GENOMIC MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY RETINOIDS

点击翻译按钮获取中文摘要

Retinoids inhibit the tumor promotion phase of mutistep carcinogenesis. We have conducted investigations of chemoprevention of hepatocellular carcinoma by retinoids and recently confirmed the clinical effects of acyclic retinoid on second primary hepatocarcinogenesis (Internat'l Hepatol Commun 3 : S4,1995). Clarification of the mechanisms of such action of retinoids is essential to establish the ratiomale for prevention of various carcinomas including hepatocellular carcinoma.In the present study using murine model of hepatocarcinogenesis and human hepatoma-derived cell lines, we have elucidated two possible mechanisms of retinoid action ; differentiation induction and apoptosis induction. The former mechanism was exerted by a signal which started with the binding of retinoid with nuclear retinoid receptors (Mol Carcinogenesis 10 : 151-158,1994). The latter mechanism was exerted via interruption of autocrine/paracrine loop of transforming growth factor-alpha by ratinoid (Biochem Biophys Res Commun 207 : 382-388,1995).We extended our study then to develop novel retinoid compounds, being based on the finding that one of retinoid action was exerted at the genomic level as mentioned above. We screened several possible compounds using binding affinity of them with retinoid X receptor as a marker, and identified three new candidates (Biochem Biophys Res Commun 209 : 66-72,1995).We evaluate these results as very important to establish cancer chemoprevention with retinoids and to develop novel cancer chemopreventive agents.