Efficacy of LGD1069 (targretin), a retinoid X receptor-selective ligand, for treatment of uterine leiomyoma

The conventional treatment of uterine leiomyomas, or fibroids, with gonadot ropin-releasing hormone (GnRH) agonists is often associated with serious si de effects, necessitating short-term, palliative use of this therapy. There fore, we examined a retinoid X receptor (RXR)-selective ligand, LGD1069, as a possible treatment for leiomyoma. LGD1069 has demonstrated efficacy as a chemopreventive agent in the N-nitroso-N-methylurea (NMU)-induced rat mamm ary carcinoma model and is a therapeutic agent in several epithelial tumor models. Previous studies have shown that it has both antitumor effects and antiestrogenic activity in the rat uterus, suggesting the potential utility of this agent for treatment of hormonally dependent uterine fibroids. The expression of retinoid receptors in tumors and cell lines derived from leio myomas arising in the Eker rat was confirmed by Northern analysis. After tr eatment for 4 months with LGD1069, the number of grossly observable tumors was substantially reduced although the total incidence of tumors, including microscopic lesions, remained unaffected, suggesting an effect of the comp ound on tumor growth kinetics rather than on tumor initiation. Analysis of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelin g (TUNEL) staining and determination of 5-bromo-2-deoxyuridine (BrdU) incor poration indicated that the reduction in grossly observable tumors that occ urred in treated animals was mediated by a significant increase in the leve l of apoptosis rather than a decrease in cell proliferation. These results suggest that LGD1069 may be an effective therapeutic agent for uterine leio myoma that may inhibit tumor growth and, consequently, alleviate the sympto ms associated with this disease.