Growth inhibition of liver metastases by the anti-angiogenic drug TNP-470

Objective: This study was undertaken in order to assess the efficacy of a p otent angiogenesis inhibitor, TNP-470, on tumor growth in a syngeneic roden t model of liver metastases from colorectal cancer. Background: New blood v essel formation is a prerequisite for primary and metastatic tumor growth. TNP-470, a synthetic derivative of fumagillin when subcutaneously transplan ted into nude mice, inhibits endothelial cell proliferation and migration, as well as the growth of various human cancers. However, the antitumor effe ct of this drug has not been studied in models reproducing a natural metast atic environment. Since the liver provides an extensive vascular bed for se condary tumor growth, an antiangiogenic strategy may therefore be less effi cient for treating hepatic metastases than primary tumors. Methods: 10(7) D HD K12 colon carcinoma cells were injected intrasplenically into syngeneic ED IX rats to produce diffuse liver metastases. TNP-470 (30 mg/kg/day) was administered on alternate days starting 4 days after tumor implantation. Th e animals were sacrificed after 4 weeks and their livers were processed for histologic examination. In both the treatment and control groups (n=7), tu mor volume was determined using a computerized analytical system, and tumor microvessel density was measured by immunostaining with anti-von Willebran d Factor monoclonal antibody. Results: In vitro, TNP-470 demonstrated a dir ect toxicity towards the DHD K12 cell line with an IC50 Of 0.1 mu g/ml. Met astases were present in all animals from both groups. Liver weight (15.2 g vs 11.7 g, p=0.01), and tumor volume (1218 mm(3) vs 406 mm(3), p=0.03) were significantly reduced in the TNP-470 group compared to the control group. Tumor microvessel density was not statistically different between the two g roups (67 vs 63 microvessels/x200 field, p=0.41). Conclusion: TNP-470 inhib its the growth of liver metastases in a syngeneic rat model of colorectal c ancer. The mechanism responsible for this effect remains unclear, but may i nvolve a combination of anti-angiogenic and direct cytotoxic effects.