Effects of SP500263, a novel, potent antiestrogen, on breast cancer cells and in xenograft models.
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.
Brady
Helen
H
Signal Research Division, Celgene Corporation, San Diego California 92121, USA.
Desai
Sonal
S
Gayo-Fung
Leah M
LM
Khammungkhune
Sak
S
McKie
Jeffrey A
JA
O'Leary
Eoin
E
Pascasio
Laura
L
Sutherland
May Kung
MK
Anderson
David W
DW
Bhagwat
Shripad S
SS
Stein
Bernd
B
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
D003374:Coumarins; D020847:Estrogen Receptor Modulators; D010880:Piperidines; C448221:SP500263; D020845:Selective Estrogen Receptor Modulators