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Oral thrombostatin FM19 inhibits prostate cancer

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Topic:

Theme Issue Ratnoff Symposium 2009

DOI: http://dx.doi.org/10.1160/TH09-08-0570
Issue: 2010: 104/5 (Nov) pp. 863-1082
Pages: 1044-1048

Oral thrombostatin FM19 inhibits prostate cancer

M. T. Nieman (1), G. LaRusch (1), C. Fang (1), Y. Zhou (1), A. H. Schmaier (1)

(1) Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

Keywords

Prostate cancer, anticoagulation, oral direct thrombin inhibitor, cancer treatment

Summary

Thrombin stimulates proliferation, invasion and metastasis by cleaving protease-activated receptor 1 (PAR1) on human prostate cancer cells. Current direct thrombin inhibitors pose risks for bleeding in the cancer patients. We have developed an oral reversible direct thrombin inhibitor called FM19. FM19 inhibits thrombin-induced calcium mobilisation of PC3 cells with an IC50 of 15 μM with a 95% confidence interval of 7.3–31.6 μM. Thrombin stimulation increases PC3 cell invasion three-fold from 27.1 ± 11.4 to 66 ± 11.6. FM19 or bivalirudin reduces cell invasion at ≥0.1 μM (p≤0.02). After inoculation with PC3 cells, nude mice were treated with oral FM19 at 3 mg/ml in the drinking water. The treated mice did not have long bleeding times and only a 1.4-fold increase in their thrombin clotting time. However, with treatment, the mice have a reduced rate of tumour growth 0.26 ± 0.17 fold change/day vs. 0.55 ± 0.35 for untreated (p = 0.038), reduced fold change in tumour size 5.3 ± 0.47 to 8.9 ± 1.8 (untreated) (p=0.048), and reduced overall tumour weight 0.5 ± 0.31 g vs. 0.82 ± 0.32 g (untreated) (p=0.04). On microscopic examination, FM19 treatment reduces the number of large vessels in the tumours from 4.6 ± 2.1 per high-powered field in untreated samples to 1.4 ± 1.4 in treated samples (p≤0.04). These studies show FM19 reduces prostate tumour growth in vivo at a concentration below that needed for anticoagulation. These data suggest novel opportunities for oral direct thrombin inhibitors in cancer therapy.

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