Abstract
B2
Two different RXR agonists were examined for their ability to inhibit the formation of ER negative mammary cancers in transgenic mice. Targretin is clinically employed in the treatment of cutaneous lymphoma, and has as its primary side effect an increase in triglycerides levels. UAB-30 is a new RXR agonist (synthesized by modifying 9-cis-retinoic acid) that does not cause an increase in serum triglycerides. MMTV-Neu female mice were initially treated with dimethybenzanthracence (DMBA), 1.0 mg/mouse/week by gavage for 4 weeks. Beginning five days after the last DMBA treatment, diets were supplemented either with targretin (250 mg/kg diet) or UAB-30 (300 mg/kg diet). At 105 days after the last DMBA treatment, Targretin and UAB-30 reduced the multiplicity of mammary cancers by 72 and 61%, respectively (controls had a multiplicity of 5.7 cancers/mouse). Thus, both agonists were relatively effective. In addition, the preventive efficacy of Targretin (250 mg/kg diet), initiated either early (10 weeks of age) or late (24 weeks of age), was evaluated in female mice that were heterozygous both for MMTV-Neu and KO of the p53 tumor suppressor gene. Treatment with Targretin early or late reduced mammary cancer incidence by 46 and 16% and cancer multiplicity by 69 and 56%, respectively. In contrast, Targretin failed to inhibit the formation of lymphomas or sarcomas; two cancers that often develop in these bitransgenic mice. In summary, both agents which were previously shown to be effective in inhibiting ER positive rat mammary cancers were also effective in inhibiting ER negative mammary cancers. Furthermore, it appears that these agents are effective even if treatment is delayed to a point when mammary lesions already exist.
Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA