly (P less than 0.001) increased in both colonic anastomoses and regenerating liver and followed a time course similar to that of the enhanced tumour growth usually seen in these situations. Although the exact source of the procoagulant activity remains to be determined, the results suggest that there is a broad correlation between tissue PCA and the ability of a tissue to support metastatic tumour growth.

Topics: Anastomosis, Surgical; Animals; Blood Coagulation Factors; Colon; Humans; Liver Regeneration; Neoplasm Metastasis; Rats; Warfarin

Fibrin formation has been hypothesized to be an element of the metastatic process in cancer, and pharmacological interference with such fibrin formation has been proposed as a means of antimetastatic therapy. We have tested this hypothesis through an in vivo study of warfarin in two independent rat disease models--a model of chemical-injury-induced arterial thrombosis, and a model of spontaneous metastasis. We found 0.50 mg/kg-day warfarin to be uniformly lethal after two weeks treatment. The chronic dose of 0.25 mg/kg-day was non-toxic and produced effective anticoagulation and marked antithrombotic and antimetastatic activity. The 0.125 mg/kg-day dose produced a reduction in factor IIc (50%) and factor VIIc (70%), and resulted in statistically significant antithrombotic and antimetastatic activity. The 0.0625 mg/kg-day dose failed to reduce the vitamin K-dependent clotting factors, and failed to produce any antithrombotic or antimetastatic effects. The substantial correlation (very similar dose-response effects) among the anticoagulant, antithrombotic and antimetastatic efficacies of warfarin in the rat suggests that anticoagulation provides the pharmacological mechanism underlying both the antithrombotic and the antimetastatic effects. The poor therapeutic index we observed in the rat may be the attribute which limits the efficacy of warfarin in the treatment of human cancer.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Fibrinolytic Agents; Male; Neoplasm Metastasis; Rats; Rats, Inbred Strains; Warfarin

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

The platelet-secreted protein thrombospondin (TSP) potentiates tumor cell metastasis. Human TSP injected i.v. into mice 5 min prior to i.v. injection of T241 sarcoma cells potentiates lung tumor colony formation. Several lines of evidence suggest that the TSP-enhancing effect involves both TSP-mediated tumor cell adhesion and the host's hemostatic system: TSP potentiates the initial, rapid sequestering of tumor cells in the lung; TSP promotes the adhesion of tumor cells in vitro; the effect of TSP on tumor cell metastasis is dependent on the presence of platelets and a normal plasma clotting system, since TSP does not potentiate lung tumor colony formation in either thrombocytopenic mice or mice anticoagulated with Coumadin. Our results suggest a central role for TSP in the metastatic process.

Topics: Animals; Blood Coagulation; Blood Platelets; Cell Adhesion; Glycoproteins; Humans; Lung; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; Neuraminidase; Sarcoma, Experimental; Stimulation, Chemical; Thrombospondins; Warfarin

Patchy necrosis of the skin is a rare and unpredictable complication of oral anticoagulant therapy. Of the four patients that we have seen with this disorder, three had metastatic adenocarcinoma; in two, this was an unexpected finding. The association of a malignant neoplasm with warfarin-induced skin necrosis has not been emphasized previously. Whether such necrosis represents a clue to the presence of cancer or occurs only coincidentally in patients requiring anticoagulant therapy because of adenocarcinoma-associated thrombophlebitis must await further experience. A congenital or acquired deficiency of protein C may be the primary initiating factor.

Topics: Adenocarcinoma; Aged; Drug Eruptions; Female; Foot; Glycoproteins; Humans; Leg; Male; Necrosis; Neoplasm Metastasis; Pancreatic Neoplasms; Protein C; Sigmoid Neoplasms; Skin Diseases, Vesiculobullous; 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

The PAIII rodent metastatic prostatic adenocarcinoma model was employed to evaluate the effects of dietary warfarin, a prototypic antagonist of thrombin generation on the lymphatic and pulmonary metastases of the tumor from the tail site of subcutaneous transplantation in male Lobund Wistar (LW) rats. In addition, the anticoagulant effects of warfarin were determined in the same animals. Warfarin, administered in the diet at concentrations equivalent to 0.063, 0.125 or 0.250 mg./kg. b.w. for 30 days had no effect on final body weight, gluteal or iliac lymph node weights. Significant (p less than 0.05) dose-dependent extensions of whole blood prothrombin (WBPT), activated partial thromboplastin (WBAPTT) and clotting times (WBCT) over control values were observed with warfarin treatment. Preliminary studies demonstrated that the 0.500 mg./kg. dose produced 50 per cent mortality at +14 days. Warfarin produced significant (p less than 0.05) dose-dependent decreases in the number of PAIII pulmonary metastases as indicated by reductions in dry lung weights and lung colony numbers when compared to untreated tumor-bearing controls. While the therapeutic index of warfarin is a limiting factor in clinical use as an antimetastatic agent, these results suggest that compounds capable of altering hemostatic mechanisms may be potential inhibitors of tumor metastasis. The PAIII prostatic adenocarcinoma model may be a useful system to quantitatively evaluate potential antimetastatic and cytotoxic agents.

Topics: Adenocarcinoma; Animals; Blood Coagulation; Blood Coagulation Tests; Diet; Dose-Response Relationship, Drug; Male; Neoplasm Metastasis; Prostatic Neoplasms; Rats; Warfarin

Vitamin K deficiency, either dietary or pharmacologically induced by warfarin, was unable to affect the metastatic capacity of cells from a benzopyrene-induced fibrosarcoma in C57BL/6J mice. The same cells had a procoagulant activity, of tissue thromboplastin type, which was also completely unaffected by vitamin K antagonism or deficiency. In another murine model of spontaneous metastasis we previously suggested that depression of a particular procoagulant such as a direct factor X activator might contribute to the antimetastatic activity of warfarin. The failure of vitamin K deficiency to affect both the procoagulant and the metastatic capacity of the model reported here offers strong negative support to the same concept.

Topics: Animals; Fibrosarcoma; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Thromboplastin; Vitamin K Deficiency; Warfarin

Chronic vitamin K deficiency, either dietary or pharmacologically induced with warfarin, depressed significantly the growth of lung secondaries in a spontaneously metastasizing murine tumor, the Lewis Lung Carcinoma. This effect was associated with a marked depression of the procoagulant activity of cancer cells, which could contribute to fibrin deposition around the tumor. Cellular anticoagulation may thus be an important mechanism in the antimetastatic effect of warfarin.

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

KHT sarcomas were implanted in the right rear legs of C3H mice. An x-ray dose of 6000 rad, delivered in ten equal fractions over 12 days, resulted in 60% local tumor control, but 83% of these mice developed metastases. Three strategies to use the tumoricidal effect of x-radiation and reduce the incidence of metastases were compared. A modification of the fractionation scheme to deliver an initial large fraction of 1800 rad followed by seven 600-rad fractions resulted in a decreased incidence of metastases compared with the same dose delivered in ten equal fractions. The use of warfarin anticoagulation during the ten-fraction course of radiation resulted in a small decrease in the incidence of metastases. Immune stimulation with levamisole, injected subcutaneously every second day during the irradiation, also resulted in a decrease in the incidence of metastases. However, when warfarin or levamisole were combined with the eight-fraction radiation scheme there were fewer metastases than following the ten-fraction scheme. The combination of the eight-fraction radiation course with levamisole also produced a significant increase in primary tumor control. In this treatment regimen, therefore, levamisole appears to act as a radiation sensitizer. An hypothesis to explain this action is proposed.

Topics: Animals; Female; Levamisole; Mice; Neoplasm Metastasis; Prognosis; Radiotherapy Dosage; Sarcoma, Experimental; Warfarin

Topics: Animals; Colonic Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Rectal Neoplasms; 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 possibility that anticoagulation with warfarin might inhibit the development of spontaneous metastases from intestinal carcinomas induced by azoxymethane (AOM) was tested in Sprague-Dawley rats with and without 60% distal small-bowel resection (DSBR). Warfarin (0.5 mg/l) was added to the drinking water from 1 week or 12 weeks postoperatively, and thromboplastin times were measured thereafter. AOM was given by 12 weekly s.c. injections (10 mg/kg/week), starting 1 week after DSBR. Besides increasing the sensitivity of rats to warfarin, DSBR itself caused partial anticoagulation, probably because of vitamin K malabsorption: at 30 weeks faecal fat was 59-93% higher, while serum B12 was 40% lower (> 0.05 P > 0.005). Adaptive growth of the jejunum and caecum after DSBR was manifested by 22-76% increases in segmental weight and surface area (P < 0.001). DSBR produced a 4-fold increase in duodenojejunal tumours at 15-25 weeks (P = 0.025) and a 76% increase in colorectal tumours at 25-35 weeks (P < 0.005). Eight of 20 control rats dying after 15 weeks had lymphatic metastases, compared with 0 of 15 rats with DSBR plus warfarin from week 1 (P = 0.005). The overall prevalence of metastases was reduced by both DSBR and warfarin, when assessed independently. Intestinal carcinogenesis induced by AOM is enhanced by the adaptive response to DSBR, but anticoagulation inhibits spontaneous metastases in this model.

Topics: Animals; Blood Coagulation; Body Weight; Ileum; Intestinal Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Experimental; Postoperative Period; Rats; Warfarin

Topics: Animals; Antineoplastic Agents; Blood Coagulation; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms, Experimental; Warfarin

A study of warfarin anticoagulation as an adjunct to amputation of osteosarcomas was undertaken after finding dramatic results in experimental systems. Anticoagulation was started 7 days preoperatively, continued during the operation, and for up to six months postoperatively. Three of 21 (14%) non-anticoagulated control patients are alive at 5-11 years. Five of 9 (56%) of the anticoagulated patients remain alive 5-8 years. The presumed mechanism of increased survival is an inhibition of fibrin deposition around circulating tumor cells, thereby preventing their adherence to capillary endothelium to initiate metastasis formation.

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Osteosarcoma; Prothrombin Time; Remission, Spontaneous; Time Factors; Warfarin

Experiments were made to evaluate the potential role played by thrombogenic factors on the hematogenous arrest of circulating tumor cells in mice with demonstrable coagulopathies associated with the presence of a primary tumor, by administration of "therapeutic" doses of anticoagulants. The effects of warfarin, aspirin and heparin administration on the early arrest patterns of 125IdUrd-labelled TA3 carcinoma and Gardner lymphosarcoma cells injected intravenously into tumor-bearing mice were examined. Several hematologic parameters of carcinoma- and lymphosarcoma-bearing animals were measured prior to anticoagulation experiments and the results indicated that mice had coagulopathies similar to those found in cancer patients with disseminated intravascular coagulation syndrome, i.e., thrombocytopenia and elevated fibrinogen levels. Despite the presence of coagulation abnormalities and effective anticoagulation in recipient animals, all three agents were without effect on localization patterns of both tumor types. It was concluded that the proposed involvement of thrombogenesis in metastasis was probably not due to any role played by those clotting factors inhibited by aspirin, warfarin and heparin in early intravascular tumor cell arrest.

Topics: Animals; Anticoagulants; Aspirin; Blood Coagulation; Carcinoma; Heparin; Lymphoma, Non-Hodgkin; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neoplastic Cells, Circulating; Thromboplastin; Warfarin

Heparin and warfarin inhibit the intravascular survival of B16 melanoma cells in syngeneic C57B1/6J mice in a dose-related manner. The anticoagulant properties of these drugs appear to mediate their inhibitory effects on the survival of intravascular tumor cells. Despite the administration of large doses of heparin, a constant fraction of tumor cells survive to form lung tumors. These data indicate that coagulation dependent and coagulation independent populations of B16 cells normally survive following the intravenous injection of tumor cells.

Topics: Animals; Blood Coagulation; Cell Line; Cell Survival; Heparin; Lung Neoplasms; Male; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Prothrombin Time; Warfarin

A study was made of the effect of various cytotoxic drugs on the ability of i.v.-injected KHT sarcoma cells to form lung colonies in syngeneic C3H mice. Some enhancement of the number of lung colonies following an i.v. injection was seen following pretreatment of the mice with actinomycin D and mithramycin, while pretreatment with vinblastine, bleomycin, methotrexate, cytosine arabinoside, or 5-fluorouracil had little or no effect on lung colony formation. Pretreatment of the mice with cyclophosphamide, however, greatly increased lung colony formation (by a factor of approximately 100). This enhancement in lung colony formation was maximal when the drug was given 24 hr prio to the injection of tumor cells, but was seen as early as 2 hr and persisted as long as 8 weeks prior to the tumor cell injection. The degree of enhancement of lung colony formation was related to the dose of cyclophosphamide and was present in weaning as well as adult mice. This enhancement was not significantly reversed by anticoagulation with either aspirin or warfarin. Immunosuppression by whole-body irradiation did not affect the number of lung colonies seen in cyclophosphamide-treated mice. The mechanism by which cyclophosphamide enhances metastatic tumor growth within the lung is not known. The major effect, however, does not appear to be mediated either by specific immunological or clotting factors.

Topics: Age Factors; Animals; Antineoplastic Agents; Aspirin; Cyclophosphamide; Dactinomycin; Dose-Response Relationship, Drug; Female; Immunosuppression Therapy; Lung Neoplasms; Mice; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasm Transplantation; Plicamycin; Radiation Effects; Sarcoma, Experimental; Warfarin

Anticoagulation with warfarin is effective in decreasing experimental metastases, presumably by preventing the fibrin coagulum demonstrated to be necessary for the lodging of tumor cells. To determine the optimal level of anticoagulation for maximal antimetastatic effect, two similar experiments were completed with a methylcholanthrene-induced sarcoma in C57Bl mice. Footpad tumors were produced by tumor cell injection and the mice were divided into four equal groups: control, and groups on 1, 2, and 3 mg. per liter of warfarin, respectively. Control and anticoagulated mice were amputated at the same interval. Three weeks after amputation, all were killed and their metastases were quantitated. Prothrombin times ranged from 10 seconds in the control to 30 seconds in the 3 mg. per liter group. In Experiment 1, there was a significant reduction of pulmonary metastases at all levels of anticoagulation. The controls showed a mean number of 7.7 metastases per mouse, as compared to 2.9 (p less than 0.002) at 1 mg. per liter, 2.1 (p less than 0.0035) at 2 mg. per liter, and 0.7 (p less than 0.002) at 3 mg. per liter. In Experiment 2, the significant effect was found only at the 3 mg. per liter dose, with those mice having 2.3 metastases per mouse as compared with 5.5 in the controls (p less than 0.0001). We conclude that full anticoagulation in the range of 2.5 to 3 times normal is required for a maximal antimetastatic effect.

Topics: Animals; Blood Coagulation; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Prothrombin Time; Sarcoma, Experimental; Warfarin

Topics: Animals; Doxorubicin; Drug Synergism; Mice; Neoplasm Metastasis; Neoplastic Cells, Circulating; Sarcoma, Experimental; Warfarin

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; Aged; Autopsy; Biopsy; Carcinoma; Female; Fluorouracil; Humans; Laparotomy; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Spironolactone; Testolactone; Warfarin

Topics: Adenocarcinoma; Animals; Aspirin; Heparin; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neoplastic Cells, Circulating; Sodium Chloride; Warfarin

Topics: Animals; Fibrinolysin; Heparin; Injections, Intravenous; Neoplasm Metastasis; Neoplasms, Experimental; Protamines; Rats; Warfarin

Topics: Adenocarcinoma; Animals; Female; Fluorouracil; Leukemia L1210; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Warfarin

Topics: Animals; Anticoagulants; Fibrin; Fibrinolytic Agents; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Warfarin

Topics: Adenocarcinoma; Animals; Blood Coagulation; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Monitoring, Physiologic; Neoplasm Metastasis; Neoplasm Transplantation; Prothrombin Time; Sarcoma, Experimental; Time Factors; Transplantation, Homologous; Warfarin

Topics: Animals; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Neoplasm Metastasis; Prothrombin Time; Sarcoma; Time Factors; Warfarin

Long-term oral administration of sodium warfarin significantly reduced the incidence of spontaneous metastases in the lungs from 83 percent in controls to 8 percent in treated C57/BL/6N mice. The size and weight of primary tumors in mice treated with warfarin were less than in control mice. Length of survival was unaffected.

Topics: Animals; Female; Lung Neoplasms; Methylcholanthrene; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Warfarin

Topics: Animals; Anticoagulants; Cell Biology; Cell Movement; Humans; Leukocytes; Lymphocytes; Macrophages; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Prothrombin Time; Rabbits; Thrombosis; Warfarin

Topics: Animals; Carcinoma 256, Walker; Lung Neoplasms; Neoplasm Metastasis; Rats; Warfarin

Topics: Acenocoumarol; Aged; Anticoagulants; Cerebrovascular Disorders; Coronary Disease; Dicumarol; Drug Therapy; Ethyl Biscoumacetate; Geriatrics; Humans; Incidence; Middle Aged; Mortality; Neoplasm Metastasis; Neoplasms; Pathology; Phenindione; Thromboembolism; Warfarin