title: Effects of SP500263, a novel, potent antiestrogen, on breast cancer cells and in xenograft models.
abstract: We have compared the antitumor activities of SP500263, a novel next-generation selective estrogen receptor modulator (SERM), tamoxifen, and raloxifene side-by-side in in vitro and in vivo MCF-7 breast cancer models. In vitro, SP500263 acted as an antiestrogen and potently inhibited estrogen-dependent MCF-7 proliferation with IC(50) values in the nanomolar range. SP500263 also strongly inhibited MCF-7 proliferation in the absence of estrogen at all of the concentrations tested. To investigate the antitumor activity of SP500263 in animals, athymic nude mice were implanted with MCF-7 tumor in the presence of a tumor growth-supporting sustained release estrogen pellet. Treatment was initiated after tumors were established. SP500263, administered for 28 days through daily i.p. dosing, effectively reduced estrogen-stimulated tumor growth at 3 and 30 mg/kg. SP500263 was as efficacious as tamoxifen and superior to raloxifene at the corresponding doses. Maximum efficacy was reached with the 30 mg/kg dose. The observed effects were highly significant. SP500263 represents a member of a novel series of SERMs that is structurally unrelated to SERMs currently on the market or in clinical development. The experiments described herein demonstrate that SP500263 is efficacious in the MCF-7 proliferation assay and in a murine model of breast cancer.
authors.affiliation: Signal Research Division, Celgene Corporation, San Diego California 92121, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Brady
authors.forename: Sonal
authors.initials: S
authors.lastname: Desai
authors.forename: Leah M
authors.initials: LM
authors.lastname: Gayo-Fung
authors.forename: Sak
authors.initials: S
authors.lastname: Khammungkhune
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: McKie
authors.forename: Eoin
authors.initials: E
authors.lastname: O'Leary
authors.forename: Laura
authors.initials: L
authors.lastname: Pascasio
authors.forename: May Kung
authors.initials: MK
authors.lastname: Sutherland
authors.forename: David W
authors.initials: DW
authors.lastname: Anderson
authors.forename: Shripad S
authors.initials: SS
authors.lastname: Bhagwat
authors.forename: Bernd
authors.initials: B
authors.lastname: Stein
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003374:Coumarins / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D003374:Coumarins; D020847:Estrogen Receptor Modulators; D010880:Piperidines; C448221:SP500263; D020845:Selective Estrogen Receptor Modulators