INHIBITORY EFFECTS OF THE ANTIANGIOGENIC AGENT TNP-470 ON ESTABLISHMENT AND GROWTH OF HEMATOGENOUS METASTASIS OF HUMAN PANCREATIC-CARCINOMAIN SCID BEIGE MICE IN-VIVO

Effects on the liver of the antiangiogenesis agent O-(chloroacetyl-car bamoyl) fumagillol (TNP-470) on hematogenous metastasis of a human pan creatic carcinoma cell line were examined. One million PCI-43 cells, a human pancreas carcinoma cell line, were injected into the spleen of SCID beige mice, then TNP-470 at 30 mg/kg was administered subcutaneou sly every other day. The mice were killed 6 or 10 weeks thereafter and metastatic nodules in the liver were counted and measured microscopic ally. Metastases were inhibited and an similar to 10% loss of weight w as evident in the TNP-470-administered mice. There was no suppression in maximal size of metastatic colonies in mice given the agent for 6 w eeks, while inhibition was apparent in mice given the drug for 10 week s. Suppression of proliferation and an increase in apoptosis were evid ent in metastatic nodules in the TNP-470-administered groups, followin g stainings for proliferative cell nuclear antigen and terminal deoxyt ransferase-mediated dUTP-biotin nick endlabeling, respectively. TNP-47 0 inhibited the proliferation of human umbilical vein endothelial cell s but not PCI-43 in vitro. TNP-470 did not suppress production of vasc ular endothelial growth factor by PCI-43 cells. Neovascularization in vivo induced by PCI-43 cells was suppressed in the TNP-470-administere d mice, using a diffusion chamber placed in subcutaneous tissues of SC ID beige mice. These observations suggest that inhibition of angiogene sis is effective in suppressing establishment and subsequent growth of hematogenous micrometastases of pancreatic adenocarcinoma to the live r.