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 potent angiogenesis inhibitor, TNP-470, on tumor growth in a syngeneic rodent model of liver metastases from colorectal cancer.


BACKGROUND
New blood vessel formation is a prerequisite for primary and metastatic tumor growth. TNP-470, a synthetic derivative of fumagillin when subcutaneously transplanted into nude mice, inhibits endothelial cell proliferation and migration, as well as the growth of various human cancers. However, the antitumor effect of this drug has not been studied in models reproducing a natural metastatic environment. Since the liver provides an extensive vascular bed for secondary tumor growth, an anti-angiogenic strategy may therefore be less efficient for treating hepatic metastases than primary tumors.


METHODS
10(7) DHD K12 colon carcinoma cells were injected intrasplenically into syngeneic BD IX rats to produce diffuse liver metastases. TNP-470 (30 mg/kg/day) was administered on alternate days starting 4 days after tumor implantation. The animals were sacrificed after 4 weeks and their livers were processed for histologic examination. In both the treatment and control groups (n=7), tumor volume was determined using a computerized analytical system, and tumor microvessel density was measured by immunostaining with anti-von Willebrand Factor monoclonal antibody.


RESULTS
In vitro, TNP-470 demonstrated a direct toxicity towards the DHD K12 cell line with an IC50 of 0.1 microg/ml. Metastases were present in all animals from both groups. Liver weight (15.2 g vs 11.7 g, p=0.01), and tumor volume (1218 mm3 vs 406 mm3, 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 groups (67 vs 63 microvessels/x200 field, p=0.41).


CONCLUSIONS
TNP-470 inhibits the growth of liver metastases in a syngeneic rat model of colorectal cancer. The mechanism responsible for this effect remains unclear, but may involve a combination of anti-angiogenic and direct cytotoxic effects.
Gervaz
P
P
Department of Surgical Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Scholl
B
B
Padrun
V
V
Gillet
M
M
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D003510:Cyclohexanes; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol