9-cis-retinoic acid (9-cis), a pan-agonist for the Retinoic Acid Receptor (RAR) and the Retinoid “X” Receptor (RXR), confers significant protection against rat prostate carcinogenesis. 9-cis inhibits prostate carcinogenesis when its administration is begun either immediately after carcinogen exposure or up to 40 weeks post-carcinogen. To identify the molecular pathway(s) through which 9-cis exerts its chemopreventive activity in the prostate, two studies were conducted to evaluate the chemopreventive efficacy of an RAR agonist, 13-cis-retinoic acid (13-cis), and a specific RXR agonist, bexarotene. Prostate cancers were induced in Wistar-Unilever rats by a sequential regimen of antiandrogen - androgen - chemical carcinogen - androgen. Rats received cyproterone acetate (50 mg/day for 21 days via gavage) followed by testosterone propionate (100 mg/kg/day for 3 days via subcutaneous injection). Sixty hours after the first dose of testosterone propionate, rats (42 to 44 per group) received a single intravenous injection of N-methyl-N-nitrosourea [MNU; 30 mg/kg body weight]. Beginning one week post-MNU, chronic androgen stimulation was provided by subcutaneous implantation of 2 pellets containing 40 mg of crystalline testosterone each; pellets were replaced every 6 months. Chronic administration of 13-cis (200 mg/kg diet) was initiated at 20 weeks post-MNU, while chronic administration of bexarotene (150 or 300 mg/kg diet) was initiated at 28 weeks post-MNU. At study termination (56 weeks), accessory sex glands were harvested from all animals; cancer incidence was determined by histopathologic evaluation of interrupted step sections prepared from all glands. Administration of 13-cis resulted in a statistically significant inhibition of prostate carcinogenesis: the RAR agonist reduced cancer incidence in all accessory sex glands from 75% in dietary controls to 50% (p < 0.05), and reduced the incidence of cancers that were clearly limited to the dorsolateral/anterior prostate from 45% in dietary controls to 26% (0.05 < p < 0.10). By contrast, the RXR agonist conferred no protection against prostate carcinogenesis: control, low dose, and high dose bexarotene groups demonstrated cancer incidences of 74%, 72%, and 82% in the accessory sex glands. Similarly, the incidence of cancer in the dorsolateral/anterior prostate was 44% in dietary controls versus 33% and 50% in groups receiving the low and high doses of bexarotene, respectively. These data suggest that the chemopreventive activity of 9-cis is mediated by effects that are linked to its activity as an RAR agonist and not to its activity as an RXR agonist. Our results identify RAR as a potentially useful target for the design of drugs for prostate cancer chemoprevention. (NCI-NO1-CN-25017)

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA