Angiogenesis inhibitor TNP-470 suppresses the progression of experimentally-induced hepatocellular carcinoma in rats

We evaluated the effects of angiogenesis inhibitor, TNP-470, on hepatocellu lar carcinoma (HCCs) induced by a choline-deficient L-amino acid defined (C DAA) diet in rats. Male Fisher 344 rats were fed CDAA for 68 weeks. Rats we re treated by subcutaneous injection of TNP-470 (15 mg/kg) or saline (contr ol) three times per week from 53 to 68 weeks. At the end of the experiment, we determined the frequency and size of HCCs and glutathione S-transferase placental form (GSTP)-positive lesions, histology of liver cirrhosis, live r function, and liver weight per body weight. We also determined, using his tologic and immunohistochemical semiquantification analyses, the degree of vascularity, apoptosis and proliferation in HCC and adjacent tissues. Treat ment with TNP-470 resulted in a reduction of the size and frequency of HCC compared to untreated rats. However, TNP-470 did not influence the histolog y of liver cirrhosis and liver function. The liver weight per body weight o f TNP-470-treated rats was slightly heavier in comparison with that of the controls. Treatment with TNP-470 significantly reduced tumor vascularity re lative to the controls. There were no significant differences in the Ki-67 labeling index of HCCs between TNP-470 treated and control rats. The freque ncy of apoptotic hepatoma cells in TNP-470-treated rats was higher than in control rats. Our results indicate that TNP-470 suppresses the progression of CDAA-induced HCCs in rats through inhibition of angiogenesis, and sugges t that TNP-470 might be useful clinically for HCCs.