Antithrombotics Inhibit Tumor Metastasis

Abstract number: P1802

Brüggemann¹ LW, Versteeg² HH, Reitsma¹ PH, Spek¹ CA

¹¹Laboratory for Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands ¹¹Laboratory for Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands ²²Dept. of Immunology, C204, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

The coagulation system plays a dual role in tumor biology. On the one hand tumors may increase susceptibility for thrombosis, on the other hand treatment with anti-thrombotics may protect against metastasis. We set out to study the antimetastatic effect in more detail in a mouse melanoma metastasis model. Normal mice or fibrinogen depleted mice (using Ancrod; 1.5 U/mouse) (C57Bl/6) were injected with 3 · 10⁵ B16F0 melanoma cells in the tail vein. Metastases in the lung were scored 2 weeks after injection. Single doses of the following anti-thrombotic compounds were administered 30 minutes before injection of the melanoma cells: 1) Low molecular weight heparin (Fraxiparin, a combined FXa/thrombin inhibitor; 600 UaXa/kg), 2) Tick Anti-Coagulant protein (TAP, FXa inhibitor; 25 µl 200 mM), 3) Active-site inactivated FVIIa (2.5 mg/kg) and 4) PEG-hirudin (specific thrombin inhibitor, 10 mg/kg). In addition a group of mice were treated with PEG-hirudin 3.5 days after injection of melanoma cells. All inhibitors diminished the number of metastases compared to the untreated control group. Pretreatment with PEG-hirudin showed the most striking effect by decreasing the number of metastases from 300 ± 48 to 7 ± 9 (P= 0.03). The corresponding figures for the other compounds were: Fraxiparin 150 ± 60, TAP 120 ± 90 and FVIIai 100 ± 75. Delayed treatment with PEG-hirudin diminished the number of metastases to 150 ± 60 (P= 0.05), indicating that thrombin inhibition at the early stage of metastasis is clearly favorable. Depletion of fibrinogen had no effect on the number of metastases (260 ± 150, P= 0.5), inhibition of PAR-1 on the tumor cells showed a significant reduction (to 140 ± 80) in metastases, whereas PAR-1 inhibition of the host marginally reduced metastasis (280 ± 30). Overall, these data indicate that anticoagulant drugs diminish metastasis by early stage thrombin-inhibition (probably inhibiting adhesion or migration of tumor cells) in a coagulation independent manner.