The importance of coagulation activation in
cancer patients is suggested by the clinical finding 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-1) 4 h before
intravenous administration of
melanoma cells (2.0 x 105) markedly (89%) reduced lung
tumor formation (3 +/- 2) compared with controls (31 +/- 23; P < 0.001). In a second group of animals,
tinzaparin (10 mg kg-1, 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
tinzaparin-treated animals, despite a 4-fold prolongation of the whole blood clotting time after a single s.c. dose of
tinzaparin (10 mg kg-1). Administration of
tumor cells (2 x 106) caused a rapid and significant fall in platelet count 15 min after injection (a sensitive marker of intravascular coagulation) in controls (939 +/- 37 vs. 498 +/- 94 x 106 mL-1, P < 0.01), but this was prevented by
tinzaparin treatment (921 +/- 104 x 106 mL-1). These data provide further experimental evidence to support the potential for
LMWH as antimetastatic agents.