Abstract Number: 5677 Retinoid receptor dependent and independent effects of potential chemopreventive phenylretinamides: mechanistic studies in-vitro and in-vivo John L. Clifford, Susan Fischer, Hui Xu, Anita Sabichi, Changchun Zou, Xiulan Yang, Vernon E. Steele, Gary J. Kelloff, Reuben Lotan, Scott M. Lippman, University of Texas MD Anderson Cancer Center, Houston, TX; University of Texas MD Anderson Cancer Center, Smithville, TX; National Cancer Institute, Bethesda, MD. Fenretinide (N-[4-Hydroxyphenyl]retinamide or 4HPR) is a retinoid analog with antitumor and chemopreventive activities. In addition to 4HPR, there are several other new phenylretinamides bearing hydroxyl, carboxyl or methoxyl residues on carbons 2,3 and 4 of the terminal phenylamine ring (2HPR, 3HPR, 2CPR, 3CPR, 4CPR and 4MPR). Based on several studies it is hypothesized that these agents can act independent of the nuclear retinoid receptor pathway. To test this hypothesis directly, we have previously analyzed the activity of these retinamides in-vitro on a panel of F9 cell lines, which includes wild type (WT) and mutant lines which lack expression of RAR gamma, RXR alpha or both receptors (KO). Two distinct effects of the phenylretinamides were identified in the F9 system. The first is a rapid induction of apoptosis (requiring treatment with a concentration greater than 1uM) caused by all of the phenylretinamides, and the second is a delayed induction of differentiation (with 1uM treatment) observed only with those phenylretinamides bearing hydroxyl or carboxyl groups on the terminal phenylamine ring. We have now compared the chemopreventive effects 4HPR (receptor dependent and independent activity) and 4MPR (receptor independent only) with all-trans retinoic acid (ATRA) (receptor dependent activity only) in the DMBA/TPA 2-stage mouse skin carcinogenesis model. All three agents had tumor suppressive activity, with ATRA being the most potent, implicating retinoid receptor activation in this effect. The chemopreventive effect of 4HPR was similar to 4MPR, suggesting that although 4HPR can activate retinoid receptors in F9 cells, its action in the 2-stage model may involve primarily retinoid receptor independent effects. We explored the potential mechanism of the chemopreventive effect in-vitro by analyzing primary cultures of mouse keratinocytes treated with the same retinoids. All three retinoids could induce apoptosis with short-term treatment and only ATRA and 4HPR induced a limited G1 accumulation. This finding is consistent with the concept that the cell cycle effect is receptor dependent, while the apoptosis induction is not. We propose that 4HPR, and other phenylretinamides bearing charged groups on the terminal phenylamine ring, may exert therapeutic and chemopreventive effects by acting as both chemotoxic drugs and as classic receptor-activating retinoids. Supported in part by the CRED (ES07784) and NCI CA78560. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.