A number of
retinoid X receptor (RXR) agonists have proven to be highly effective in preventing
methylnitrosourea (MNU) induced
mammary cancers. However, these agonists have side effects; particularly causing an increase in serum
triglyceride levels. A series of
ligands for RXR were designed based on computer modeling to the
ligand binding domain (LBD) of the RXR receptors and on structure-activity relationships. The chemopreventive effects of these
retinoids were evaluated in the relatively long-term MNU model. As a short-term assay to predict their efficacy, the ability of the
retinoids to modulate cell proliferation and apoptosis was also determined in
mammary cancers after only 7 days of treatment. The five UAB
retinoids evaluated included two Class I UAB
retinoids (UAB20, UAB112) and three Class II UAB
retinoids (UAB30, 4-methyl-UAB30 and the
benzosuberone-analog of UAB30). The previously evaluated RXR agonist
targretin and the pan-agonist
9-cis-retinoic acid (9-cis-RA), which interacts with both RAR and RXR receptors, were included as positive agonists known to prevent
cancer in the MNU model. In the prevention studies, in which the agents were administered beginning 5 days after MNU until the end of the study,
targretin (150 mg/kg diet) and 4-methyl-UAB30 (200 mg/kg diet) were highly effective in decreasing
cancer numbers by 75-85%. UAB30 (200 mg/kg diet) and 9-cis-RA (60 mg/kg diet) gave intermediate inhibitions of 60 and 45%, respectively.
Targretin (15 mg/kg diet), UAB20 (200 mg/kg diet) and the
benzosuberone analog of UAB30 (200 mg/kg diet) showed limited activity by decreasing
cancer multiplicity 25-30%, while UAB112 had no effect on
mammary cancer multiplicity. A direct correlation was observed between the long-term chemopreventive efficacy of these agents and their ability to decrease cell proliferation in
mammary cancers after short-term treatment. Furthermore, the highly effective agents (4-methyl-UAB30 and
targretin at 150 mg/kg diet) increased apoptosis 3-5 times, while agents with moderate or limited preventive efficacy failed to significantly increase apoptosis. Although the more effective
retinoid treatments increased serum
triglycerides 2.5- to 4.0-fold, one moderately effective agent (UAB30) had no significant effect on
lipid levels. In summary, a short-term in vivo method has been identified for screening newly synthesized
retinoids both for chemopreventive efficacy and for their adverse effect on serum
triglycerides.