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.
OBJECTIVE
Tamoxifen is an antiestrogen used in women who have estrogen receptor (ER)-alpha-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.


METHODS
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-alpha (IC(50), 14 nM). In ER-alpha-positive human MCF-7 breast carcinoma cells, ERA-923 inhibits estrogen-stimulated growth (IC(50), 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 17beta-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.
Greenberger
L M
LM
Wyeth-Ayerst Research, Oncology and Immunoinflammatory Research, Pearl River, NY 10965, USA. greenblm@war.wyeth.com
Annable
T
T
Collins
K I
KI
Komm
B S
BS
Lyttle
C R
CR
Miller
C P
CP
Satyaswaroop
P G
PG
Zhang
Y
Y
Frost
P
P
D000818:Animals; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D012680:Sensitivity and Specificity; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development; D023041:Xenograft Model Antitumor Assays
C439584:2-(4-hydroxyphenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-1H-indol-5-ol; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D007211:Indoles; D010880:Piperidines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol