Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin

Shaker A. Mousa; Robert Linhardt; John L. Francis; Ali Amirkhosravi

doi:10.1160/TH06-05-0289

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(06): 816-821
DOI: 10.1160/TH06-05-0289

Cellular Proteolysis and Oncology

Schattauer GmbH

Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin

Shaker A. Mousa

¹The Pharmaceutical Research Institute at Albany, Albany College of Pharmacy, Albany, New York, USA

,

Robert Linhardt

²Rensselaer Polytechnic Institute, Troy, New York, USA

,

John L. Francis

³Florida Hospital Institute of Translational Research, Orlando, Florida, USA

,

Ali Amirkhosravi

³Florida Hospital Institute of Translational Research, Orlando, Florida, USA

› Author Affiliations

Abstract

Summary

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 NALMWH 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.

Keywords

Heparin - low-molecular-weight heparin - metastasis - anticoagulant

Full Text

References

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