Anti-thrombotics in thrombosis and cancer
Pharmaceutical Research Institute (PRI), Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208-3492, USA.Future Oncology (Impact Factor: 2.48). 07/2005; 1(3):395-403. DOI: 10.1517/14796618.104.22.1685
Many cancer patients have a reportedly hypercoagulable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin or its low-molecular-weight fractions interfere with various processes involved in tumor growth and metastasis. These include fibrin formation; binding of heparin to angiogenic growth factors, such as basic fibroblast growth factor and vascular endothelial growth factor; modulation of tissue factor; and perhaps other more important modulatory mechanisms, such as enhanced tissue factor pathway inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of low-molecular-weight heparin (LMWH), as compared with unfractionated heparin, on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Studies from the author's laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa, and LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth and tumor metastasis. Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH, warfarin, anti-VIIa, or TFPI may be a useful therapeutic method for the inhibition of angiogenesis associated with human tumor growth and metastasis. Additionally, antiplatelet drugs may have an impact on tumor metastasis, and the combination of antiplatelets and anticoagulants at adjusted doses may provide greater benefits to cancer patients.
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ABSTRACT: Low-molecular-weight heparins (LMWH) exhibit potent anticoagulant efficacy via their plasmatic effects on thrombin and factor Xa. These agents are also effective in releasing endothelial tissue factor pathway inhibitor (TFPI), the natural inhibitor of tissue factor, and exhibit significant anti-metastatic effects in experimental animal models. However, the potential for bleeding complications has slowed down the more widespread adoption of LMWH therapy in cancer patients. In this study, the effect of a non-anticoagulant form of LMWH (NA-LMWH) on experimental lung metastasis and tumor cell-induced platelet aggregation in vivo was compared to the LMWH enoxaparin. Using the B16 melanoma mouse model of metastasis, subcutaneous (s.c.) injection of NA-LMWH or enoxaparin (10 mg/kg), three hours before intravenous (i.v.) injection of metastatic melanoma cells, followed by daily doses for 14 days, reduced lung tumor formation by 70% (P < 0.001). I.v. injection of tumor cells resulted in a significant (50-62%, P < 0.01) fall in platelet counts. Pre-injection (i.v.) of enoxaparin completely abolished the tumor cell-induced thrombocytopenia, whereas NA-LMWH had no effect. Four hours after a single s.c. dose, enoxaparin but not NA-LMWH prolonged the clotting time three-fold and delayed the time to clot initiation more than 10-fold as measured by a Sonoclot analyzer and by thromboelastography, respectively. Enoxaparin but not NA-LMWH demonstrated a significant anticoagulant effect in mice. Both NA-LMWH and enoxaparin caused similar TFPI release from endothelial cells in vitro. These data provide evidence to support the potential of NA-LMWH as an anti-metastatic agent without any significant impact on coagulation.Thrombosis and Haemostasis 12/2006; 96(6):816-21. DOI:10.1160/TH06-05-0289 · 4.98 Impact Factor
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ABSTRACT: Stress and depression were reported as negative prognostic factors in breast cancer patients and monoamine oxidase (MAO) activity was considered a marker of mental suffering. MAO activity in platelets was determined in a group of newly diagnosed breast cancer patients, after the communication of diagnosis and surgery, using the Mental Adjustment to Cancer (MAC) and Hospital Anxiety and Depression scales (HADS). The analysis of regression indicated that hopelessness-helplessness positively correlated with depression, anxiety and anxious preoccupation. Monoamine oxidase (MAO) activity displayed a positive regression coefficient with depression score. At follow-up, Cox analysis of survival indicated that MAO activity was a marginally significant risk factor. Further research in a larger group of patients may support the present results, showing that MAO activity is a biological marker of difficulties in mental adaptation to cancer and is a risk factor for survival.Anticancer research 05/2007; 27(3B):1715-9. · 1.83 Impact Factor
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ABSTRACT: The overexpression of multidrug resistance protein (MRP1), associated with high levels of intracellular glutathione (GSH), is a well characterized mechanism of multidrug resistance (MDR) in several malignancies. Various chemosensitizers have been used in vitro to modulate the MRP1 activity, but the high toxicity limits their clinical application. Unfractionated heparin (UFH), is frequently used to prevent thrombo-embolic complications in cancer patients. This in vitro study aimed to elucidate the potential role of UFH as a sensitizer in anticancer clinical chemotherapy. The human leukemic doxorubicin-resistant cell line (HL60/doxo), which overexpresses the MRP1 protein was treated with UFH alone or in combination with three different concentrations of doxo. The intracellular accumulation and cytotoxicity of doxo and the cellular GSH content were measured in comparison with the leukotriene LTD4 receptor antagonist, MK571, a specific MRP1 inhibitor. UFH increased doxo accumulation and cytotoxicity in the HL60/doxo cell line with respect to cells treated with doxo alone. UFH also decreased the cellular GSH content in the HL60/doxo cells with respect to the control, suggesting a potential involvement of UFH in doxo co-transport with GSH. Our results demonstrate that UFH modulates MRP1-mediated MDR in HL60/doxo cells expressing high MRP1 levels. These findings suggest a potential clinical application of heparin as an adjuvant to overcome MRP1-mediated drug resistance in cancer patients.Anticancer research 01/2007; 27(1A):351-5. · 1.83 Impact Factor
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