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

Abstract

To cite this article: Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a low-molecular-weight heparin. J Thromb Haemost 2003; 1: 1972±6. See also lorio A et al. Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants. This issue, pp. 1906±13.Summary. The importance of coagulation activation in cancer patients is suggested by the clinical ®nding of hypercoagulability, 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 (10 mg kg À1 ) 4 h before intravenous administration of melanoma cells (2.0 Â 10 5 ) markedly (89%) reduced lung tumor formation (3 AE 2) compared with controls (31 AE 23; P < 0.001). In a second group of animals, tinzaparin (10 mg kg À1 , s.c.) administered daily for 14 days 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 tinzaparintreated animals, despite a 4-fold prolongation of the whole blood clotting time after a single s.c. dose of tinzaparin (10 mg kg À1 ). Administration of tumor cells (2 Â 10 6 ) caused a rapid and signi®cant fall in platelet count 15 min after injection (a sensitive marker of intravascular coagulation) in controls (939 AE 37 vs. 498 AE 94 Â 10 6 mL À1 , P < 0.01), but this was prevented by tinzaparin treatment (921 AE 104 Â 10 6 mL À1 ). These data provide further experimental evidence to support the potential for LMWH as antimetastatic agents.

Long‐term thrombin inhibition promotes cancer cell extravasation in a mouse model of experimental metastasis

“…The direct thrombin inhibitor hirudin, for instance, dramatically reduced the number of lung metastases when administered just before cancer cell inoculation [6]. With indirect thrombin inhibitors, namely LMWHs, comparable effects have been observed, although not as dramatic as with hirudin treatment [7,8]. Unfortunately, hirudin has to be administered via subcutaneous injections and has a rather narrow therapeutic window [9], compromising its safety.…”

Heparin-Like Drugs with Antiangiogenic Activity

“…LMWH present important advantages if compared to UFH: enhanced bioavailability after subcutaneous administration, prolonged half-life and more interesting pharmacokinetic properties, reduced thrombocytopenia and a more predictable dose response (Grande & Caparro, 2005;Khorana et al, 2003). (Amirkhosravi et al, 2003;Gasowska et al, 2009;Mousa & Mohamed, 2004a;Mousa & Mohamed, 2004b;Mousa & Petersen, 2009;Norrby, 2006) Dalteparin Fragmin Nitrous acid depolymerization 6.000 (Khorana et al, 2003;Marchetti et al, 2008;Norrby, 2006;Norrby & Nordenhem, 2010;Takahashi et al, 2005) Enoxaparin Clexane…”

Heparin as an Inhibitor of Cancer Progression

“…There is accumulating evidence that heparin, apart from its anticoagulant activity, can block P-and L-selectin, affect activity of growth factors and cytokines, release tissue factor pathway inhibitor (TFPI), inhibit heparanase and angiogenesis, alter interactions with integrins and modulate protease activity and thereby the composition of extracellular matrix [15,29,[31][32][33][34][35]. While any of these activities may affect cancer progression (Figure 1), the experimental evidence from a number of studies strongly indicates that heparin affects early events in the metastatic cascade.…”

“…Heparins have also the ability to release tissue factor pathway inhibitor (TFPI) from the blood vessel walls and thereby affect metastasis [35]. Application of LMWH -Tinzaparin led to a reduction of metastasis.…”

“…Application of LMWH -Tinzaparin led to a reduction of metastasis. Intravenous injection of recombinant TFPI at the time of tumor cell injection significantly attenuated metastasis of melanoma [35,48]. The extent of heparin mediated TFPI release and its contribution to inhibition of cancer progression requires further in vivo investigation in the context of other non-anticoagulant activities of heparin.…”