Carcinogenesis Advance Access published online on December 12, 2005
Carcinogenesis, doi:10.1093/carcin/bgi308
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1 Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
* To whom correspondence should be addressed. 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 triglycerides 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 seven 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 five 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 2.5-4.0 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.
Received September 19, 2005
Revised October 26, 2005
Accepted December 6, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers
Clinton J. Grubbs 1 *,
Ronald A. Lubet 2,
Venkatram R. Atigadda 3,
Konstantin Christov 4,
Anil M. Deshpande 3,
Vivek Tirmal 1,
Gang Xia 3,
Kirby I. Bland 1,
Isao Eto 5,
Wayne J. Brouillette 3,
and
Donald D. Muccio 3
2 Division of Cancer Prevention, National Cancer Institute, Bethesda MD
3 Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL
4 Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL
5 Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
Clinton J. Grubbs, E-mail: clinton.grubbs{at}ccc.uab.edu
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