Oral thrombostatin FM19 inhibits prostate cancer.

Abstract

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.

• Authors: Marvin T Nieman, Gretchen LaRusch, Chao Fang, Yihua Zhou, Alvin H Schmaier
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 104 Issue 5 Pg. 1044-8 (Nov 2010) ISSN: 2567-689X [Electronic] Germany
• PMID: 20886199 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antithrombins
• Peptide Fragments
• bradykinin (1-5)
• Thrombin
• Bradykinin

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage)
• Antithrombins (administration & dosage)
• Blood Coagulation (drug effects)
• Bradykinin (administration & dosage)
• Calcium Signaling (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Peptide Fragments (administration & dosage)
• Prostatic Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Thrombin (antagonists & inhibitors, metabolism)
• Time Factors
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays