title: Characterization of new estrogen receptor destabilizing compounds: effects on estrogen-sensitive and tamoxifen-resistant breast cancer.
abstract: BACKGROUND
  Antiestrogens of the selective estrogen receptor modulator (SERM) type, such as tamoxifen, have two major limitations: their mixed agonist and antagonist profile and the development of tumor resistance. We characterized two new pure antiestrogens-ZK-703 and ZK-253-that belong to the class of specific estrogen receptor destabilizers (SERDs), which includes fulvestrant, and compared their activity with that of fulvestrant and tamoxifen.
  
  
  METHODS
  Effects of antiestrogens on the growth of estrogen-dependent breast tumors in vivo were determined using several mouse xenograft models (including the tamoxifen-sensitive tumors MCF7, T47D, and MV3366 and the tamoxifen-resistant tumors ZR75-1 and MCF7/TAM) and chemically induced (nitrosomethyl urea [NMU] and dimethylbenzanthracene [DMBA]) rat breast cancer models (groups of 10 animals). We determined the initial response and effects on hormone receptor levels and the time to relapse after treatment (i.e., time to reach a predetermined tumor size threshold). Estrogen receptor (ER) levels were determined by immunoassay.
  
  
  RESULTS
  ZK-703 (administered subcutaneously) and ZK-253 (administered orally) were more effective than tamoxifen or fulvestrant at inhibiting the growth of ER-positive breast cancer in all xenograft models. For example, MCF7 tumors relapsed (i.e., reached the size threshold) in 10 weeks in mice treated with tamoxifen but in 30 weeks in mice treated with ZK-703. ZK-703 and ZK-253 also prevented further tumor progression in tamoxifen-resistant breast cancer models to a similar extent (more than 30 weeks in mice with ZR75-1 and MCF7/TAM tumors). In the chemically induced rat breast cancer models, orally administered ZK-703 and ZK-253 caused a nearly complete (>80%) inhibition of tumor growth. ER levels were dramatically reduced in MCF7 tumors after 5 weeks of ZK-703 treatment compared with ER levels in vehicle-treated tumors; by contrast, ER levels in tamoxifen-treated tumors were higher than those in control tumors.
  
  
  CONCLUSIONS
  ZK-703 and ZK-253 are potent, long-term inhibitors of growth in both tamoxifen-sensitive and tamoxifen-resistant breast cancer models.
authors.affiliation: Research Laboratories of Schering AG, Berlin, Germany. jens.hoffmann@schering.de
authors.forename: Jens
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Rolf
authors.initials: R
authors.lastname: Bohlmann
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heinrich
authors.forename: Helmut
authors.initials: H
authors.lastname: Hofmeister
authors.forename: Jörg
authors.initials: J
authors.lastname: Kroll
authors.forename: Hermann
authors.initials: H
authors.lastname: Künzer
authors.forename: Rosemarie B
authors.initials: RB
authors.lastname: Lichtner
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishino
authors.forename: Karsten
authors.initials: K
authors.lastname: Parczyk
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sauer
authors.forename: Hille
authors.initials: H
authors.lastname: Gieschen
authors.forename: Hannes-F
authors.initials: HF
authors.lastname: Ulbrich
authors.forename: Martin R
authors.initials: MR
authors.lastname: Schneider
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004967:Estrogens / Q000097:blood; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008770:Methylnitrosourea; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C481962:ZK253; C481961:ZK703; D013629:Tamoxifen; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D008770:Methylnitrosourea