Antimetastatic effect of tinzaparin, a low-molecular-weight heparin

Abstract

The importance of coagulation activation in cancer patients is suggested by the clinical finding of hypercoagul-ability, experimental enhancement of metastasis and angiogenesis by coagulation factors such as tissue factor (TF) and thrombin and the possible antitumor effects of anticoagulant agents. Tinzaparin is a low-molecular-weight heparin (LMWH) with a relatively high molecular weight distribution and high sulfate to carboxylate ratio. In addition to its ability to inhibit thrombin and factor Xa, tinzaparin is particularly effective at releasing endothelial tissue factor pathway inhibitor (TFPI), the natural inhibitor of both procoagulant and non-coagulant effects of TF. The present study was undertaken to investigate the effect of tinzaparin on lung metastasis using a B16 melanoma model in experimental mice. Tinzaparin's anticoagulant effect in mice and its ability to release TFPI from human endothelial cells at various time points were demonstrated. Subcutaneous (s.c.) injection of tinzaparin (lOmg kg 1) 4h before intravenous administration of melanoma cells (2.0 × 10 5) markedly (89%) reduced lung tumor formation (3 ± 2) compared with controls (31 ±23; P< 0.001). In a second group of animals, tinzaparin (l0 mg kg -1, s.c.) administered daily for 14days following the initial (pretumor cell) dose, before assessment of lung seeding, reduced tumor formation by 96% (P < 0.001). No bleeding problems were observed in any of the tinzaparin-treated animals, despite a 4-fold prolongation of the whole blood clotting time after a single s.c. dose of tinzaparin (l0 mg kg -1). Administration of tumor cells (2 × 10 6) caused a rapid and significant fall in platelet count 15 min after injection (a sensitive marker of intra vascular coagulation) in controls (939±37 vs. 498±94 × 10 6 mL -1, P<0.01), but this was prevented by tinzaparin treatment (921 ± 104 × 10 6 mL -1). These data provide further experimental evidence to support the potential for LMWH as antimetastatic agents. © 2003 International Society on Thrombosis and Haemostasis.