Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy.

Abstract

Human plasminogen-derived angiostatin is one of the most potent antiangiogenic agents currently known. However, it is unclear whether angiostatin is also effective against accelerated tumor growth induced by local up-regulation of growth factors, including angiogenesis stimulators, such as in regenerating liver. Prior to addressing this question, we tested, in mice, whether continuous administration of angiostatin could improve its biological effects. This assumption was based on the relatively short half-life of angiostatin in mice, as well as on the theoretical necessity to suppress tumor-induced angiogenesis continually. The findings presented here clearly indicate continuous administration to be superior to the conventional twice-daily bolus injections. Using the maximally effective regimen of 100 mg/kg/day via s.c. pump infusion, we found angiostatin to not only suppress s.c. primary tumors but also to significantly inhibit the outgrowth of colorectal hepatic metastases in resting liver and even to inhibit accelerated tumor growth in regenerating liver after 70% partial hepatectomy. In conclusion, angiostatin could play an important role in patients subjected to partial hepatectomy to prevent outgrowth of residual micrometastases, provided it is administered continuously to obtain maximal biological effects.