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A New Antiestrogen, 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride (ERA-923), Inhibits the Growth of Tamoxifen-sensitive and -resistant Tumors and Is Devoid of Uterotropic Effects in Mice and Rats

Wyeth-Ayerst Research, Oncology and Immunoinflammatory Research, Pearl River, New York 10965 [L. M. G., T. A., K. I. C., Y. Z., P. F.]; Women’s Health Research Institute, Collegeville, Pennsylvania 19426 [B. S. K., C. R. L.]; Chemical Sciences, Collegeville, Pennsylvania 19426 [C. P. M.]; and Department of Obstetrics and Gynecology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033 [P. G. S.]

Purpose: Tamoxifen is an antiestrogen used in women who have estrogen receptor (ER)--positive breast cancer. Unfortunately, resistance to tamoxifen is common in women with metastatic disease and side effects, including increased risk of endometrial cancer, exist. Here we describe the activity of a new selective ER modulator, ERA-923, in preclinical models focused on these limitations.

Experimental Design: The ability of ERA-923, 4-OH tamoxifen, or raloxifene to inhibit estrogen-stimulated growth was evaluated in cell-based and xenograft assays with tumor cells that are sensitive or resistant to tamoxifen. Uterine effects of selective ER modulators were compared in rodents.

Results: ERA-923 potently inhibits estrogen binding to ER- (IC₅₀, 14 nM). In ER--positive human MCF-7 breast carcinoma cells, ERA-923 inhibits estrogen-stimulated growth (IC₅₀, 0.2 nM) associated with cytostasis. In vitro, a MCF-7 variant with inherent resistance to tamoxifen (10-fold) or 4-OH tamoxifen (>1000-fold) retains complete sensitivity to ERA-923. Partial sensitivity to ERA-923 exists in MCF-7 variants that have acquired profound tamoxifen resistance. In tumor-bearing animals, ERA-923 (10 mg/kg/day given p.o.) inhibits 17ß-estradiol-stimulated growth in human tumors derived from MCF-7, EnCa-101 endometrial, or BG-1 ovarian carcinoma cells, including a MCF-7-variant that is inherently resistant to tamoxifen. Raloxifene is inactive in the MCF-7 xenograft model. Unlike tamoxifen, droloxifene, or raloxifene, ERA-923 is not uterotropic in immature rats or ovariectomized mice. Consistent with this, tamoxifen, but not ERA-923, stimulates the growth of EnCa-101 tumors.

Conclusions: In preclinical models, ERA-923 has an improved efficacy and safety compared with tamoxifen. Clinical trials with ERA-923 are in progress.

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