title: Regression of Novikoff rat hepatocellular carcinoma following locoregional administration of a novel formulation of clofazimine in lipiodol.
abstract: We report here that, clofazimine (CFZ) treatment (0.1-10 microM) 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 microM), 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.
authors.affiliation: Department of Surgery, St George Hospital, University of New South Wales, Kogarah, Sydney, NSW 2217, Australia.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Pourgholami
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Ross W
authors.initials: RW
authors.lastname: Stephens
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D001391:Azo Compounds / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002991:Clofazimine / Q000627:therapeutic use*; D004396:Coloring Agents / Q000494:pharmacology; D003287:Contrast Media / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D007459:Iodized Oil / Q000494:pharmacology / Q000627:therapeutic use*; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D013997:Time Factors
chemical_list: D001391:Azo Compounds; D004396:Coloring Agents; D003287:Contrast Media; D007459:Iodized Oil; D002991:Clofazimine; C011049:oil red O