title: Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers.
abstract: 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.
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA. clinton.grubbs@ccc.uab.edu
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Grubbs
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Venkatram R
authors.initials: VR
authors.lastname: Atigadda
authors.forename: Konstantin
authors.initials: K
authors.lastname: Christov
authors.forename: Anil M
authors.initials: AM
authors.lastname: Deshpande
authors.forename: Vivek
authors.initials: V
authors.lastname: Tirmal
authors.forename: Gang
authors.initials: G
authors.lastname: Xia
authors.forename: Kirby I
authors.initials: KI
authors.lastname: Bland
authors.forename: Isao
authors.initials: I
authors.lastname: Eto
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Brouillette
authors.forename: Donald D
authors.initials: DD
authors.lastname: Muccio
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D008055:Lipids / Q000737:chemistry; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000517:prevention & control; D008956:Models, Chemical; D008968:Molecular Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D008055:Lipids; D047490:Retinoid X Receptor alpha; D012176:Retinoids; D014280:Triglycerides