title: STX140 is efficacious in vitro and in vivo in taxane-resistant breast carcinoma cells.
abstract: OBJECTIVE
  The aim of these studies was to characterize the action of STX140 in a P-glycoprotein-overexpressing tumor cell line both in vitro and in vivo. In addition, its efficacy was determined against xenografts derived from patients who failed docetaxel therapy.
  
  
  METHODS
  The effects of STX140, Taxol, and 2-methoxyestradiol (2-MeOE2) on cell proliferation, cell cycle, and apoptosis were assessed in vitro in drug-resistant cells (MCF-7(DOX)) and the parental cell line (MCF-7(WT)). Mice bearing an MCF-7(DOX) tumor on one flank and an MCF-7(WT) tumor on the other flank were used to assess the in vivo efficacy. Furthermore, the responses to STX140 of three xenografts, derived from drug-resistant patients, were assessed.
  
  
  RESULTS
  In this study, STX140 caused cell cycle arrest, cyclin B1 induction, and subsequent apoptosis of both MCF-7(DOX) and MCF-7(WT) cells. Taxol and 2-MeOE2 were only active in the MCF-7(WT) parental cell line. Although both STX140 and Taxol inhibited the growth of xenografts derived from MCF-7(WT) cells, only STX140 inhibited the growth of tumors derived from MCF-7(DOX) cells. 2-MeOE2 was ineffective at the dose tested against both tumor types. Two out of the three newly derived docetaxel-resistant xenografts, including a metastatic triple-negative tumor, responded to STX140 but not to docetaxel treatment.
  
  
  CONCLUSIONS
  STX140 shows excellent efficacy in both MCF-7(WT) and MCF-7(DOX) breast cancer xenograft models, in contrast to Taxol and 2-MeOE2. The clinical potential of STX140 was further highlighted by the efficacy seen in xenografts recently derived from patients who had failed on taxane therapy.
authors.affiliation: Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College London, St Mary's Hospital, London, UK. simon.newman@imperial.ac.uk
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: Paul A
authors.initials: PA
authors.lastname: Foster
authors.forename: Chloe
authors.initials: C
authors.lastname: Stengel
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Day
authors.forename: Yaik T
authors.initials: YT
authors.lastname: Ho
authors.forename: Jean-Gabriel
authors.initials: JG
authors.lastname: Judde
authors.forename: Myriam
authors.initials: M
authors.lastname: Lassalle
authors.forename: Gregoire
authors.initials: G
authors.lastname: Prevost
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
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: D000077584:2-Methoxyestradiol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D004963:Estrenes / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use*; D050257:Tubulin Modulators / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C526438:2-methoxyestradiol-3,17-O,O-bis(sulfamate); D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004963:Estrenes; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D017239:Paclitaxel