Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor.
Recombinant desulfatohirudin (r-hirudin), a highly specific inhibitor of thrombin, was examined to determine whether it would inhibit production of experimental lung metastasis by B16-F10 melanoma cells. In in vitro assays using mouse plasma, the high level of procoagulant activity in B16-F10 cells was significantly inhibited by r-hirudin in a dose-dependent manner. From 15 to 120 min after s.c. administration into C57BL/6 mice, r-hirudin (10 mg/kg) markedly prolonged clotting time in a time course pattern that directly correlated with that of blood distribution of 125I-labeled r-hirudin. The production of experimental lung metastasis by B16-F10 cells was significantly inhibited by r-hirudin administered s.c. at time points ranging from 120 min before to 60 min after tumor cell inoculation with the most significant effects found in mice given r-hirudin 15 or 2 min before the i.v. injection of tumor cells. The organ distribution of [125I]IdUrd-labeled tumor cells demonstrated a clear difference in the lungs of mice treated with r-hirudin and the lungs of control mice, and these differences directly correlated with the number of lung tumor colonies found 3 weeks later. The inhibition of lung metastasis was not due to direct antitumor effects of r-hirudin. These results suggest that inhibition of coagulation events by r-hirudin significantly inhibit experimental lung metastasis during a critical time of 60 min after the entry of tumor cells into the circulation.
Esumi
N
N
Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Fan
D
D
Fidler
I J
IJ
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000097:blood / Q000627:therapeutic use*; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000517:prevention & control* / Q000556:secondary*; D008546:Melanoma, Experimental / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; C060225:desirudin