Chemoprevention of hepatocellular carcinoma. Proof of concept in animal models

In the present work, we have evaluated the possibility of pre- venting liver carcinogenesis in rats at two stages of development. In the first series of experiments, we induced foci of altered hepato- cytes, (FAH) which represent the first events in rodent liver car- cinogenesis, using the chemical mutagens diethylnitrosamine (DEN) and acetylaminofluorene (AAF). In the second part of the work, we used repeated weekly injections of DEN only that gave rise to significant fibrosis at 11 weeks and the development of malignant tumours at 16 weeks. We chose to assess the chemopre- ventive effect of three different drugs : pioglitazone, lanreotide and S-trans-trans-farnesylthiosalicylic acid (FTS). Pioglitazone (PGZ) is an agonist of peroxisome proliferator-activated receptor gamma (PPARg), itself a member of the nuclear receptor superfamily, responsible for the modulation of a number of metabolic pathways, including cell differentiation, metabolism of lipids and inflamma- tion. Lanreotide (LAN) is a somatostatin analogue that has an inhibitory effect on the release of several hormones, such as growth hormone and serotonine. FTS is a specific antagonist of the proto- ocogene Ras, tested here based on the rationale that Ras is activat- ed in many hepatocellular carcinomas (HCC).