title: In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy.
abstract: OBJECTIVE
  Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model.
  
  
  METHODS
  MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly.
  
  
  RESULTS
  STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity.
  
  
  CONCLUSIONS
  This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.
authors.affiliation: Department of Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College Faculty of Medicine, St. Mary's Hospital, London, United Kingdom. paul.foster@imperial.ac.uk
authors.forename: Paul A
authors.initials: PA
authors.lastname: Foster
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Chander
authors.forename: Chloe
authors.initials: C
authors.lastname: Stengel
authors.forename: Roma
authors.initials: R
authors.lastname: Jhalli
authors.forename: Lawrence L W
authors.initials: LL
authors.lastname: Woo
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
mesh_terms: D000818:Animals; D001378:Azasteroids / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D001378:Azasteroids; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C515227:STX 213; D004958:Estradiol; D043266:Steryl-Sulfatase