Suppression of pulmonary metastasis by angiogenesis inhibitor TNP-470 in murine osteosarcoma.
We treated a murine osteosarcoma cell line, LM8, which preferentially metastasizes to the lungs, with a new angiogenesis inhibitor, TNP-470, to evaluate the efficacy of this compound in the suppression of pulmonary metastasis of osteosarcoma. In an in vivo experiment, tumor cells were inoculated i.v. into C3H mice, and TNP-470 or vehicle alone (control group) was administered s.c. every day for 3 weeks. In the TNP-470-treated groups, both the number of pulmonary metastatic nodules and the lung wet weight were significantly reduced in a dose-dependent manner. Similarly, vascular density in the metastatic tumors estimated by immunohistochemical staining with anti-von-Willebrand factor antibody as an endothelial marker were significantly reduced. No severe side-effects were found. In an in vitro experiment, viable tumor cells were counted after 3 days' treatment with TNP-470. The 50% inhibitory concentration was 0.6 ng/ml for LM8, which was more sensitive than other tumor cells previously reported. Our results show that TNP-470 suppresses the pulmonary metastasis of LM8 and suggest that both its anti-angiogenic activity and cytostatic activity towards LM8 are responsible for the antitumor effect.
Mori
S
S
Department of Orthopedic Surgery, Center for Adult Diseases, Osaka, Japan.
Ueda
T
T
Kuratsu
S
S
Hosono
N
N
Izawa
K
K
Uchida
A
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D008175:Lung Neoplasms / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012516:Osteosarcoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol