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[Cancer Research 58, 479-484, February 1, 1998]
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Beyond Tamoxifen: The Retinoid X Receptor-selective Ligand LGD1069 (TARGRETIN) Causes Complete Regression of Mammary Carcinoma1

Eric D. Bischoff, Marco M. Gottardis, Thomas E. Moon, Richard A. Heyman and William W. Lamph2

Departments of Retinoid Research [E. D. B., R. A. H., W. W. L.], Clinical Research [T. E. M.], and Endocrine Research [M. M. G.], Ligand Pharmaceuticals, Inc., San Diego, California 92121

Recently, we reported that LGD1069, a high-affinity ligand for the retinoid X receptors (RXRs), was shown to have an efficacy equivalent to that of tamoxifen (TAM) as a chemopreventive agent in the N-nitroso-N-methylurea-induced rat mammary carcinoma model. Furthermore, LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of "retinoid-associated" toxicities. Due to the high efficacy and benign profile of this RXR agonist as a suppressor of carcinogenesis, we examined its role as a therapeutic agent on established mammary carcinomas. In the rat mammary carcinoma model, N-nitroso-N-methylurea was used to induce tumors, and the tumors were allowed to grow to an established size prior to initiation of treatment. LGD1069-treated animals showed complete regression in 72% of treated tumors and had a reduced tumor load compared to control. In addition, the combination of LGD1069 and TAM showed increased efficacy over either agent alone. Histopathological analysis showed a reduction of LGD1069-treated tumor malignancy, an increase in differentiation, and a sharp decrease in cellular proliferation compared to vehicle-treated control tumors. These data demonstrate that the RXR-selective ligand LGD1069 is a highly efficacious therapeutic agent for mammary carcinoma and enhances the activity of TAM.

1 Presented in part at the 88th Annual Meeting of the AACR, held April 12–16, 1997, in San Diego, CA.

2 To whom requests for reprints should be addressed, at Department of Retinoid Research, Ligand Pharmaceuticals, Inc., 10255 Science Center Drive, San Diego, CA 92121. Phone: (619) 535-3900; Fax: (619) 550-7730; E-mail: wlamph@ligand.com.

Received 10/27/97. Accepted 12/16/97.




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