BEYOND TAMOXIFEN - THE RETINOID-X RECEPTOR-SELECTIVE LIGAND LGD1069 (TARGRETIN) CAUSES COMPLETE REGRESSION OF MAMMARY-CARCINOMA

Recently, we reported that LGD1069, a high-affinity ligand for the ret inoid 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 w as very well tolerated during 13 weeks of chronic therapy with no clas sic signs of ''retinoid-associated'' toxicities. Due to the high effic acy and benign profile of this RXR agonist as a suppressor of carcinog enesis, we examined its role as a therapeutic agent on established mam mary carcinomas, In the rat mammary carcinoma model, N-nitroso-N-methy lurea was used to induce tumors, and the tumors were allowed to grow t o an established size prior to initiation of treatment. LGD1069-treate d 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 tumo r malignancy, an increase in differentiation, and a sharp decrease in cellular proliferation compared to vehicle-treated control tumors, The se data demonstrate that the RXR-selective ligand LGD1069 is a highly efficacious therapeutic agent for mammary carcinoma and enhances the a ctivity of TAM.