BIOCHEMICAL CHARACTERISTICS AND DIFFERENTIATING ACTIVITY OF 4-OXO ANALOGS OF RETINOIC ACID

3-Methyl-4-oxoretinoic acid and 3-cinnamyl-4-oxoretinoic acid bind to a cellular retinoic acid-binding protein (CRABP-II) and to a retinoic acid-receptor protein (RAR alpha). These analogs of 4-oxoretinoic acid , as well as the parent compound, have less binding affinity than reti noic acid. Cotransfection assays in CV-1 cells with plasmids containin g cDNAs for RAR alpha, RAR beta and RAR gamma (homodimers) and RAR alp ha-RXR alpha and RAR beta-RXR alpha (heterodimers), indicate that 3-ci nnamyl-4-oxoretinoic acid induces relatively less transcriptional acti vity than 4-oxoretinoic acid and its 3-methyl analog, both of which ar e less effective than retinoic acid. In differentiating mouse F9 embry ocarcarcinoma cells, the order of effectiveness is retinoic acid > 4-o xoretinoic acid = 3-methyl-4-oxoretinoic acid > 3-cinnamyl-4-oxoretino ic acid. This order of potency is similar to that for inhibition of in duction of ornithine decarboxylase (ODC) activity and for prevention o f papillomas on the skin of mice. Binding to CRABP-II and activation o f RARs appear to be important factors for expression of differentiatin g activity, inhibition of induction of ODC activity, and prevention of papillomas on the skin of mice.