Antitumor and antivascular effects of AC-7700, a combretastatin A-4 derivative, against rat liver cancer

Abstract

Unlike the many chemotherapeutic agents that do not effectively stop blood flow or induce necrosis in hepatocellular carcinoma, AC-7700 has been shown to inhibit tubulin polymerization and selectively stop tumor blood flow. The aim of this study was to elucidate the antivascular and antitumor effects of AC-7700 on rat hepatoma. AH-130 cells, a rat hepatoma cell line, were solidified and implanted into the liver of Donryu rats. Vascularity of the liver tumor was directly identified by in-vivo fluorescence microscopy from 0 to 60 min after the injection of 10 mg/kg AC-7700. To observe the antivascular effect of AC-7700, the vascular density of the tumor was measured and assessed as the ratio of preinjection to postinjection values. The antitumor effects were evaluated with histopathologic findings and analysis of animal survival. In-vivo microscopic observation showed that tumor perfusion diminished within 30 min after AC-7700 administration. Vascular density in the AC-7700 group was significantly less than that in the control group at 60 min (AC-7700, 26.3 +/- 16.4%; control, 88.5 +/- 9.2%; P < 0.001). After AC-7700 injection, marked necrosis of tumor cells was observed histologically, and tumor area was decreased significantly (AC-7700, 11.5 +/- 15.4 mm2; control, 43.5 +/- 18.3 mm2; P < 0.05). The survival rate (50%) of the AC-7700 group animals was better than that of the control group (0%; P < 0.01). Markedly decreased tumor perfusion was induced by AC-7700 within 30 min, and this decrease may have contributed to the tumor necrosis and favorable outcome in the treatment group. AC-7700 appears to be a promising agent for the treatment of hepatocellular carcinoma.