o-(chloroacetylcarbamoyl)fumagillol and Postoperative-Complications

Early relapse with distant metastasis often is observed in patients with cancer after resection of the primary tumor. It is considered that resection of the primary tumor induces activation of systemic angiogenesis and enhances progression of remote metastasis. The authors show that resection of the primary osteosarcoma tumor enhances progression of pulmonary metastasis in animal osteosarcoma models. Matrigel plug neovascularization assay revealed that systemic angiogenic activity was elevated after primary tumor removal (tumor intact group, 1.61 +/- 0.21 g/dL; tumor removed group, 4.92 +/- 0.35 g/dL). In addition, serum concentration of the angiogenesis inhibitor, endostatin, decreased significantly after primary tumor removal. Treatment with the antiangiogenic reagent TNP-470 suppressed postoperative progression of pulmonary metastasis. These results indicate the possibility that activation of angiogenic activity after resection of osteosarcoma tumors enhances progression of pulmonary metastasis. The current data also suggest that administration of antiangiogenic reagents can prevent progression of pulmonary metastasis in osteosarcoma postoperatively.

Topics: Angiogenesis Inhibitors; Animals; Bone Neoplasms; Collagen; Cyclohexanes; Disease Models, Animal; Endostatins; Endothelial Growth Factors; Female; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Lymphokines; Mice; Mice, Inbred BALB C; O-(Chloroacetylcarbamoyl)fumagillol; Osteosarcoma; Peptide Fragments; Postoperative Complications; Sesquiterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Anastomotic intimal hyperplasia (AIH) remains an unsolved problem. Angiogenesis around the anastomosis is one of the important mechanisms accelerating AIH. In this study, we investigated the effects of an antiangiogenic agent AGM-1470 (O-[chloroacetyl-carbamoyl] fumagillol: AGM) on the thickness of AIH after expanded polytetrafluoroethylene grafting.. Study 1: Smooth muscle cells (SMCs) were cultured to form 3-mm-side square colonies by using 4 kinds of culture medium, containing AGM at concentrations of 0, 0.1, 1.0, and 10 ng/mL. The SMC colony spreading distance in each group was measured as an index of mitogenic activity. The isolated proliferative activity of SMCs was also assessed. Study 2: Male New Zealand white rabbits underwent inlay expanded polytetrafluoroethylene grafting of the carotid arteries. They were divided in 4 groups (control, vehicle, AGM [0.5], and AGM [5]) in which no topical application, Vaseline ointment, Vaseline ointment containing 0.5 mg AGM, or Vaseline ointment containing 5 mg AGM was applied to the anastomoses, respectively. Rabbits were fed a high-cholesterol diet for 2 weeks before and 8 weeks after the operation. AIH thickness was measured and capillary formation and SMC accumulation around the anastomoses were examined with immunohistochemical staining.. Study 1: AGM suppressed SMC migratory activity in a cytostatic, but not cytotoxic, manner. Study 2: AGM ointment inhibited AIH in proportion to its concentration and also suppressed new capillary formation around the anastomoses and SMC accumulation in AIH.. Topical application of the antiangiogenic agent AGM may become an important strategy for preventing AIH.

Topics: Angiogenesis Inhibitors; Animals; Blood Vessel Prosthesis; Carotid Arteries; Cell Division; Cell Movement; Cells, Cultured; Coloring Agents; Cyclohexanes; Hypercholesterolemia; Hyperplasia; Male; Models, Animal; O-(Chloroacetylcarbamoyl)fumagillol; Ointments; Polytetrafluoroethylene; Postoperative Complications; Rabbits; Sesquiterpenes; Tunica Intima; Vascular Patency