Acyclic retinoids and cancer chemoprevention

-___ Abstract Human trials of cancer chemoprevention employing antitumor promoter retinoids are currently progressing worldwide and are targeting mainly skin, lung, uterine cervix or breast cancers. Although the inhibitory effects of various synthetic retinoids on experimental cancers and tumor-derived cell lines are promising, several problems with adverse effects such as mucocutaneous disorders, teratogenicity or hyperlipidemia still remain to be solved before clinical application. In an attempt to develop new analogs that are much safer in clinical use, we have synthesized acyclic retinoids which bind to cellular retinoic acidbinding protein (CRABP) with affinities as high as that of all-retinoic acid. Among these acyclic retinoids, 3,7,11 , I 5-tetramethyl-2,4,6,lO,l~-hexadecapentaenoic acid or E-5166 showed a better therapeutic index than the trimethyl methoxyphenyl analog of retinoic acid (TMMP or Etretinate) on mouse skin papilloma and, in particular, on experimental liver tumors induced by 3'-methyl-4-dimethylaminoazobenzene in rats as well as in spontaneous hepatoma-bearing mice (C?H/HeNCrj). E-5166 also regulated a human hepatoma-derived cell line: PLC/PRF/5 (Alexander cell) in terms of both cell growth and alpha-fetoprotein production. Following these observations, application of E-5166 has cleared the Phase I trial in cirrhotic patients who are regarded as a high-risk group for hepatoma, that is now the third leading cause of male cancer death in Japan.