Regression of Novikoff rat hepatocellular carcinoma following locoregional administration of a novel formulation of clofazimine in lipiodol

We report here that, clofazimine (CFZ) treatment (0.1-10 muM) led to inhibition of in vitro proliferation of hepatocellular carcinoma (HCC) cell lines Hep3-beta, HuH-7, HepG2, SKHEP-1, PLC/PRF-5 and Novikoff. A 24 h exposure of human HuH-7 cells to various concentrations of CFZ dissolved in lipiodol (CFZ-L 10-160 muM), followed by 4 days treatment with medium alone, also led to dose-dependant inhibition of post-treatment cell growth. In vivo, direct intratumoural and intrahepatic arterial injection (IHA) of CFZ-L led to profound inhibition of orthotopic growth of rat Novikoff liver tumours (P < 0.0001 and P < 0.005, respectively). On the contrary, daily oral administration of 150 mg/kg CFZ for 7 days, did not influence the rate of Novikoff tumour growth. Histological examination of rat tumours, revealed the presence of lipiodol in tumour cells, 7 days after treatment with a single IHA dose. Histopathology did not show any abnormality in liver, lung or bowel sections taken from animals 1 week after IHA administration of CFZ-L. Similarly, liver function tests were all normal compared to saline treated animals. Deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labelling revealed the presence of large numbers of apoptotic cells in the CFZ-L treated tumours. Thus, intraarterial administration of the highly lipophilic antiproliferative agent CFZ in lipiodol solution may represent an effective and yet safe strategy for the regional treatment of HCCs. (C) 2003 Elsevier Ireland Ltd. All rights reserved.