title: 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.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Marvin T
authors.initials: MT
authors.lastname: Nieman
authors.forename: Gretchen
authors.initials: G
authors.lastname: LaRusch
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhou
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Schmaier
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000991:Antithrombins / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000991:Antithrombins; D010446:Peptide Fragments; C079000:bradykinin (1-5); D013917:Thrombin; D001920:Bradykinin