title: Thrombin inhibitor, argatroban, prevents tumor cell migration and bone metastasis.
abstract: It is well known that malignant cells show procoagulant activity, which is associated with their metastatic potential. Thrombin, the key enzyme of the blood coagulation system, is generated around tumor cells, promoting the migration and metastasis of tumor cells. In this study, we evaluated the effect of argatroban, a specific thrombin inhibitor, on the migration and metastasis of B16BL6 melanoma cells. In vitro argatroban dose-dependently inhibited cell migration, the maximum inhibition being observed in the presence of 10 microM argatroban (p < 0.0001). In order to investigate the antimetastatic effect of the thrombin inhibitor, we used an animal model that we have reported previously. C57BL6 mice which had received a bone (femur or tibia) transplanted into the dorsal subcutis were injected with B16 melanoma cells into the left heart ventricle. Intraperitoneal injection of argatroban (9 mg/kg/day for 4 weeks) significantly reduced the number of limbs with metastatic lesions as compared to a placebo (p < 0.05). These results suggest that argatroban was associated with reduced melanoma metastases by inhibiting cell migration. Our results showed that argatroban is effective for treatment of bone metastasis.
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu City, Japan. Barbon1865@aol.com
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Asanuma
authors.forename: Hiroki
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hayashi
authors.forename: Noritaka
authors.initials: N
authors.lastname: Okuyama
authors.forename: Masashi
authors.initials: M
authors.lastname: Seto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Matsumine
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kusuzaki
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Atsumasa
authors.initials: A
authors.lastname: Uchida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000991:Antithrombins / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D010875:Pipecolic Acids / Q000494:pharmacology*; D013449:Sulfonamides
chemical_list: D000970:Antineoplastic Agents; D000991:Antithrombins; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban